Fanconi_Anemia

Genetic MONDO:0019391 Bone Marrow Failure Congenital Disorder

Fanconi anemia is a rare inherited bone marrow failure syndrome characterized by genomic instability, congenital abnormalities, progressive bone marrow failure, and increased susceptibility to malignancies. Most cases result from biallelic pathogenic variants in genes encoding components of the Fanconi anemia/BRCA DNA interstrand crosslink repair pathway, with recognized exceptions including X-linked FANCB and autosomal dominant RAD51-associated disease (FA-R). Between 21 and 22 complementation groups are cited depending on nomenclature and curation conventions, with FANCA accounting for 60-70% of cases. The phenotypic spectrum is highly variable even within the same complementation group, reflecting genetic modifiers and environmental factors.

Mappings

Histopathology

Differentials

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Classifications

Harrison's Chapter

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Definitions

2024 FA Clinical Care Guidelines Screening Indicator Set (Table 1)

Manifestations listed in Table 1 of the 5th edition Fanconi Anemia Clinical Care Guidelines that should raise suspicion for FA and trigger diagnostic screening workup.

CASE_DEFINITION Suspected Fanconi anemia in pediatric and adult clinical settings

Table 1 FA screening indicators

Major congenital, hematologic, and reproductive indicators associated with FA.

Core clinical characteristics

Short stature
Microcephaly
Anterior pituitary hypoplasia
Interrupted pituitary stalk
Hearing impairment
Microphthalmia
Epicanthus
Ptosis
Strabismus
Cataract
Triangular face
Micrognathia
Cleft palate
Abnormal heart morphology
Tracheoesophageal fistula
Esophageal atresia
Duodenal atresia
Jejunal atresia
Anal atresia
Annular pancreas
Intestinal malrotation
Abnormality of the genitourinary system
Absent thumb
Hypoplasia of the radius
Clinodactyly
Aplasia/Hypoplasia of the ulna
Toe syndactyly
Talipes equinovarus
Hemivertebrae
Fused cervical vertebrae
Scoliosis
Kyphosis
Absent/hypoplastic coccyx
Cafe-au-lait spot
Hyperpigmentation of the skin
Pancytopenia
Myelodysplasia
Leukemia
Cryptorchidism
Hypospadias
Micropenis
Aplasia/hypoplasia of the uterus
Gonadal dysgenesis
Vaginal atresia

Notes: This criteria set is intended to guide screening suspicion and referral; it is not a strict diagnostic-count rule.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Table 1. Manifestations that are indicators for Fanconi anemia screening."

The FA guideline explicitly defines Table 1 manifestations as indicators that should prompt FA screening.

Notes: This is a screening definition/case-identification aid. Definitive FA diagnosis still requires confirmatory genetic and/or chromosome breakage testing.

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Inheritance

Autosomal Recessive

X-linked

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Subtypes

pathway tier

Core Complex Subtypes

FA core complex genes (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FANCT/UBE2T) encode the E3 ubiquitin ligase complex that monoubiquitinates the FANCD2-FANCI heterodimer. Patients with core complex mutations generally have a later age of cancer onset compared to downstream pathway defects.

FA-A
FA-B
FA-C
FA-E
FA-F
FA-G
FA-L
FA-T

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"Patients with FANCA mutations developed cancer at a significantly older age compared to patients with mutations in other Fanconi genes (mean 18.5 and 5.2 years, respectively, P=0.001)"

Israeli cohort demonstrates later cancer onset in core complex (FANCA) vs downstream gene mutations.

ID Complex Subtypes

The FANCD2-FANCI heterodimer is monoubiquitinated by the core complex and recruited to DNA damage sites. Mutations in these genes cause intermediate-severity FA phenotypes.

FA-D2
FA-I

Downstream Effector Subtypes

Downstream effector genes (BRCA2/FANCD1, BRIP1/FANCJ, PALB2/FANCN, RAD51C/FANCO, RAD51/FANCR, BRCA1/FANCS, SLX4/FANCP, ERCC4/FANCQ, XRCC2/FANCU, MAD2L2/FANCV, RFWD3/FANCW) mediate homologous recombination repair downstream of FANCD2-FANCI. Patients with FANCD1/BRCA2 and FANCN/PALB2 mutations have notably earlier cancer onset and increased risk of childhood solid tumors including medulloblastoma and Wilms tumor.

FA-D1
FA-J
FA-N
FA-O
FA-P
FA-Q
FA-R
FA-S
FA-U
FA-V
FA-W

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"Patients with downstream mutations were found to have significantly more skull anomalies (P<0.001), central nervous system (CNS) abnormalities (P=0.005) and genitourinary anomalies (P=0.03), compared with patients with core complex mutations."

Israeli cohort demonstrates more severe congenital anomaly profile in downstream pathway gene mutations.

complementation group

FA-A MONDO:0009215

60-70% FANCA

Most common complementation group, accounting for 60-70% of all FA cases. FANCA is a component of the FA core complex. Patients tend to develop cancer at a later age compared to other FA subtypes.

Show evidence (2 references)

PMID:31558676 SUPPORT Human Clinical

"two-thirds of genetically diagnosed patients had biallelic FANCA mutations. These numbers are similar to the International Fanconi Anemia Registry, in which 60% of the diagnosed patients had FANCA mutations"

Israeli cohort confirms FANCA accounts for approximately 60-70% of FA cases.

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms FANCA causes autosomal recessive FA.

FA-B MONDO:0010351

<1% FANCB {'name': 'X-linked recessive'}

X-linked FA subtype caused by hemizygous FANCB mutations. FANCB is part of the FA core complex. Affected males may have more severe congenital anomalies including VACTERL association.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"a hemizygous pathogenic variant in FANCB known to cause X-linked FA"

GeneReviews confirms FANCB causes X-linked Fanconi anemia.

FA-C MONDO:0009213

~10-15% FANCC

Second or third most common FA complementation group depending on population. FANCC is a component of the FA core complex. Common Ashkenazi Jewish founder mutation (IVS4+4A>T).

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"FANCA (67%), FANCC (13%), FANCG (14%), FANCJ (3%) and FANCD1 (2%)"

Israeli cohort shows FANCC accounts for 13% of genetically diagnosed FA cases.

FA-D1 MONDO:0011584

~2% BRCA2

Caused by biallelic BRCA2 mutations. Associated with very early-onset malignancies including medulloblastoma, Wilms tumor, and AML, typically before age 5. Distinct from heterozygous BRCA2 carriers who develop breast/ovarian cancer.

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"one patient with a FANCD1 mutation developed medulloblastoma at the age of 3 years. Patients with FANCD1 mutations have been previously described as uniquely developing solid tumors early in life"

Confirms early-onset solid tumors in FANCD1/BRCA2 patients.

FA-D2 MONDO:0009214

~3% FANCD2

FANCD2 is one of two components of the ID complex that is monoubiquitinated by the core complex. FANCD2 mutations cause a moderate FA phenotype.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms FANCD2 causes autosomal recessive FA.

FA-E MONDO:0010953

<1% FANCE

FANCE is a component of the FA core complex that directly interacts with FANCD2.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms FANCE causes autosomal recessive FA.

FA-F MONDO:0011325

<1% FANCF

FANCF is a core complex adaptor protein required for complex assembly and stability.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms FANCF causes autosomal recessive FA.

FA-G MONDO:0013565

~10% FANCG

Third most common complementation group in some populations, accounting for up to 14% of cases. FANCG/XRCC9 is a component of the FA core complex.

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"FANCA (67%), FANCC (13%), FANCG (14%), FANCJ (3%) and FANCD1 (2%)"

Israeli cohort shows FANCG accounts for 14% of genetically diagnosed FA cases.

FA-I MONDO:0012186

<1% FANCI

FANCI forms the ID heterodimer with FANCD2. The complex is monoubiquitinated by the core complex and recruited to sites of DNA interstrand crosslinks.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms FANCI causes autosomal recessive FA.

FA-J MONDO:0012187

~3% BRIP1

Caused by biallelic mutations in BRIP1 (BACH1), a BRCA1-interacting helicase involved in homologous recombination repair. Heterozygous BRIP1 mutations confer increased breast cancer risk.

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"FANCA (67%), FANCC (13%), FANCG (14%), FANCJ (3%) and FANCD1 (2%)"

Israeli cohort shows FANCJ accounts for 3% of genetically diagnosed FA cases.

FA-L MONDO:0013566

<1% FANCL

FANCL is the E3 ubiquitin ligase of the FA core complex responsible for monoubiquitinating FANCD2 and FANCI.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms FANCL causes autosomal recessive FA.

FA-N MONDO:0012565

<1% PALB2

Caused by biallelic PALB2 mutations. Like FA-D1 (BRCA2), associated with very early-onset childhood malignancies. Heterozygous PALB2 mutations are a moderate-penetrance breast cancer susceptibility allele.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms PALB2/FANCN causes autosomal recessive FA.

FA-O MONDO:0013248

<1% RAD51C

Caused by biallelic RAD51C mutations. RAD51C functions in homologous recombination downstream of FANCD2. Heterozygous RAD51C mutations confer ovarian cancer susceptibility.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms RAD51C/FANCO causes autosomal recessive FA.

FA-P MONDO:0013499

<1% SLX4

Caused by biallelic SLX4 mutations. SLX4 is a scaffold protein that coordinates multiple structure-specific endonucleases for interstrand crosslink repair.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms SLX4/FANCP causes autosomal recessive FA.

FA-Q MONDO:0014108

<1% ERCC4

Caused by biallelic ERCC4/XPF mutations. ERCC4 is a structure-specific endonuclease also implicated in nucleotide excision repair, creating a phenotypic overlap with xeroderma pigmentosum and Cockayne syndrome.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms ERCC4/FANCQ causes autosomal recessive FA.

FA-R MONDO:0014986

<1% RAD51 {'name': 'Autosomal dominant'}

Caused by heterozygous dominant-negative RAD51 mutations. The only autosomal dominant form of FA. All reported cases arise de novo.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"a heterozygous pathogenic variant in RAD51 known to cause autosomal dominant FA"

GeneReviews confirms RAD51/FANCR causes autosomal dominant FA via de novo mutations.

FA-S MONDO:0054748

<1% BRCA1

Caused by biallelic BRCA1 mutations. Extremely rare, with phenotypic overlap with both FA and hereditary breast/ovarian cancer syndrome. Heterozygous BRCA1 carriers have high breast and ovarian cancer risk.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms BRCA1/FANCS causes autosomal recessive FA.

FA-T MONDO:0014638

<1% UBE2T

Caused by biallelic UBE2T mutations. UBE2T is the E2 ubiquitin-conjugating enzyme that works with the FANCL E3 ligase to monoubiquitinate the ID complex.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms UBE2T/FANCT causes autosomal recessive FA.

FA-U MONDO:0014987

<1% XRCC2

Caused by biallelic XRCC2 mutations. XRCC2 is a RAD51 paralog involved in homologous recombination repair.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms XRCC2/FANCU causes autosomal recessive FA.

FA-V MONDO:0014985

<1% MAD2L2

Caused by biallelic MAD2L2/REV7 mutations. MAD2L2 functions in translesion synthesis and also plays roles in mitotic checkpoint signaling.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms MAD2L2/FANCV causes autosomal recessive FA.

FA-W MONDO:0044325

<1% RFWD3

Caused by biallelic RFWD3 mutations. RFWD3 is an E3 ubiquitin ligase that ubiquitinates RPA at stalled replication forks to promote homologous recombination.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms RFWD3/FANCW causes autosomal recessive FA.

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Pathophysiology

DNA Repair Deficiency

Mutations in FA genes impair the body's ability to repair DNA damage, leading to increased sensitivity to crosslinking agents and propensity for chromosomal instability.

Show evidence (1 reference)

PMID:35596788 SUPPORT Human Clinical

"At least 22 genes are associated with Fanconi anemia, constituting the Fanconi anemia DNA repair pathway. This pathway coordinates multiple processes and proteins to facilitate the repair of DNA adducts including interstrand crosslinks (ICLs)"

Bone Marrow Failure

Inability of the bone marrow to produce sufficient blood cells due to hematopoietic stem cell defects.

Show evidence (1 reference)

PMID:38424108 SUPPORT Model Organism

"we identify increased protein synthesis rates in the fetal hematopoietic stem cell pool at the onset of hematopoietic failure in Fanconi Anemia, a prototypical DNA repair disorder that manifests with bone marrow failure."

Demonstrates that bone marrow failure is a defining manifestation of Fanconi anemia, with origins in fetal HSC dysfunction.

Genomic Instability

Increased tendency for genomic alterations including chromosomal breaks, deletions, and rearrangements.

Show evidence (1 reference)

PMID:35596788 SUPPORT Human Clinical

"ICLs can interfere with DNA transactions, including replication and transcription. If not properly removed and repaired, ICLs cause DNA breaks and lead to genomic instability, a hallmark of cancer."

Hematopoietic Stem Cell Attrition

Progressive depletion of long-term hematopoietic stem cells in bone marrow due to replication stress, aldehyde-induced DNA damage, and chronic inflammatory signaling.

hematopoietic stem cell link

response to aldehyde link cellular response to oxidative stress link

bone marrow link

Show evidence (2 references)

PMID:38424108 SUPPORT Model Organism

"proteostasis deregulation itself is driven by excess sterile inflammatory activity in hematopoietic and stromal cells within the fetal liver, and dampened Type I interferon signaling similarly restores fetal Fancd2-/- long-term hematopoietic stem cells to wild type-equivalent numbers."

Demonstrates that inflammatory signaling drives HSC pool deficits in FA, and that dampening inflammation rescues HSC numbers.

PMID:24037726 PARTIAL Human Clinical

"the FA proteins might counteract aldehyde-induced genotoxicity in hematopoietic stem cells"

Establishes that aldehydes cause genotoxicity in HSCs and FA proteins normally protect against this damage.

Translesion Synthesis Defect

Impaired ability to bypass DNA lesions during replication through translesion synthesis polymerases, requiring functional FANCD2-FANCI complex and PCNA monoubiquitination.

translesion synthesis link

Show evidence (1 reference)

PMID:25237197 PARTIAL Other

"Establishing the interaction network involving the FA proteins and their associated partners has revealed an intersection of FA with several DNA repair pathways, including homologous recombination, DNA mismatch repair, nucleotide excision repair, and translesion DNA synthesis."

Demonstrates that the FA pathway intersects with translesion DNA synthesis, establishing the mechanistic link.

Homologous Recombination Impairment

Defective repair of DNA double-strand breaks following interstrand crosslink unhooking, due to mutations in FA genes involved in HR pathway including BRCA2, PALB2, and BRCA1.

homologous recombination link

Show evidence (1 reference)

PMID:25237197 PARTIAL Other

"the fact that 5 FA genes are in fact familial breast cancer genes and FA gene mutations are found frequently in sporadic cancers suggest wider applicability in hematopoiesis and oncology."

The overlap of FA genes with breast cancer genes (BRCA1, BRCA2, PALB2) establishes the connection between FA and homologous recombination repair.

Aldehyde-Induced Genotoxicity

Endogenous aldehydes (acetaldehyde and formaldehyde) from normal metabolism generate DNA interstrand crosslinks and DNA-protein crosslinks; impaired detoxification by ALDH2 and ADH5 exacerbates DNA damage burden.

response to aldehyde link

Show evidence (2 references)

PMID:24037726 SUPPORT Human Clinical

"We examined 64 Japanese FA patients, and found that the ALDH2 variant is associated with accelerated progression of BMF"

Human clinical data showing that impaired aldehyde detoxification (ALDH2 variant) accelerates bone marrow failure in FA patients.

PMID:25237197 SUPPORT Other

"recent studies have shown a major involvement of the FA pathway in the tolerance of reactive aldehydes."

Establishes that the FA pathway is required for tolerance of aldehyde-induced DNA damage.

Core Complex Dysfunction

Mutations in FA core complex genes (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FANCM, UBE2T/FANCT) disrupt the E3 ubiquitin ligase that monoubiquitinates the FANCD2-FANCI complex, abolishing the central signaling step of the FA pathway. FANCA mutations account for 60-70% of all FA cases.

FANCA link FANCB link FANCC link FANCG link

FA nuclear complex link

protein ubiquitination link

Show evidence (1 reference)

PMID:35596788 PARTIAL Human Clinical

"At least 22 genes are associated with Fanconi anemia, constituting the Fanconi anemia DNA repair pathway."

Core complex genes form the upstream signaling arm of the FA pathway.

ID Complex Dysfunction

Mutations in FANCD2 or FANCI disrupt the central ID2 complex whose monoubiquitination is the critical signaling event in FA pathway activation. In wild type, the core complex E3 ligase monoubiquitinates both FANCD2 and FANCI, causing the ID2 heterodimer to clamp onto chromatin at stalled replication forks and recruit downstream nucleases and HR effectors. Loss of either subunit abolishes this signaling hub.

FANCD2 link FANCI link

protein monoubiquitination link interstrand cross-link repair link

Show evidence (1 reference)

PMID:32106311 SUPPORT Human Clinical

"This reflects the indispensable role of FANCB protein in the enzymatic activation of FANCD2 monoubiquitination, an essential step in the repair of DNA interstrand crosslinks."

FANCD2 monoubiquitination is the essential central step in ICL repair.

Downstream Effector Dysfunction

Mutations in downstream effector genes (BRCA2/FANCD1, PALB2/FANCN, BRCA1/FANCS, RAD51C/FANCO, XRCC2/FANCU) impair homologous recombination and translesion synthesis. These overlap with familial breast/ovarian cancer genes; biallelic mutations produce the most severe FA phenotypes with early-onset solid tumors and more congenital anomalies.

BRCA2 link BRCA1 link

Show evidence (1 reference)

PMID:25237197 PARTIAL Other

"the fact that 5 FA genes are in fact familial breast cancer genes and FA gene mutations are found frequently in sporadic cancers suggest wider applicability in hematopoiesis and oncology."

Downstream FA genes overlap with breast cancer susceptibility genes.

Inflammatory Bone Marrow Microenvironment

Excess sterile inflammatory signaling (TNF-alpha, interferon-gamma, Type I interferons) in the bone marrow creates a hostile microenvironment for HSCs. Both hematopoietic and stromal cells contribute to chronic inflammation, driving proteostasis deregulation and accelerating stem cell attrition.

hematopoietic stem cell link

inflammatory response link

bone marrow link

Show evidence (1 reference)

PMID:38424108 SUPPORT Model Organism

Inflammatory signaling in the BM microenvironment drives HSC loss in FA.

Developmental Progenitor Apoptosis

Unrepaired DNA damage in rapidly dividing embryonic progenitor cells activates p53-dependent apoptosis during critical developmental windows. This mechanism underlies the congenital malformations of FA, explaining the midline predominance of anomalies and correlation between pathway position and congenital abnormality burden.

apoptotic process link embryo development link

Show evidence (1 reference)

PMID:26369989 PARTIAL Human Clinical

"The incidence of central nervous system (CNS) abnormalities in FA is higher than previously reported, with a midline predominance that points to impact in the early stages of CNS development."

Midline predominance of anomalies supports developmental progenitor loss during embryogenesis.

Clonal Evolution

Progressive accumulation of somatic mutations and chromosomal aberrations in genomically unstable hematopoietic cells drives clonal selection and malignant transformation. Characteristic cytogenetic changes include gain of 1q and 3q and loss of 7q. Clones with selective growth advantage expand, leading to MDS and AML. Single-cell DNA sequencing has revealed polyclonal evolution at the MDS stage, with sequential acquisition of driver mutations and MDM4-mediated p53 dampening via chromosome 1q gain as the canonical initiating event.

hematopoietic stem cell link

bone marrow link

Show evidence (4 references)

PMID:31558676 PARTIAL Human Clinical

"30% developed myelodysplastic syndrome (MDS), leukemia and/or solid tumors"

30% malignancy rate reflects ongoing clonal evolution in FA HSCs.

PMID:36736290 SUPPORT Human Clinical

"Clonal hematopoiesis driven by chromosome 1q/MDM4 trisomy defines a canonical route toward leukemia in Fanconi anemia."

Longitudinal study of 335 FA patients showing chromosome 1q gain (containing MDM4) as the most common early clonal event, dampening p53 and driving clonal hematopoiesis.

PMID:36167633 SUPPORT Human Clinical

"Polyclonal evolution of Fanconi anemia to MDS and AML revealed at single cell resolution."

Single-cell DNA sequencing of FA patients transforming to MDS/AML revealed polyclonal patterns with sequential acquisition of UBASH3A, SF3B1, RUNX1, and IDH2 mutations.

+ 1 more reference

Epithelial Cancer Susceptibility

Impaired genome maintenance in epithelial tissues renders them vulnerable to accumulation of oncogenic mutations. Squamous epithelia of the head/neck, oral cavity, esophagus, and anogenital regions are particularly susceptible due to high proliferative turnover and exposure to environmental mutagens including HPV.

epithelial cell link

Show evidence (3 references)

PMID:20301575 SUPPORT Human Clinical

"Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA."

Confirms epithelial tissue susceptibility to malignancy in FA.

PMID:36912284 PARTIAL In Vitro

"We developed the Fanconi Anemia Cancer Cell Line Resource (FA-CCLR) to foster new work on the origins, treatment and prevention of FA-associated carcinomas. The FA-CCLR consists of Fanconi-isogenic head and neck squamous cell carcinoma (HNSCC) cell line pairs generated from five individuals with..."

Isogenic FA/sporadic HNSCC cell line pairs provide a platform to identify FA-dependent cancer phenotypes and test therapeutic strategies.

PMID:36450981 PARTIAL Computational

"Genomic signature of Fanconi anaemia DNA repair pathway deficiency in cancer."

Computational genomic analysis defined the primary structural variant signature of FA pathway deficiency in squamous cancers, enabling computational classification of FA-associated vs sporadic carcinomas.

HPV-Mediated Epithelial Damage

Human papillomavirus infection compounds epithelial cancer risk in FA patients. HPV oncoproteins E6 and E7 degrade p53 and Rb tumor suppressors, further disabling the already compromised DNA damage response. HPV vaccination is recommended to reduce gynecologic and oropharyngeal cancer risk.

Show evidence (1 reference)

PMID:20301575 PARTIAL Human Clinical

"Human papilloma virus (HPV) vaccination to reduce the risk for gynecologic cancer in females"

HPV vaccination recommendation implies HPV is a significant co-factor for epithelial cancer in FA.

Endocrine Gland Dysfunction

Widespread endocrine abnormalities affect approximately 73-80% of FA patients. Developmental pituitary/hypothalamic defects (68% have small pituitary on MRI), direct effects of genomic instability on endocrine cell function, and chronic illness contribute. Manifests as GH deficiency, hypothyroidism, glucose dysregulation, hypogonadism, dyslipidemia, and metabolic syndrome.

pituitary gland link

Show evidence (2 references)

PMID:17426088 SUPPORT Human Clinical

"Endocrine abnormalities were present in 73%, including short stature and/or GH deficiency (51%), hypothyroidism (37%), midline brain abnormalities (17%)"

Giri et al. documents 73% endocrine abnormality prevalence.

PMID:26369989 SUPPORT Human Clinical

"Abnormalities were identified in 18 (90%) patients with FA, the commonest being a small pituitary (68%, p < 0.01 females and p < 0.001 males)"

Small pituitary in 68% provides anatomical basis for endocrine dysfunction.

Congenital Structural Anomalies

Developmental progenitor loss during embryogenesis causes structural malformations affecting limbs, heart, kidneys, GI tract, ears, and genitourinary system. Approximately 75% of FA patients have at least one congenital anomaly, with burden correlating with complementation group, mutation type, and pathway position.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies."

75% of FA patients have physical abnormalities.

CNS Developmental Anomalies

Midline brain structural defects from neural progenitor loss during early CNS development. Includes small pituitary (68%), posterior fossa abnormalities (30% including Chiari I malformation and Dandy-Walker variant), and corpus callosum structural variation (30%).

brain link pituitary gland link

Show evidence (2 references)

PMID:26369989 SUPPORT Human Clinical

"Abnormalities were identified in 18 (90%) patients with FA, the commonest being a small pituitary (68%, p < 0.01 females and p < 0.001 males)"

90% brain MRI abnormality rate with midline predominance.

PMID:26369989 SUPPORT Human Clinical

"Posterior fossa abnormalities were seen in six cases (30%, p = 0.01) including Chiari I malformation (n = 3), Dandy-Walker variant (n = 2) and cerebellar atrophy (n = 2)."

Posterior fossa and corpus callosum anomalies reflect early CNS developmental impact.

Skin Pigmentation Changes

Melanocyte progenitor defects during embryonic development cause characteristic pigmentary anomalies including café-au-lait spots and hypopigmented patches. Skin pigmentation changes are the most common congenital anomaly in FA, affecting over 50% of patients.

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"More than half had café-au-lait spots (52.3%) followed by renal anomalies (39.6%)."

Café-au-lait spots are the most common congenital anomaly in the Israeli FA cohort.

MYC-Driven HSPC Dysfunction

Single-cell RNA sequencing of primary FA patient bone marrow HSPCs revealed MYC overexpression as a novel pathogenic driver alongside p53 and TGF-beta upregulation. Distinct HSPC subpopulations co-expressing high TP53 or high MYC coexist in FA bone marrow. MYC-high HSPCs show downregulation of cell adhesion genes (including CXCR4), promoting enhanced egress from bone marrow to peripheral blood and contributing to HSC exhaustion and bone marrow failure.

hematopoietic stem cell link

regulation of gene expression link

bone marrow link

Show evidence (2 references)

PMID:32997960 SUPPORT Human Clinical

"In addition to overexpression of p53 and TGF-β pathway genes, we identified high levels of MYC expression. We correspondingly observed coexistence of distinct HSPC subpopulations expressing high levels of TP53 or MYC in FA bone marrow (BM)."

scRNA-seq of primary FA patient HSPCs identifies MYC as a novel driver of BMF alongside known p53/TGF-beta pathways.

PMID:32997960 SUPPORT Model Organism

"Inhibiting MYC expression with the BET bromodomain inhibitor (+)-JQ1 reduced the clonogenic potential of FA patient HSPCs but rescued physiological and genotoxic stress in HSPCs from FA mice, showing that MYC promotes proliferation while increasing DNA damage."

BET inhibitor targeting MYC rescues genotoxic stress in FA mouse HSPCs, validating MYC as a therapeutic target.

Differentiation-Induced Genotoxic Stress

Transcriptional reprogramming during hematopoietic differentiation generates a surge of genotoxic stress from formaldehyde, an obligate by-product of oxidative protein demethylation during transcription regulation. In the absence of functional FA DNA repair, this differentiation-associated DNA damage causes aborted differentiation and depletion of FA progenitor cells, providing a mechanistic explanation for the hematopoietic-specific failure in FA despite it being a germline disorder.

hematopoietic precursor cell link

hematopoietic progenitor cell differentiation link response to aldehyde link

Show evidence (1 reference)

PMID:33338401 SUPPORT In Vitro

"reprogramming transcription during hematopoietic differentiation results in an overload of genotoxic stress, which causes aborted differentiation and depletion of FA mutant progenitor cells. DNA damage onset most likely arises from formaldehyde, an obligate by-product of oxidative protein..."

Demonstrates that transcriptional reprogramming during differentiation generates formaldehyde-induced DNA damage that specifically depletes FA-deficient progenitors.

iPSC-Revealed p53-Driven Progenitor Exhaustion

Induced pluripotent stem cell modeling of FA hematopoietic differentiation revealed that FANCA-deficient human hematopoietic progenitor cells undergo accelerated terminal differentiation driven by p53/p21 activation. GAS6 (growth arrest specific 6) was identified as a novel p53 target gene; GAS6 signaling modulation rescues hematopoiesis. This iPSC-based new approach methodology overcomes the lack of faithful murine FA models and enables drug screening for FA therapeutics.

hematopoietic precursor cell link

intrinsic apoptotic signaling pathway by p53 class mediator link

Show evidence (2 references)

PMID:33002135 SUPPORT In Vitro

"FANCA-deficient human HPCs underwent accelerated terminal differentiation driven by activation of p53/p21. We identified growth arrest specific 6 (GAS6) as a novel target of activated p53 in FANCA-deficient HPCs and modulate GAS6 signaling to rescue hematopoiesis in FANCA-deficient cells."

iPSC-derived FA model reveals p53/p21/GAS6 axis driving progenitor exhaustion and validates GAS6 as a therapeutic target.

PMID:33512438 PARTIAL In Vitro

"disease model iPSCs displayed drastically defective cell expansion when stimulated into hematopoietic differentiation in vitro, displaying increased levels of DNA damage. The expansion defect was partially reversed by treatment with a new small molecule termed C1, which is an agonist of ALDH2"

ADH5/ALDH2-deficient iPSCs modeling FA-like aldehyde toxicity confirm hematopoietic differentiation defects and identify ALDH2 agonism as a rescue strategy.

⬡

Causal Graph

graph LR
    Genomic_Instability["Genomic Instability"]
    Hematopoietic_Stem_Cell_Attrition["Hematopoietic Stem Cell Attrition"]
    HPV_Mediated_Epithelial_Damage["HPV-Mediated Epithelial Damage"]
    iPSC_Revealed_p53_Driven_Progenitor_Exhaustion["iPSC-Revealed p53-Driven Progenitor Exhaustion"]
    Developmental_Progenitor_Apoptosis["Developmental Progenitor Apoptosis"]
    ID_Complex_Dysfunction["ID Complex Dysfunction"]
    Hearing_Loss["Hearing Loss"]
    DNA_Repair_Deficiency["DNA Repair Deficiency"]
    Café_au_Lait_Spots["Café-au-Lait Spots"]
    Skin_Pigmentation_Changes["Skin Pigmentation Changes"]
    Aplastic_Anemia["Aplastic Anemia"]
    Increased_Risk_of_Leukemia["Increased Risk of Leukemia"]
    Impaired_Fertility["Impaired Fertility"]
    Microcephaly["Microcephaly"]
    Abnormal_Glucose_Homeostasis["Abnormal Glucose Homeostasis"]
    Aldehyde_Induced_Genotoxicity["Aldehyde-Induced Genotoxicity"]
    MYC_Driven_HSPC_Dysfunction["MYC-Driven HSPC Dysfunction"]
    Developmental_Delay["Developmental Delay"]
    Translesion_Synthesis_Defect["Translesion Synthesis Defect"]
    Genitourinary_Malformations["Genitourinary Malformations"]
    Differentiation_Induced_Genotoxic_Stress["Differentiation-Induced Genotoxic Stress"]
    Pancytopenia["Pancytopenia"]
    Downstream_Effector_Dysfunction["Downstream Effector Dysfunction"]
    Hypopigmentation["Hypopigmentation"]
    Congenital_Heart_Defects["Congenital Heart Defects"]
    Hypothyroidism["Hypothyroidism"]
    Congenital_Structural_Anomalies["Congenital Structural Anomalies"]
    CNS_Developmental_Anomalies["CNS Developmental Anomalies"]
    Early_Onset_Solid_Tumors_in_FANCD1_BRCA2["Early-Onset Solid Tumors in FANCD1/BRCA2"]
    Dental_and_Craniofacial_Anomalies["Dental and Craniofacial Anomalies"]
    Epithelial_Cancer_Susceptibility["Epithelial Cancer Susceptibility"]
    Intrauterine_Growth_Retardation["Intrauterine Growth Retardation"]
    Osteopenia_and_Osteoporosis["Osteopenia and Osteoporosis"]
    Inflammatory_Bone_Marrow_Microenvironment["Inflammatory Bone Marrow Microenvironment"]
    Endocrine_Gland_Dysfunction["Endocrine Gland Dysfunction"]
    Short_Stature["Short Stature"]
    Delayed_Puberty_and_Hypogonadism["Delayed Puberty and Hypogonadism"]
    Clonal_Evolution["Clonal Evolution"]
    Cryptorchidism["Cryptorchidism"]
    Myelodysplastic_Syndrome["Myelodysplastic Syndrome"]
    Strabismus["Strabismus"]
    Skeletal_Anomalies["Skeletal Anomalies"]
    Growth_Hormone_Deficiency["Growth Hormone Deficiency"]
    Bone_Marrow_Failure["Bone Marrow Failure"]
    Radial_Ray_Defects["Radial Ray Defects"]
    Core_Complex_Dysfunction["Core Complex Dysfunction"]
    Microphthalmia["Microphthalmia"]
    Absent_or_Hypoplastic_Thumbs["Absent or Hypoplastic Thumbs"]
    Renal_Anomalies["Renal Anomalies"]
    Squamous_Cell_Carcinoma["Squamous Cell Carcinoma"]
    Structural_Anomalies["Structural Anomalies"]
    Homologous_Recombination_Impairment["Homologous Recombination Impairment"]

    DNA_Repair_Deficiency --> Genomic_Instability
    Bone_Marrow_Failure --> Pancytopenia
    Bone_Marrow_Failure --> Aplastic_Anemia
    Genomic_Instability --> Hematopoietic_Stem_Cell_Attrition
    Genomic_Instability --> Developmental_Progenitor_Apoptosis
    Genomic_Instability --> Clonal_Evolution
    Genomic_Instability --> Epithelial_Cancer_Susceptibility
    Hematopoietic_Stem_Cell_Attrition --> Bone_Marrow_Failure
    Translesion_Synthesis_Defect --> Genomic_Instability
    Homologous_Recombination_Impairment --> Genomic_Instability
    Aldehyde_Induced_Genotoxicity --> Hematopoietic_Stem_Cell_Attrition
    Core_Complex_Dysfunction --> DNA_Repair_Deficiency
    ID_Complex_Dysfunction --> DNA_Repair_Deficiency
    Downstream_Effector_Dysfunction --> Homologous_Recombination_Impairment
    Inflammatory_Bone_Marrow_Microenvironment --> Hematopoietic_Stem_Cell_Attrition
    Developmental_Progenitor_Apoptosis --> Congenital_Structural_Anomalies
    Developmental_Progenitor_Apoptosis --> CNS_Developmental_Anomalies
    Developmental_Progenitor_Apoptosis --> Endocrine_Gland_Dysfunction
    Developmental_Progenitor_Apoptosis --> Skin_Pigmentation_Changes
    Developmental_Progenitor_Apoptosis --> Intrauterine_Growth_Retardation
    Clonal_Evolution --> Myelodysplastic_Syndrome
    Clonal_Evolution --> Increased_Risk_of_Leukemia
    Epithelial_Cancer_Susceptibility --> Squamous_Cell_Carcinoma
    Epithelial_Cancer_Susceptibility --> Early_Onset_Solid_Tumors_in_FANCD1_BRCA2
    HPV_Mediated_Epithelial_Damage --> Epithelial_Cancer_Susceptibility
    Endocrine_Gland_Dysfunction --> Growth_Hormone_Deficiency
    Endocrine_Gland_Dysfunction --> Hypothyroidism
    Endocrine_Gland_Dysfunction --> Abnormal_Glucose_Homeostasis
    Endocrine_Gland_Dysfunction --> Delayed_Puberty_and_Hypogonadism
    Endocrine_Gland_Dysfunction --> Osteopenia_and_Osteoporosis
    Endocrine_Gland_Dysfunction --> Short_Stature
    Endocrine_Gland_Dysfunction --> Impaired_Fertility
    Congenital_Structural_Anomalies --> Skeletal_Anomalies
    Congenital_Structural_Anomalies --> Radial_Ray_Defects
    Congenital_Structural_Anomalies --> Absent_or_Hypoplastic_Thumbs
    Congenital_Structural_Anomalies --> Congenital_Heart_Defects
    Congenital_Structural_Anomalies --> Genitourinary_Malformations
    Congenital_Structural_Anomalies --> Renal_Anomalies
    Congenital_Structural_Anomalies --> Hearing_Loss
    Congenital_Structural_Anomalies --> Microphthalmia
    Congenital_Structural_Anomalies --> Strabismus
    Congenital_Structural_Anomalies --> Structural_Anomalies
    Congenital_Structural_Anomalies --> Dental_and_Craniofacial_Anomalies
    Congenital_Structural_Anomalies --> Cryptorchidism
    CNS_Developmental_Anomalies --> Microcephaly
    CNS_Developmental_Anomalies --> Developmental_Delay
    Skin_Pigmentation_Changes --> Café_au_Lait_Spots
    Skin_Pigmentation_Changes --> Hypopigmentation
    MYC_Driven_HSPC_Dysfunction --> Hematopoietic_Stem_Cell_Attrition
    MYC_Driven_HSPC_Dysfunction --> Bone_Marrow_Failure
    Differentiation_Induced_Genotoxic_Stress --> Hematopoietic_Stem_Cell_Attrition
    Differentiation_Induced_Genotoxic_Stress --> Bone_Marrow_Failure
    iPSC_Revealed_p53_Driven_Progenitor_Exhaustion --> Hematopoietic_Stem_Cell_Attrition
    iPSC_Revealed_p53_Driven_Progenitor_Exhaustion --> Bone_Marrow_Failure

    style Genomic_Instability fill:#dbeafe
    style Hematopoietic_Stem_Cell_Attrition fill:#dbeafe
    style HPV_Mediated_Epithelial_Damage fill:#dbeafe
    style iPSC_Revealed_p53_Driven_Progenitor_Exhaustion fill:#dbeafe
    style Developmental_Progenitor_Apoptosis fill:#dbeafe
    style ID_Complex_Dysfunction fill:#dbeafe
    style Hearing_Loss fill:#fef3c7
    style DNA_Repair_Deficiency fill:#dbeafe
    style Café_au_Lait_Spots fill:#fef3c7
    style Skin_Pigmentation_Changes fill:#dbeafe
    style Aplastic_Anemia fill:#fef3c7
    style Increased_Risk_of_Leukemia fill:#fef3c7
    style Impaired_Fertility fill:#fef3c7
    style Microcephaly fill:#fef3c7
    style Abnormal_Glucose_Homeostasis fill:#fef3c7
    style Aldehyde_Induced_Genotoxicity fill:#dbeafe
    style MYC_Driven_HSPC_Dysfunction fill:#dbeafe
    style Developmental_Delay fill:#fef3c7
    style Translesion_Synthesis_Defect fill:#dbeafe
    style Genitourinary_Malformations fill:#fef3c7
    style Differentiation_Induced_Genotoxic_Stress fill:#dbeafe
    style Pancytopenia fill:#fef3c7
    style Downstream_Effector_Dysfunction fill:#dbeafe
    style Hypopigmentation fill:#fef3c7
    style Congenital_Heart_Defects fill:#fef3c7
    style Hypothyroidism fill:#fef3c7
    style Congenital_Structural_Anomalies fill:#dbeafe
    style CNS_Developmental_Anomalies fill:#dbeafe
    style Early_Onset_Solid_Tumors_in_FANCD1_BRCA2 fill:#fef3c7
    style Dental_and_Craniofacial_Anomalies fill:#fef3c7
    style Epithelial_Cancer_Susceptibility fill:#dbeafe
    style Intrauterine_Growth_Retardation fill:#fef3c7
    style Osteopenia_and_Osteoporosis fill:#fef3c7
    style Inflammatory_Bone_Marrow_Microenvironment fill:#dbeafe
    style Endocrine_Gland_Dysfunction fill:#dbeafe
    style Short_Stature fill:#fef3c7
    style Delayed_Puberty_and_Hypogonadism fill:#fef3c7
    style Clonal_Evolution fill:#dbeafe
    style Cryptorchidism fill:#fef3c7
    style Myelodysplastic_Syndrome fill:#fef3c7
    style Strabismus fill:#fef3c7
    style Skeletal_Anomalies fill:#fef3c7
    style Growth_Hormone_Deficiency fill:#fef3c7
    style Bone_Marrow_Failure fill:#dbeafe
    style Radial_Ray_Defects fill:#fef3c7
    style Core_Complex_Dysfunction fill:#dbeafe
    style Microphthalmia fill:#fef3c7
    style Absent_or_Hypoplastic_Thumbs fill:#fef3c7
    style Renal_Anomalies fill:#fef3c7
    style Squamous_Cell_Carcinoma fill:#fef3c7
    style Structural_Anomalies fill:#fef3c7
    style Homologous_Recombination_Impairment fill:#dbeafe

●

Phenotypes

Blood(6) Cardiovascular(7) Digestive(8) Ear(5) Endocrine(6) Eye(6) Genitourinary(13) Head and Neck(10) Integument(4) Limbs(9) Metabolism(1) Musculoskeletal(8) Nervous System(5) Growth(2) Other(2)

Blood 6

Pancytopenia VERY_FREQUENT Pancytopenia (HP:0001876)

Decreased levels of red blood cells, white blood cells, and platelets. Over 80% of FA patients develop bone marrow failure. Typically presents in the first decade, often initially with thrombocytopenia or leukopenia. Notably, patients with FANCD1/BRCA2 mutations may not develop BMF. FA-S (biallelic BRCA1) patients also characteristically lack bone marrow failure.

Show evidence (1 reference)

PMID:35596788 SUPPORT Human Clinical

"Fanconi anemia is a genetic disorder that is characterized by bone marrow failure, as well as a predisposition to malignancies including leukemia and squamous cell carcinoma (SCC)."

Context-specific annotations (4)

VERY_FREQUENT

Over 80% of FA patients develop bone marrow failure.

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"82% of the patients developed BMF"

Israeli cohort quantifies BMF prevalence at 82%.

Genetic FA-D1 FANCD1/BRCA2 EXCLUDED

Neither FANCD1/BRCA2 patient in the Israeli cohort developed BMF. One was transplanted for AML before age 6 months; the other had no complications by age 17.

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"neither of the patients with FANCD1 mutations developed BMF"

FANCD1/BRCA2 patients characteristically lack bone marrow failure.

Genetic FA-S BRCA1 HOMOZYGOUS EXCLUDED

FA-S (biallelic BRCA1) patients characteristically lack bone marrow failure, distinguishing them from most other FA complementation groups.

Show evidence (1 reference)

PMID:38146508 SUPPORT Human Clinical

"Unlike most other types of FA, FA-S patients lack bone marrow failure."

FA-S defined by absence of BMF despite other FA features.

Japanese

The ALDH2*2 dominant-negative variant (rs671), carried by nearly half of the Japanese population, is associated with accelerated BMF progression in FA patients. Birth weight and physical abnormalities were not affected.

Show evidence (1 reference)

PMID:24037726 SUPPORT Human Clinical

"the ALDH2 variant is associated with accelerated progression of BMF, while birth weight or the number of physical abnormalities was not affected"

ALDH2*2 acts as a genetic modifier accelerating BMF in Japanese FA patients.

Increased Risk of Leukemia FREQUENT Leukemia (HP:0001909)

The incidence of AML is 13% by age 50 years. Patients with FANCA mutations develop cancer at a significantly older age (mean 18.5 years) compared to non-FANCA groups (mean 5.2 years, P=0.001). Patients with FANCC mutations show a trend toward more MDS. FANCG patients may have less MDS and cancer overall. All FANCA patients in the Israeli cohort developed their first cancer after age 10, while all non-FANCA patients developed cancer by age 10.

Show evidence (1 reference)

PMID:24037726 SUPPORT Human Clinical

"It is characterized by phenotypes including progressive bone marrow failure (BMF), developmental abnormalities, and increased occurrence of leukemia and cancer."

Clinical description confirming that increased leukemia occurrence is a defining phenotype of FA.

Context-specific annotations (5)

Genetic FA-A FANCA Onset: mean 18.5y min 10.0y max y

All FANCA patients in the Israeli cohort developed their first cancer after age 10.

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"Patients with FANCA mutations developed cancer at a significantly older age compared to patients with mutations in other Fanconi genes (mean 18.5 and 5.2 years, respectively, P=0.001)"

FANCA patients have later onset of hematologic malignancy.

Genetic FANCC FANCD1/BRCA2 FANCG FANCJ/BRIP1 Onset: mean 5.2y min y max 10.0y

Non-FANCA complementation groups tested in the Israeli cohort (FANCC, FANCD1, FANCG, FANCJ). Not exhaustive of all non-FANCA groups but represents the specific genes analyzed.

All non-FANCA patients in the Israeli cohort developed cancer by age 10. FANCC mutations show a trend toward more MDS. FANCG patients may have less MDS and cancer overall.

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"Patients with FANCA mutations developed cancer at a significantly older age compared to patients with mutations in other Fanconi genes (mean 18.5 and 5.2 years, respectively, P=0.001)"

Same abstract sentence viewed from non-FANCA perspective; non-FANCA groups developed cancer significantly earlier (mean 5.2 years vs 18.5 years, P=0.001).

Genetic nonsense

Patients with nonsense mutations developed first cancer at a significantly younger age than patients with deletions (P=0.011).

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"patients with nonsense and splice site mutations developed the first cancer at a significantly lower age than patients with deletions (P=0.011 and P=0.012, respectively)"

Mutation type affects cancer onset age independent of gene identity.

Genetic splice_site

Patients with splice site mutations developed first cancer at a significantly younger age than patients with deletions (P=0.012).

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"patients with nonsense and splice site mutations developed the first cancer at a significantly lower age than patients with deletions (P=0.011 and P=0.012, respectively)"

Splice site mutations associated with earlier cancer onset.

Genetic FA-G FANCG

Trend toward less MDS and cancer in patients with FANCG mutations compared to other FA genes (not statistically significant).

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"There was a trend towards more MDS in patients with FANCC mutations and less MDS and cancer in patients with FANCG mutations, compared with patients with mutations in other genes (NS)."

FANCG mutations may be associated with a milder malignancy phenotype.

Aplastic Anemia VERY_FREQUENT Anemia (HP:0001903)

Show evidence (1 reference)

PMID:24037726 SUPPORT Human Clinical

"It is characterized by phenotypes including progressive bone marrow failure (BMF), developmental abnormalities, and increased occurrence of leukemia and cancer."

Progressive bone marrow failure is a cardinal feature of FA leading to aplastic anemia.

Thrombocytopenia FREQUENT Thrombocytopenia (HP:0001873)

Listed in FA clinical screening manifestations and commonly contributes to bleeding risk.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Anemia; leukopenia; thrombocytopenia; aplastic anemia; myelodysplastic syndrome"

FA guidelines include thrombocytopenia among core bone marrow failure manifestations.

Leukopenia FREQUENT Decreased total leukocyte count (HP:0001882)

Included in the FA screening phenotype table for bone marrow failure manifestations.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Anemia; leukopenia; thrombocytopenia; aplastic anemia; myelodysplastic syndrome"

FA guidelines include leukopenia as a characteristic hematologic manifestation.

Myelodysplastic Syndrome FREQUENT Myelodysplasia (HP:0002863)

In the Israeli cohort, 30% of patients developed MDS, leukemia, and/or solid tumors. Patients with non-FANCA mutations (FANCC, FANCD1, FANCG, FANCJ) developed first cancer (including MDS) significantly earlier than FANCA patients (mean 5.2 vs 18.5 years, P=0.001). There was a trend toward more MDS in FANCC patients.

Show evidence (2 references)

PMID:31558676 SUPPORT Human Clinical

"30% developed myelodysplastic syndrome (MDS), leukemia and/or solid tumors"

Israeli cohort documents that 30% of FA patients developed MDS, leukemia, and/or solid tumors.

PMID:31558676 SUPPORT Human Clinical

"The mean age of the first cancer was 18.5 years (SD 6.3 years) for patients with FANCA, relative to 5.2 years (SD 3.7 years) for patients with FANCC, FANCD1, FANCG and FANCJ mutations, with a statistically significant difference (P=0.001)."

Demonstrates significantly earlier cancer onset in non-FANCA complementation groups.

Context-specific annotations (1)

Onset: mean 13.3y min y max y

Mean age of first MDS event was 13.3 years in the Israeli cohort. There was a trend toward more MDS in FANCC patients.

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"30% developed myelodysplastic syndrome (MDS), leukemia and/or solid tumors"

Israeli cohort documents MDS as part of the 30% cancer rate in FA patients.

Cardiovascular 7

Congenital Heart Defects OCCASIONAL Abnormal heart morphology (HP:0001627)

Part of the VACTERL association overlap with FA. Heart abnormalities contribute to the congenital abnormality burden score (CABS). Patients with missense mutations had significantly less congenital heart disease (P=0.022) in the Israeli cohort. Downstream FA genes (FANCD1, FANCJ) may be associated with more severe congenital anomalies.

Show evidence (3 references)

PMID:20301575 SUPPORT Human Clinical

"Treatment of growth deficiency, limb anomalies, ocular anomalies, renal malformations, genital anomalies, hypothyroidism, cardiac anomalies, and dermatologic manifestations as recommended by the subspecialty care provider."

GeneReviews lists cardiac anomalies as part of the FA clinical spectrum requiring subspecialty management.

PMID:31558676 SUPPORT Human Clinical

"Patients with missense mutations had significantly less congenital heart disease (P=0.022)."

Israeli cohort study found genotype-phenotype correlation for cardiac defects and mutation type.

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Patent ductus arteriosus; atrial septal defect; ventri cular septal defect; coarctation; situs inversus; truncus arteriosus"

FA guidelines enumerate specific congenital heart defects within the diagnostic manifestation table.

Context-specific annotations (1)

Genetic missense OCCASIONAL

Missense mutations associated with significantly less congenital heart disease (P=0.022) in the Israeli cohort.

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"Patients with missense mutations had significantly less congenital heart disease (P=0.022)."

Missense mutations are protective relative to other mutation types for cardiac defects.

Patent Ductus Arteriosus OCCASIONAL Patent ductus arteriosus (HP:0001643)

Listed in FA guideline cardiac manifestations used for FA screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Patent ductus arteriosus; atrial septal defect; ventri cular septal defect; coarctation; situs inversus; truncus arteriosus"

FA guidelines explicitly enumerate patent ductus arteriosus in the cardiac anomaly list.

Atrial Septal Defect OCCASIONAL Atrial septal defect (HP:0001631)

Listed in FA guideline cardiac manifestations used for FA screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Patent ductus arteriosus; atrial septal defect; ventri cular septal defect; coarctation; situs inversus; truncus arteriosus"

FA guidelines list atrial septal defect among congenital cardiac anomalies.

Ventricular Septal Defect OCCASIONAL Ventricular septal defect (HP:0001629)

Listed in FA guideline cardiac manifestations used for FA screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Patent ductus arteriosus; atrial septal defect; ventri cular septal defect; coarctation; situs inversus; truncus arteriosus"

FA guidelines include ventricular septal defect among congenital heart findings.

Coarctation of Aorta OCCASIONAL Coarctation of aorta (HP:0001680)

Listed in FA guideline cardiac manifestations used for FA screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Patent ductus arteriosus; atrial septal defect; ventri cular septal defect; coarctation; situs inversus; truncus arteriosus"

FA guidelines list coarctation among congenital cardiovascular defects.

Truncus Arteriosus OCCASIONAL Truncus arteriosus (HP:0001660)

Listed in FA guideline cardiac manifestations used for FA screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Patent ductus arteriosus; atrial septal defect; ventri cular septal defect; coarctation; situs inversus; truncus arteriosus"

FA guidelines include truncus arteriosus among congenital cardiac anomalies.

Situs Inversus OCCASIONAL Situs inversus totalis (HP:0001696)

Listed in FA guideline cardiac manifestations used for FA screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Patent ductus arteriosus; atrial septal defect; ventri cular septal defect; coarctation; situs inversus; truncus arteriosus"

FA guidelines list situs inversus in the congenital cardiac manifestation table.

Digestive 8

Esophageal Atresia OCCASIONAL Esophageal atresia (HP:0002032)

Included in the FA guideline atresia spectrum used for diagnostic screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Atresias: esophageal, duodenal, jejunal"

FA guidelines explicitly list esophageal atresia among congenital gastrointestinal findings.

Duodenal Atresia OCCASIONAL Duodenal atresia (HP:0002247)

Included in the FA guideline atresia spectrum used for diagnostic screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Atresias: esophageal, duodenal, jejunal"

FA guidelines explicitly include duodenal atresia among congenital gastrointestinal findings.

Jejunal Atresia OCCASIONAL Jejunal atresia (HP:0005235)

Included in the FA guideline atresia spectrum used for diagnostic screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Atresias: esophageal, duodenal, jejunal"

FA guidelines explicitly list jejunal atresia among congenital gastrointestinal abnormalities.

Anal Atresia OCCASIONAL Anal atresia (HP:0002023)

Included in FA guideline diagnostic manifestations as imperforate or bifurcated anus.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Anal malformations: imperforate or bifurcated anus"

FA guidelines list anal malformations among congenital features prompting FA screening.

Intestinal Malrotation OCCASIONAL Intestinal malrotation (HP:0002566)

Included in FA guideline gastrointestinal screening manifestations.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Intestinal malrotation"

FA guidelines include intestinal malrotation in the congenital GI anomaly spectrum.

Annular Pancreas OCCASIONAL Annular pancreas (HP:0001734)

Listed in the FA guideline gastrointestinal anomaly table.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Annular pancreas"

FA guidelines include annular pancreas among congenital gastrointestinal findings that should trigger FA evaluation.

Tracheoesophageal Fistula OCCASIONAL Tracheoesophageal fistula (HP:0002575)

Included as a diagnostic screening manifestation in FA clinical care guidelines.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Tracheoesophageal fistula"

FA guidelines list tracheoesophageal fistula within gastrointestinal congenital anomalies.

Rectovaginal Fistula OCCASIONAL Rectovaginal fistula (HP:0000143)

Included in the FA guideline female-genital manifestations used for FA screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"rectovaginal fistula; vaginal atresia; late menarche; early menopause;"

FA guidelines include rectovaginal fistula in the female genital anomaly spectrum.

Ear 5

Hearing Loss OCCASIONAL Hearing impairment (HP:0000365)

In the Israeli FA cohort, 18% of patients had hearing loss, all with a conductive component. Hearing loss contributes to the congenital abnormality burden score (CABS). Hearing aids may be helpful per otolaryngology evaluation.

Show evidence (3 references)

PMID:31558676 SUPPORT Human Clinical

"Of the 18% of the patients with hearing loss, all had a conductive component"

Israeli cohort documents 18% hearing loss prevalence with conductive component in FA patients.

PMID:20301575 SUPPORT Human Clinical

"Hearing aids may be helpful for hearing loss as per otolaryngologist"

GeneReviews recommends hearing evaluation and hearing aids as part of FA management.

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"The incidence of hearing loss and congenital ear malformation is much higher in patients with FA than previously reported"

Fanconi Anemia Clinical Care Guidelines report hearing-loss prevalence and associated congenital ear anomalies.

Abnormal Pinna Morphology OCCASIONAL Abnormal pinna morphology (HP:0000377)

Included in FA guideline otologic manifestations and supported by dedicated ear-phenotype sections.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Otology Hearing loss (conductive, sensorineural, or mixed); abnormal pinna; atretic,"

FA guidelines list abnormal pinna as part of otologic manifestations.

External Auditory Canal Atresia OCCASIONAL Atresia of the external auditory canal (HP:0000413)

Described in FA guideline otologic sections as part of structural ear anomalies.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"an absent ear canal, an anomaly known as aural atresia."

Guidelines directly describe absent ear canal (aural atresia) in FA patients.

External Auditory Canal Stenosis OCCASIONAL Stenosis of the external auditory canal (HP:0000402)

Included in FA guideline otologic manifestations as a narrow/atretic canal.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"atretic, narrow canal; and abnormal middle e ar bones"

FA guidelines include narrow ear canal in the otologic anomaly profile.

Middle Ear Ossicle Abnormalities OCCASIONAL Abnormality of the middle ear ossicles (HP:0004452)

Included in FA guideline otologic manifestations as abnormal middle ear bones.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"narrow canal; and abnormal middle e ar bones"

FA guidelines include abnormal middle ear bones in the otologic anomaly profile.

Endocrine 6

Anterior Pituitary Hypoplasia OCCASIONAL Anterior pituitary hypoplasia (HP:0010627)

Included in FA guideline CNS screening manifestations as small pituitary/stalk anomalies.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Small pituitary and stalk interruption; agenesis of corpus callosum; cerebellar hypoplasia; hydrocephalus ; dilated ventricles; developmental delay"

FA guidelines include small pituitary as a CNS manifestation prompting FA screening.

Interrupted Pituitary Stalk OCCASIONAL Interrupted pituitary stalk (HP:0034978)

Included in FA guideline CNS screening manifestations as stalk interruption.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Small pituitary and stalk interruption; agenesis of corpus callosum; cerebellar hypoplasia; hydrocephalus ; dilated ventricles; developmental delay"

FA guidelines explicitly include pituitary stalk interruption among CNS abnormalities.

Hypothyroidism FREQUENT Hypothyroidism (HP:0000821)

About 80% of FA patients have at least one endocrine abnormality. Hypothyroidism is one of the most common endocrine manifestations. Annual TSH and free T4 screening is recommended.

Show evidence (1 reference)

PMID:25575015 SUPPORT Human Clinical

"About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility."

Consensus review documents hypothyroidism as a common endocrine abnormality in FA.

Context-specific annotations (1)

FREQUENT

37% prevalence in the NCI cohort (n=45, Giri et al. 2007). Annual TSH and free T4 screening is recommended.

Show evidence (1 reference)

PMID:17426088 SUPPORT Human Clinical

"short stature and/or GH deficiency (51%), hypothyroidism (37%)"

Giri et al. NCI cohort quantifies hypothyroidism at 37% in FA patients.

Growth Hormone Deficiency FREQUENT Secondary growth hormone deficiency (HP:0008240)

GH deficiency affects approximately 51% of FA patients (Giri et al. 2007, NCI cohort). Patients with GH deficiency were significantly shorter than those without (P=0.01). Growth hormone therapy may be used but requires careful monitoring given cancer predisposition. Ninety-two percent of FA patients aged 18 or older had osteopenia or osteoporosis.

Show evidence (2 references)

PMID:17426088 SUPPORT Human Clinical

"short stature and/or GH deficiency (51%)"

NCI cohort study of 45 FA patients found GH deficiency in 51%, establishing it as a frequent phenotype.

PMID:25575015 SUPPORT Human Clinical

Consensus review identifies GH deficiency as a recognized endocrine abnormality in FA.

Context-specific annotations (1)

FREQUENT

51% of FA patients had short stature and/or GH deficiency in the NCI cohort (n=45). Only GH deficiency correlated significantly with short stature (P=0.01). Midline brain abnormalities were found in 17% of patients, and 60% of those were GH-deficient.

Show evidence (1 reference)

PMID:17426088 SUPPORT Human Clinical

"short stature and/or GH deficiency (51%), hypothyroidism (37%), midline brain abnormalities (17%) (these patients had very short stature and 60% were GH-deficient)"

Giri et al. NCI cohort quantifies GH deficiency at 51% with pituitary abnormality association.

Delayed Puberty and Hypogonadism FREQUENT Delayed puberty (HP:0000823)

Pubertal delay and hypogonadism are among the most common endocrine abnormalities in FA (present in up to 80% of patients with at least one endocrine abnormality). Pubertal staging and hormone levels should be assessed at puberty and every two years until complete.

Show evidence (1 reference)

PMID:25575015 SUPPORT Human Clinical

Consensus review identifies pubertal delay and hypogonadism as prominent endocrine features of FA.

Context-specific annotations (1)

VERY_FREQUENT

65% of peripubertal or postpubertal FA patients had gonadal dysfunction in the NCI cohort (Giri et al. 2007).

Show evidence (1 reference)

PMID:17426088 SUPPORT Human Clinical

"65% of peripubertal or postpubertal patients had gonadal dysfunction"

Giri et al. NCI cohort quantifies gonadal dysfunction at 65% in peripubertal/postpubertal FA patients.

Delayed Menarche OCCASIONAL Delayed menarche (HP:0012569)

Included in the FA guideline female-genital and endocrine-reproductive manifestation spectrum.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"rectovaginal fistula; vaginal atresia; late menarche; early menopause;"

FA guidelines include late menarche among female reproductive manifestations.

Eye 6

Hypertelorism OCCASIONAL Hypertelorism (HP:0000316)

Included in FA guideline facial manifestations used for diagnostic screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Facial FA facies; triangular face; micrognathia; pointed chin; mid -face hypoplasia; facial nerve palsy; microsomia; hypertelorism; hypotelorism; cleft palate"

FA guidelines list hypertelorism within the congenital facial anomaly spectrum.

Hypotelorism OCCASIONAL Hypotelorism (HP:0000601)

Included in FA guideline facial manifestations used for diagnostic screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Facial FA facies; triangular face; micrognathia; pointed chin; mid -face hypoplasia; facial nerve palsy; microsomia; hypertelorism; hypotelorism; cleft palate"

FA guidelines include hypotelorism among listed facial abnormalities.

Microphthalmia OCCASIONAL Microphthalmia (HP:0000568)

Ophthalmic anomalies are listed among the congenital features present in approximately 75% of FA patients. Microphthalmia may be more common in patients with higher congenital abnormality burden scores.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"ophthalmic and genitourinary tract anomalies"

GeneReviews lists ophthalmic anomalies including microphthalmia among FA congenital features.

Strabismus OCCASIONAL Strabismus (HP:0000486)

Part of the ophthalmic anomaly spectrum in FA.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"ophthalmic and genitourinary tract anomalies"

GeneReviews lists ophthalmic anomalies as part of the FA congenital phenotype spectrum.

Cataract OCCASIONAL Cataract (HP:0000518)

Included in the FA guideline diagnostic manifestation table under eye abnormalities.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Microphthalmia; epicanthal folds; almond -shaped fissures; ptosis; strabismus; cataracts"

FA guidelines enumerate cataracts among ocular manifestations associated with FA.

Ptosis OCCASIONAL Ptosis (HP:0000508)

Included in FA guideline eye-abnormality screening manifestations.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"ptosis"

FA guidelines list ptosis among ocular abnormalities associated with FA.

Genitourinary 13

Genitourinary Malformations OCCASIONAL Abnormality of the genitourinary system (HP:0000119)

Genitourinary anomalies were significantly more common in patients with downstream FA gene mutations (FANCD1, FANCJ) compared to core complex mutations (P=0.03) in the Israeli cohort.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies"

Context-specific annotations (1)

Genetic FANCD1/BRCA2 FANCJ/BRIP1 FREQUENT

Downstream FA pathway genes

Genitourinary anomalies were significantly more common in patients with downstream FA gene mutations compared to core complex mutations (P=0.03).

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

Downstream FA pathway mutations enriched for genitourinary anomalies.

Impaired Fertility FREQUENT Infertility (HP:0000789)

Male infertility is very common due to primary gonadal failure. Female fertility is reduced but pregnancies have been reported. Fertility preservation counseling should be offered early.

Show evidence (1 reference)

PMID:25575015 SUPPORT Human Clinical

Impaired fertility is listed as a key endocrine abnormality in FA patients.

Context-specific annotations (2)

MALE VERY_FREQUENT

Near-universal azoospermia due to primary gonadal failure.

Show evidence (1 reference)

PMID:25575015 SUPPORT Human Clinical

Male infertility in FA is near-universal due to gonadal failure and azoospermia.

FEMALE FREQUENT

Reduced fertility with diminished ovarian reserve and premature menopause, but pregnancies have been reported.

Show evidence (1 reference)

PMID:25575015 SUPPORT Human Clinical

Female fertility is reduced but not absent; successful pregnancies have been documented.

Cryptorchidism OCCASIONAL Cryptorchidism (HP:0000028)

Part of the genitourinary anomaly spectrum. Genital anomalies were significantly more common in patients with downstream FA gene mutations (FANCD1, FANCJ) compared to core complex mutations in the Israeli cohort.

Show evidence (2 references)

PMID:20301575 SUPPORT Human Clinical

"ophthalmic and genitourinary tract anomalies"

GeneReviews lists genitourinary anomalies including genital anomalies as part of FA.

PMID:31558676 SUPPORT Human Clinical

Israeli cohort found genitourinary anomalies enriched in downstream FA gene mutations (FANCD1, FANCJ).

Context-specific annotations (1)

Genetic FANCD1/BRCA2 FANCJ/BRIP1 FREQUENT

Downstream FA pathway genes

Genitourinary anomalies including cryptorchidism were significantly more common in downstream FA gene mutations (P=0.03).

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

Downstream pathway mutations enriched for genitourinary anomalies including cryptorchidism.

Testicular Aplasia or Hypoplasia OCCASIONAL Aplasia/Hypoplasia of the testes (HP:0010468)

Included in FA guideline male genital manifestations used for diagnostic screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Undescended, small or absent testis; microphalus; hypospadias; micropenis; absent testis; infertility"

FA guidelines list small or absent testis among male genital abnormalities.

Hypospadias OCCASIONAL Hypospadias (HP:0000047)

Listed in FA guideline male genital manifestations used for diagnostic screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Undescended, small or absent testis; microphalus; hypospadias; micropenis; absent testis; infertility"

FA guidelines include hypospadias among recognized male genital anomalies.

Micropenis OCCASIONAL Micropenis (HP:0000054)

Included in FA guideline male genital manifestations used for diagnostic screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Undescended, small or absent testis; microphalus; hypospadias; micropenis; absent testis; infertility"

FA guidelines include micropenis among male genital anomalies associated with FA.

Bicornuate Uterus OCCASIONAL Bicornuate uterus (HP:0000813)

Included in the FA guideline female-genital manifestations used for FA screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Hypoplastic, absent or bicornuate uterus; gonadal dysgenesis; small ovaries;"

FA guidelines list bicornuate uterus in the female genital anomaly spectrum.

Uterine Aplasia or Hypoplasia OCCASIONAL Aplasia/hypoplasia of the uterus (HP:0008684)

Included in the FA guideline female-genital manifestations used for FA screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Hypoplastic, absent or bicornuate uterus; gonadal dysgenesis; small ovaries;"

FA guidelines explicitly include hypoplastic or absent uterus among female genital anomalies.

Gonadal Dysgenesis OCCASIONAL Gonadal dysgenesis (HP:0000133)

Included in the FA guideline female-genital manifestations used for FA screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Hypoplastic, absent or bicornuate uterus; gonadal dysgenesis; small ovaries;"

FA guidelines include gonadal dysgenesis among female genital abnormalities.

Ovarian Hypoplasia OCCASIONAL Aplasia/Hypoplasia of the ovary (HP:0010462)

Included in the FA guideline female-genital manifestations as small ovaries.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Hypoplastic, absent or bicornuate uterus; gonadal dysgenesis; small ovaries;"

FA guidelines report small ovaries within the female reproductive anomaly profile.

Vaginal Atresia OCCASIONAL Vaginal atresia (HP:0000148)

Included in the FA guideline female-genital manifestations used for FA screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"rectovaginal fistula; vaginal atresia; late menarche; early menopause;"

FA guidelines list vaginal atresia among congenital female genital findings.

Premature Ovarian Insufficiency OCCASIONAL Premature ovarian insufficiency (HP:0008209)

Included in the FA guideline female-genital manifestations as early menopause.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"rectovaginal fistula; vaginal atresia; late menarche; early menopause;"

FA guidelines list early menopause among female reproductive manifestations.

Renal Anomalies FREQUENT Abnormality of the genitourinary system (HP:0000119)

In the Israeli FA cohort, 39.6% of patients had renal anomalies, making it the second most common congenital anomaly after skin pigmentation changes. Renal anomalies contribute to the congenital abnormality burden score.

Show evidence (3 references)

PMID:31558676 SUPPORT Human Clinical

"More than half had café-au-lait spots (52.3%) followed by renal anomalies (39.6%)."

Israeli cohort found renal anomalies in nearly 40% of FA patients.

PMID:20301575 SUPPORT Human Clinical

"ophthalmic and genitourinary tract anomalies"

GeneReviews lists genitourinary tract anomalies as part of the FA congenital spectrum.

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Horseshoe, ectopic, hypoplastic, dysplastic, absent, hydronephrosis, hydroureter"

FA guidelines list common renal malformation patterns in affected patients.

Head and Neck 10

Microcephaly OCCASIONAL Microcephaly (HP:0000252)

Part of the congenital anomaly spectrum. Skull anomalies were significantly more common in patients with downstream FA gene mutations (FANCD1, FANCJ) compared to core complex mutations (P<0.001). FA-S (biallelic BRCA1) patients also frequently present with microcephaly.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

Context-specific annotations (3)

Genetic FANCD1/BRCA2 FANCJ/BRIP1 VERY_FREQUENT

Downstream FA pathway genes

Skull anomalies were significantly more common in patients with downstream FA gene mutations compared to core complex mutations (P<0.001).

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

Downstream pathway mutations associated with significantly more skull anomalies including microcephaly.

Genetic FA-S BRCA1 HOMOZYGOUS VERY_FREQUENT

FA-S (biallelic BRCA1) patients frequently present with microcephaly.

Show evidence (1 reference)

PMID:38146508 SUPPORT Human Clinical

"this FA-S cohort phenotype includes short stature, microcephaly, facial dysmorphisms"

Microcephaly is a characteristic feature of the FA-S phenotype.

VERY_FREQUENT

90% of FA patients (18/20) had brain MRI abnormalities including small pituitary (68%), posterior fossa abnormalities (30%), and corpus callosum structural variation (30%). The high incidence of midline CNS anomalies points to impact in early stages of CNS development.

Show evidence (1 reference)

PMID:26369989 SUPPORT Human Clinical

"Abnormalities were identified in 18 (90%) patients with FA, the commonest being a small pituitary (68%, p < 0.01 females and p < 0.001 males)"

Stivaros et al. found 90% of FA patients have brain MRI abnormalities, much higher than previously recognized.

Micrognathia OCCASIONAL Micrognathia (HP:0000347)

Included in the FA guideline facial manifestations that should raise suspicion for FA.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Facial FA facies; triangular face; micrognathia; pointed chin; mid -face hypoplasia; facial nerve palsy; microsomia; hypertelorism; hypotelorism; cleft palate"

FA guidelines explicitly list micrognathia among facial abnormalities in the screening table.

Cleft Palate OCCASIONAL Cleft palate (HP:0000175)

Listed in FA guideline facial manifestations used for diagnostic screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Facial FA facies; triangular face; micrognathia; pointed chin; mid -face hypoplasia; facial nerve palsy; microsomia; hypertelorism; hypotelorism; cleft palate"

FA guidelines include cleft palate in the facial anomaly spectrum.

Triangular Face OCCASIONAL Triangular face (HP:0000325)

Included in FA guideline facial manifestations used for diagnostic screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Facial FA facies; triangular face; micrognathia; pointed chin; mid -face hypoplasia; facial nerve palsy; microsomia; hypertelorism; hypotelorism; cleft palate"

FA guidelines list triangular face among characteristic facial findings.

Midface Retrusion OCCASIONAL Midface retrusion (HP:0011800)

Included in FA guideline facial manifestations as mid-face hypoplasia.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Facial FA facies; triangular face; micrognathia; pointed chin; mid -face hypoplasia; facial nerve palsy; microsomia; hypertelorism; hypotelorism; cleft palate"

FA guidelines include mid-face hypoplasia among facial abnormalities.

Pointed Chin OCCASIONAL Pointed chin (HP:0000307)

Included in FA guideline facial manifestations used for diagnostic screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Facial FA facies; triangular face; micrognathia; pointed chin; mid -face hypoplasia; facial nerve palsy; microsomia; hypertelorism; hypotelorism; cleft palate"

FA guidelines list pointed chin among characteristic facial findings.

Facial Palsy OCCASIONAL Facial palsy (HP:0010628)

Included in FA guideline facial manifestations used for diagnostic screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Facial FA facies; triangular face; micrognathia; pointed chin; mid -face hypoplasia; facial nerve palsy; microsomia; hypertelorism; hypotelorism; cleft palate"

FA guidelines explicitly include facial nerve palsy among congenital facial abnormalities.

Epicanthus OCCASIONAL Epicanthus (HP:0000286)

Included in FA guideline eye manifestations used for diagnostic screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Eyes Microphthalmia; epicanthal folds; almond -shaped fissures; ptosis; strabismus; cataracts"

FA guidelines list epicanthal folds as part of the ophthalmic phenotype spectrum.

Almond-Shaped Palpebral Fissures OCCASIONAL Almond-shaped palpebral fissure (HP:0007874)

Included in FA guideline eye manifestations used for diagnostic screening.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Eyes Microphthalmia; epicanthal folds; almond -shaped fissures; ptosis; strabismus; cataracts"

FA guidelines list almond-shaped fissures in the ophthalmic manifestation profile.

Dental and Craniofacial Anomalies FREQUENT Abnormality of the dentition (HP:0000164)

In a systematic review with 46 additional Brazilian cases, 93.5% of FA patients exhibited dental/craniofacial anomalies. Root abnormalities (69.6%), tooth rotation (54.3%), and tooth agenesis (26%) were most common. Anomalies in tooth size and shape were more prevalent in patients who underwent HSCT at age 14 or older.

Show evidence (1 reference)

PMID:39568270 SUPPORT Human Clinical

"In our cohort, 93.5% of patients exhibited anomalies, primarily root abnormalities (69.6%), tooth rotation (54.3%), and tooth agenesis (26%)."

Systematic review demonstrates very high prevalence of dental anomalies in FA patients.

Integument 4

Café-au-Lait Spots FREQUENT Cafe-au-lait spot (HP:0000957)

One of the abnormal skin pigmentation findings in FA

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

Abnormal skin pigmentation, including café-au-lait spots, is among the physical abnormalities present in ~75% of FA patients.

Context-specific annotations (1)

FREQUENT

52.3% of patients in the Israeli cohort had café-au-lait spots, the most common congenital anomaly.

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"More than half had café-au-lait spots (52.3%) followed by renal anomalies (39.6%)."

Quantitative frequency from Israeli FA cohort (n=111).

Squamous Cell Carcinoma FREQUENT Squamous cell carcinoma (HP:0002860)

Cancer surveillance is critical due to genomic instability and persistent epithelial cancer risk. Solid tumors in the Israeli cohort appeared at a mean age of 26.6 years, significantly later than MDS/leukemia. All solid tumors in that cohort were in patients with FANCA mutations or undiagnosed patients. HPV vaccination is recommended to reduce risk. Oral examination every 6 months from age 9-10 years and annual nasolaryngoscopy from age 10 years are recommended.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA."

GeneReviews confirms elevated risk of solid tumors including head/neck and skin squamous cell carcinomas.

Context-specific annotations (3)

Onset: mean 26.6y min y max y

All solid tumors in the Israeli cohort were in patients with FANCA mutations or undiagnosed patients. Mean age of solid tumor onset was 26.6 years, significantly later than MDS/leukemia.

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"for solid tumors 26.6 years (SD 4.9)"

Mean solid tumor onset at 26.6 years, significantly later than MDS (13.3y) and leukemia (10.8y).

FEMALE

Female FA patients have elevated risk of gynecologic squamous cell carcinomas (vulvar, cervical) at young ages. HPV vaccination is recommended. Gynecologic assessment annually from age 13; Pap smear annually from age 18.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"Human papilloma virus (HPV) vaccination to reduce the risk for gynecologic cancer in females"

GeneReviews specifically highlights gynecologic cancer risk in female FA patients and recommends HPV vaccination.

Genetic FA-S BRCA1 HOMOZYGOUS

FA-S (biallelic BRCA1) patients have predisposition to breast/ovarian cancer and/or childhood cancers, distinct from the typical FA SCC spectrum.

Show evidence (1 reference)

PMID:38146508 SUPPORT Human Clinical

"predisposition to breast/ovarian cancer and/or childhood cancers"

FA-S cancer spectrum includes breast/ovarian cancer rather than the typical SCC pattern.

Hypopigmentation FREQUENT Abnormality of the skin (HP:0000951)

The combination of hypo- and hyperpigmented skin lesions is characteristic of FA. In the Israeli cohort, skin pigmentation changes (café-au-lait spots) were the most common congenital anomaly (52.3%).

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"abnormal skin pigmentation"

GeneReviews lists abnormal skin pigmentation among the physical abnormalities present in ~75% of FA patients.

Hyperpigmentation FREQUENT Hyperpigmentation of the skin (HP:0000953)

Included in FA guideline skin findings and commonly co-occurs with hypopigmented lesions.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Skin Café au lait macules; generalized hypo - or hyperpigmentation"

FA guidelines list generalized hyperpigmentation among characteristic skin findings.

Limbs 9

Radial Ray Defects FREQUENT Hypoplasia of the radius (HP:0002984)

Common skeletal manifestation in FA; can include absent or hypoplastic thumbs

Show evidence (2 references)

PMID:20301575 SUPPORT Human Clinical

"skeletal malformations of the upper and/or lower limbs"

GeneReviews confirms upper limb skeletal malformations as a common feature of FA.

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Radius: absent, hypoplastic"

FA guidelines enumerate radial hypoplasia/aplasia among screening manifestations.

Absent or Hypoplastic Thumbs FREQUENT Absent thumb (HP:0009777)

Part of the radial ray anomaly spectrum. More prevalent in core complex complementation groups (FANCA, FANCC, FANCG). The VACTERL phenotype is overrepresented in FA complementation groups D1, E, and F.

Show evidence (3 references)

PMID:20301575 SUPPORT Human Clinical

"skeletal malformations of the upper and/or lower limbs"

GeneReviews confirms upper limb skeletal malformations as common in FA.

PMID:16015582 SUPPORT Human Clinical

"all have radial ray anomalies and 12 of these 13 subjects show at least 1 other feature of FA"

In FA patients with VACTERL phenotype, all had radial ray anomalies including thumb abnormalities.

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Thumb: absent, hypoplastic, triphalangeal, polydactyly"

FA guidelines list thumb malformation subtypes as characteristic upper-limb findings.

Small Thenar Eminence OCCASIONAL Small thenar eminence (HP:0001245)

Included in the FA guideline upper-limb diagnostic manifestations.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Thenar-eminence: hypoplastic, absent"

FA guidelines list thenar eminence hypoplasia or absence among characteristic upper-limb abnormalities.

First Metacarpal Aplasia or Hypoplasia OCCASIONAL Aplasia/Hypoplasia of the 1st metacarpal (HP:0010026)

Included in the FA guideline upper-limb diagnostic manifestations.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Others: absent first metacarpal, clinodactyly"

FA guidelines explicitly include absent first metacarpal among upper-limb anomalies.

Clinodactyly OCCASIONAL Clinodactyly (HP:0030084)

Included in the FA guideline upper-limb diagnostic manifestations.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Others: absent first metacarpal, clinodactyly"

FA guidelines list clinodactyly in the upper-limb anomaly profile.

Ulnar Aplasia or Hypoplasia OCCASIONAL Aplasia/Hypoplasia of the ulna (HP:0006495)

Included in the FA guideline upper-limb diagnostic manifestations.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Ulna: short, dysplastic"

FA guidelines list short and dysplastic ulna among characteristic upper-limb findings.

Toe Syndactyly OCCASIONAL Toe syndactyly (HP:0001770)

Included in FA guideline lower-limb manifestations.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Feet: toe syndactyly, abnormal toes, club feet"

FA guidelines explicitly include toe syndactyly among lower-limb anomalies.

Clubfoot OCCASIONAL Talipes equinovarus (HP:0001762)

Included in FA guideline lower-limb manifestations as club feet.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Feet: toe syndactyly, abnormal toes, club feet"

FA guidelines include club feet among lower-limb findings used in FA screening.

Abnormal Toe Morphology OCCASIONAL Abnormal toe morphology (HP:0001780)

Included in FA guideline lower-limb manifestations as abnormal toes.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Feet: toe syndactyly, abnormal toes, club feet"

FA guidelines explicitly list abnormal toes among lower-limb anomalies.

Metabolism 1

Abnormal Glucose Homeostasis OCCASIONAL Abnormal glucose homeostasis (HP:0011014)

Part of the metabolic/endocrine abnormalities seen in up to 80% of FA patients. Two-hour glucose tolerance testing and insulin levels are recommended as part of annual endocrine surveillance.

Show evidence (1 reference)

PMID:25575015 SUPPORT Human Clinical

Consensus review identifies abnormal glucose/insulin metabolism as part of the FA endocrine phenotype.

Context-specific annotations (1)

FREQUENT

39% of FA patients had abnormal glucose/insulin metabolism in the NCI cohort (Giri et al. 2007). 21% met criteria for metabolic syndrome.

Show evidence (1 reference)

PMID:17426088 SUPPORT Human Clinical

"abnormal glucose/insulin metabolism (39%)"

Giri et al. NCI cohort quantifies glucose/insulin abnormalities at 39%.

Musculoskeletal 8

Skeletal Anomalies FREQUENT Multiple skeletal anomalies (HP:0005775)

Includes areas such as the radius, thumb, and hips

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

Context-specific annotations (4)

Genetic FA-C FANCC

Rib abnormalities were observed only in patients with FANCC mutations in the Israeli cohort — exclusive to this complementation group.

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"Rib abnormalities were observed only in patients with FANCC mutations."

FANCC-exclusive rib anomaly pattern.

Genetic FA-D1 FANCD1/BRCA2

Cleft lip was significantly more common in patients with FANCD1 mutations compared with other FA genes (P<0.001).

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"Cleft lip was more common in patients with FANCD1 mutations, compared with other FA genes (P<0.001)."

FANCD1/BRCA2 specifically enriched for cleft lip.

Genetic FA-B FANCB truncating Severe

FANCB deletion or truncation variants produce earlier-than-average onset of bone marrow failure and more severe congenital abnormalities. Missense variants with residual FANCD2 monoubiquitination activity are associated with more favorable outcome. FANCB is X-linked, so only males are affected.

Show evidence (1 reference)

PMID:32106311 SUPPORT Human Clinical

"Those with FANCB deletion or truncation demonstrate earlier-than-average onset of bone marrow failure and more severe congenital abnormalities compared with a large series of FA individuals in published reports."

Jung et al. 19-child FANCB cohort shows truncating variants produce severe congenital abnormality phenotype.

Genetic FA-I FANCI

44% of FA patients with FANCI mutations (7/16) met criteria for VACTERL association (at least 3 features), significantly overrepresented compared to ~5% in FA overall.

Show evidence (1 reference)

PMID:26590883 SUPPORT Human Clinical

"There are now 16 reported cases of FA due to FANCI of whom 7 have at least 3 features of the VACTERL association (44%)."

FANCI mutations are disproportionately associated with VACTERL phenotype in FA.

Hip Dysplasia OCCASIONAL Hip dysplasia (HP:0001385)

Included in the FA guideline lower-limb diagnostic manifestations.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Lower limb Hips: congenital dislocation/dysplasia, malrotation"

FA guidelines include congenital hip dislocation or dysplasia among lower-limb abnormalities.

Hemivertebrae OCCASIONAL Hemivertebrae (HP:0002937)

Included within vertebral anomalies listed in FA diagnostic manifestation tables.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"hemivertebrae; Klippel -Feil; scoliosis; kyphosis"

FA guidelines enumerate hemivertebrae and related spinal anomalies as part of vertebral involvement.

Scoliosis OCCASIONAL Scoliosis (HP:0002650)

Included in the FA guideline vertebral anomaly manifestations.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Web, hemivertebrae; Klippel -Feil; scoliosis; kyphosis; coccygeal apl asia"

FA guidelines list scoliosis among vertebral abnormalities in the screening table.

Kyphosis OCCASIONAL Kyphosis (HP:0002808)

Included in the FA guideline vertebral anomaly manifestations.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Web, hemivertebrae; Klippel -Feil; scoliosis; kyphosis; coccygeal apl asia"

FA guidelines list kyphosis among vertebral abnormalities in the screening table.

Fused Cervical Vertebrae OCCASIONAL Fused cervical vertebrae (HP:0002949)

FA guideline vertebral manifestations list Klippel-Feil among spinal findings.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Web, hemivertebrae; Klippel -Feil; scoliosis; kyphosis; coccygeal apl asia"

FA guidelines include Klippel-Feil in vertebral abnormalities, represented by fused cervical vertebrae.

Absent or Hypoplastic Coccyx OCCASIONAL Absent/hypoplastic coccyx (HP:0008436)

FA guideline vertebral manifestations include coccygeal aplasia.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Web, hemivertebrae; Klippel -Feil; scoliosis; kyphosis; coccygeal apl asia"

FA guidelines include coccygeal aplasia in the vertebral anomaly profile.

Osteopenia and Osteoporosis VERY_FREQUENT Osteopenia (HP:0000938)

92% of FA patients aged 18 or older had osteopenia or osteoporosis in the NCI cohort (Giri et al. 2007). May be compounded by GH deficiency, hypogonadism, and post-HSCT conditioning effects.

Show evidence (1 reference)

PMID:17426088 SUPPORT Human Clinical

"Ninety-two percent of the patients 18 yr or older had osteopenia or osteoporosis."

Near-universal bone density loss in adult FA patients.

Nervous System 5

Agenesis of Corpus Callosum OCCASIONAL Agenesis of corpus callosum (HP:0001274)

Listed in FA guideline CNS screening manifestations.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"agenesis of corpus callosum"

FA guidelines include corpus callosum agenesis among central nervous system anomalies.

Cerebellar Hypoplasia OCCASIONAL Cerebellar hypoplasia (HP:0001321)

Included in FA guideline CNS screening manifestations.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"cerebellar hypoplasia"

FA guidelines list cerebellar hypoplasia among central nervous system abnormalities.

Developmental Delay OCCASIONAL Intellectual disability (HP:0001249)

Developmental delay contributes to the congenital abnormality burden score. Patients with splice site mutations had significantly more CNS anomalies and developmental delay (P=0.038) compared with other mutation types. Patients with downstream FA gene mutations (FANCD1, FANCJ) had significantly more CNS abnormalities (P=0.005). FA-S (biallelic BRCA1) patients frequently present with intellectual disability.

Show evidence (2 references)

PMID:31558676 SUPPORT Human Clinical

"Patients with splice site mutations had significantly more CNS anomalies and developmental delay, compared with the other patients (P=0.03 and P=0.038, respectively)."

Israeli cohort found developmental delay associated with splice site mutations in FA.

PMID:38146508 SUPPORT Human Clinical

"this FA-S cohort phenotype includes short stature, microcephaly, facial dysmorphisms, hypo/hyperpigmented lesions, intellectual disability, chromosomal sensitivity to crosslinking agents and predisposition to breast/ovarian cancer and/or childhood cancers"

FA-S (BRCA1 biallelic) patients commonly present with intellectual disability.

Context-specific annotations (3)

Genetic splice_site FREQUENT

Patients with splice site mutations had significantly more CNS anomalies and developmental delay (P=0.038) compared with other mutation types.

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"Patients with splice site mutations had significantly more CNS anomalies and developmental delay, compared with the other patients (P=0.03 and P=0.038, respectively)."

Splice site mutations specifically associated with developmental delay in FA.

Genetic FANCD1/BRCA2 FANCJ/BRIP1 FREQUENT

Downstream FA pathway genes

Downstream FA gene mutations associated with significantly more CNS abnormalities (P=0.005) compared to core complex mutations.

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

Downstream pathway mutations enriched for CNS abnormalities.

Genetic FA-S BRCA1 HOMOZYGOUS VERY_FREQUENT

FA-S (biallelic BRCA1) patients frequently present with intellectual disability as part of the characteristic FA-S phenotypic spectrum.

Show evidence (1 reference)

PMID:38146508 SUPPORT Human Clinical

"this FA-S cohort phenotype includes short stature, microcephaly, facial dysmorphisms, hypo/hyperpigmented lesions, intellectual disability"

Intellectual disability is a defining feature of the FA-S subtype.

Hydrocephalus OCCASIONAL Hydrocephalus (HP:0000238)

Included in the FA guideline central nervous system screening manifestations.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Small pituitary and stalk interruption; agenesis of corpus callosum; cerebellar hypoplasia; hydrocephalus ; dilated ventricles; developmental delay"

FA guidelines list hydrocephalus in the CNS anomaly spectrum used for screening.

Ventriculomegaly OCCASIONAL Ventriculomegaly (HP:0002119)

Included in the FA guideline CNS screening manifestations as dilated ventricles.

Show evidence (1 reference)

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"dilated ventricles"

FA guidelines list dilated ventricles among CNS manifestations warranting FA screening.

Growth 2

Short Stature FREQUENT Short stature (HP:0004322)

In the Israeli cohort, 57% met criteria for short stature. Patients with downstream FA gene mutations (FANCD1, FANCJ) were significantly shorter than core complex patients (P=0.003). Patients with deletion mutations were shorter than those with nonsense mutations (P=0.018). Contributing factors include GH deficiency, hypothyroidism, and constitutional factors.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

GeneReviews confirms short stature as one of the common physical abnormalities in FA.

Context-specific annotations (3)

57% met criteria for short stature in the Israeli cohort (n=111).

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"57% fit criteria for short stature"

Quantitative frequency data from Israeli FA cohort of 111 patients.

Genetic FANCD1/BRCA2 FANCJ/BRIP1 More severe

Downstream FA pathway genes

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"Patients with mutations in the downstream genes FANCD1 and FANCJ were significantly shorter compared with the others (P=0.003)"

Downstream pathway gene mutations associated with more severe growth deficiency.

Genetic deletion More severe

Deletion mutations associated with shorter stature than nonsense mutations.

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"Patients with deletions were shorter than patients with nonsense mutations (P=0.018)"

Mutation type affects severity of growth phenotype.

Intrauterine Growth Retardation OCCASIONAL Intrauterine growth retardation (HP:0001511)

In the Israeli cohort, 20% of FA patients were born small for gestational age. Growth deficiency often begins prenatally and continues postnatally.

Show evidence (1 reference)

PMID:31558676 SUPPORT Human Clinical

"20% were born small for the gestational age, and 57% fit criteria for short stature."

Israeli cohort documents 20% small for gestational age prevalence in FA.

Context-specific annotations (1)

OCCASIONAL

20% born SGA in the Israeli cohort. ALDH2*2 variant did not affect birth weight in Japanese FA patients, suggesting prenatal growth restriction is independent of aldehyde-mediated damage.

Show evidence (2 references)

PMID:31558676 SUPPORT Human Clinical

"20% were born small for the gestational age, and 57% fit criteria for short stature."

20% SGA prevalence in Israeli FA cohort.

PMID:24037726 SUPPORT Human Clinical

"the ALDH2 variant is associated with accelerated progression of BMF, while birth weight or the number of physical abnormalities was not affected"

Birth weight unaffected by ALDH2 status, suggesting different mechanism for prenatal growth restriction.

Other 2

Structural Anomalies OCCASIONAL

Includes esophageal atresia, duodenal atresia, and other malformations

Show evidence (2 references)

PMID:20301575 SUPPORT Human Clinical

"Physical abnormalities, present in approximately 75% of affected individuals"

GeneReviews confirms congenital abnormalities are present in ~75% of FA patients.

file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md SUPPORT Human Clinical

"Atresias: esophageal, duodenal, jejunal"

FA guidelines list GI atresias as part of the congenital anomaly spectrum used for FA screening.

Early-Onset Solid Tumors in FANCD1/BRCA2 VERY_FREQUENT

FANCD1/BRCA2 and FANCN/PALB2 patients have the most severe cancer phenotype with near-invariable early-onset malignancy. In the Israeli cohort, one FANCD1 patient developed medulloblastoma at age 3. These patients require cancer screening from a very young age. Neither FANCD1 patient in the Israeli cohort developed BMF, distinguishing this subtype. FA-S (biallelic BRCA1) patients also lack bone marrow failure but have cancer predisposition.

Show evidence (2 references)

PMID:31558676 SUPPORT Human Clinical

"Patients with FANCD1 mutations have been previously described as uniquely developing solid tumors early in life"

Confirms early-onset solid tumor predisposition unique to FANCD1/BRCA2 subtype.

PMID:38146508 SUPPORT Human Clinical

"Unlike most other types of FA, FA-S patients lack bone marrow failure."

FA-S (biallelic BRCA1) patients have cancer predisposition but lack BMF, similar to FANCD1.

🧬

Genetic Associations

FANCA (Pathogenic Variants)

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms FANCA is one of the 21 genes causing autosomal recessive Fanconi anemia.

FANCB (Pathogenic Variants)

X-linked

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"a hemizygous pathogenic variant in FANCB known to cause X-linked FA"

GeneReviews confirms FANCB causes X-linked Fanconi anemia.

FANCC (Pathogenic Variants)

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms FANCC is one of the 21 genes causing autosomal recessive Fanconi anemia.

FANCE (Pathogenic Variants)

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms FANCE is one of the 21 genes causing autosomal recessive Fanconi anemia.

FANCF (Pathogenic Variants)

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms FANCF is one of the 21 genes causing autosomal recessive Fanconi anemia.

FANCG (Pathogenic Variants)

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms FANCG is one of the 21 genes causing autosomal recessive Fanconi anemia.

FANCL (Pathogenic Variants)

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms FANCL is one of the 21 genes causing autosomal recessive Fanconi anemia.

FANCM (Pathogenic Variants)

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews lists FANCM among FA-associated genes; some ontology resources classify FANCM-related disease separately from canonical FA complementation groups.

UBE2T (Pathogenic Variants)

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms UBE2T (FANCT) is one of the 21 genes causing autosomal recessive Fanconi anemia.

FANCD2 (Pathogenic Variants)

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms FANCD2 is one of the 21 genes causing autosomal recessive Fanconi anemia.

FANCI (Pathogenic Variants)

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms FANCI is one of the 21 genes causing autosomal recessive Fanconi anemia.

SLX4 (Pathogenic Variants)

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms SLX4 (FANCP) is one of the 21 genes causing autosomal recessive Fanconi anemia.

BRCA2 (Pathogenic Variants)

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms BRCA2 (FANCD1) is one of the 21 genes causing autosomal recessive Fanconi anemia.

PALB2 (Pathogenic Variants)

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms PALB2 (FANCN) is one of the 21 genes causing autosomal recessive Fanconi anemia.

BRCA1 (Pathogenic Variants)

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms BRCA1 (FANCS) is one of the 21 genes causing autosomal recessive Fanconi anemia.

BRIP1 (Pathogenic Variants)

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms BRIP1 (FANCJ) is one of the 21 genes causing autosomal recessive Fanconi anemia.

ERCC4 (Pathogenic Variants)

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms ERCC4 (FANCQ) is one of the 21 genes causing autosomal recessive Fanconi anemia.

RAD51C (Pathogenic Variants)

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms RAD51C (FANCO) is one of the 21 genes causing autosomal recessive Fanconi anemia.

RAD51 (Pathogenic Variants)

Autosomal dominant

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"a heterozygous pathogenic variant in RAD51 known to cause autosomal dominant FA"

GeneReviews confirms RAD51 (FANCR) as the autosomal dominant FA subtype gene.

XRCC2 (Pathogenic Variants)

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms XRCC2 (FANCU) is one of the 21 genes causing autosomal recessive Fanconi anemia.

MAD2L2 (Pathogenic Variants)

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms MAD2L2/REV7 (FANCV) is one of the 21 genes causing autosomal recessive Fanconi anemia.

RFWD3 (Pathogenic Variants)

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"

GeneReviews confirms RFWD3 (FANCW) is one of the 21 genes causing autosomal recessive Fanconi anemia.

ALDH2 (Risk Modifier)

Show evidence (1 reference)

PMID:24037726 SUPPORT Human Clinical

"the ALDH2 variant is associated with accelerated progression of BMF"

Study of 64 Japanese FA patients showed ALDH2 deficiency accelerates bone marrow failure progression.

ADH5 (Risk Modifier)

Show evidence (1 reference)

PMID:22081012 SUPPORT In Vitro

"a synthetic lethal interaction in avian cells between ADH5, encoding the main formaldehyde-detoxifying enzyme, and the Fanconi anemia (FA) DNA-repair pathway"

Demonstrates that ADH5 formaldehyde catabolism is essential in FA-deficient cells.

KMT2D (Disease Modifier)

💊

Treatments

Hematopoietic Stem Cell Transplantation (HSCT) MAXO:0000747

The only curative treatment for the hematologic manifestations of FA, using reduced-intensity conditioning regimens due to patient sensitivity to chemotherapy and radiation.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematologic manifestations of FA"

Androgen Therapy MAXO:0000283

Can stimulate erythropoiesis and improve blood counts, often used as a bridge to transplantation.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"Administration of oral androgens (e.g., oxymetholone) improves blood counts (red cell and platelets) in approximately 50% of individuals with FA"

Growth Hormone Therapy MAXO:0000283

May be used to improve growth in affected children with short stature.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

GeneReviews recommends treatment of growth deficiency as part of comprehensive FA management.

Supportive Care MAXO:0000950

Treatment of cytopenias with transfusions, antibiotics, and monitoring for malignancy.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"granulocyte colony-stimulating factor improves the neutrophil count in some individuals"

GeneReviews confirms use of growth factors as part of supportive care for cytopenias.

Cancer Surveillance MAXO:0000126

Regular screenings for early detection of cancers, particularly acute myeloid leukemia and squamous cell carcinomas of the head and neck, oral cavity, and anogenital regions.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"oral examinations for tumors every six months beginning at age nine to ten years; annual nasolaryngoscopy beginning at age ten years"

GeneReviews recommends regular oral and nasolaryngoscopic surveillance for early cancer detection.

Genetic Counseling MAXO:0000079

Counseling for patients and families regarding inheritance patterns, recurrence risks, carrier testing, and prenatal diagnosis options.

Show evidence (1 reference)

PMID:20301575 SUPPORT Human Clinical

"Carrier testing for at-risk relatives (for autosomal recessive and X-linked FA) and prenatal and preimplantation genetic testing are possible if the pathogenic variant(s) in the family are known."

GeneReviews confirms the importance of genetic counseling for carrier testing and prenatal diagnosis.

Lentiviral Gene Therapy (FA-A) MAXO:0001001

Ex vivo lentiviral-mediated gene correction of autologous CD34+ hematopoietic stem cells with a FANCA-expressing vector, followed by reinfusion without conditioning. Single-cell RNA sequencing of gene therapy-treated patients demonstrates that corrected HSPCs revert the FA transcriptional signature, including downregulation of TGF-beta and p21 and upregulation of DNA damage response and telomere maintenance pathways.

Show evidence (2 references)

PMID:37021532 SUPPORT Human Clinical

"gene therapy reverts the transcriptional signature of FA HSPC, which then resemble the transcriptional program of healthy donor HSPC"

Single-cell RNA-seq of gene therapy-treated FA patients demonstrates molecular rescue of the FA HSPC transcriptional program.

PMID:37021532 SUPPORT Human Clinical

"a down-regulated expression of TGF-β and p21, typically up-regulated in FA HSPC, and upregulation of DNA damage response and telomere maintenance pathways"

Gene therapy corrects specific molecular defects in FA HSPCs as confirmed by scRNA-seq.

Adenine Base Editing (ABE8e) MAXO:0001001

Precision base editing approach using optimized adenine base editors (ABE8e) to correct prevalent FANCA point mutations in patient hematopoietic stem and progenitor cells without relying on double-strand breaks or homology-directed repair, which are impaired in FA cells. Restores FANCA expression and FA pathway function.

Show evidence (2 references)

PMID:36371486 SUPPORT In Vitro

"optimizing adenine base editor construct, vector type, guide RNA format, and delivery conditions leads to very effective genetic modification in multiple FA patient backgrounds"

ABE8e base editing achieves effective correction across multiple FANCA mutation backgrounds.

PMID:36371486 SUPPORT In Vitro

"Optimized base editing restored FANCA expression, molecular function of the FA pathway, and phenotypic resistance to crosslinking agents"

Base editing restores functional FA pathway activity in patient-derived HSPCs.

🌍

Environmental Factors

Protections from DNA-damaging Agents

Broad recommendation spanning both ionizing radiation and chemical genotoxins; no single specific ECTO term is used here to avoid a mismatched mapping.

Avoid exposure to agents that can cause DNA damage, such as radiation and certain chemicals.

🔬

Biochemical Markers

Chromosomal Breakage Test (Positive)

Context: Diagnostic indicator

Crosslinking Sensitivity (Increased)

Context: Diagnostic indicator (often using diepoxybutane (DEB) or mitomycin C (MMC))

📊

Related Datasets

MYC Promotes Bone Marrow Stem Cell Dysfunction in Fanconi Anemia geo:GSE157591

Single-cell RNA sequencing of bone marrow CD34+ hematopoietic stem and progenitor cells from Fanconi anemia patients and healthy donors. Reveals aberrant MYC overexpression in FA HSPCs driving proliferation-apoptosis imbalance, with transcriptomic signatures distinct from normal hematopoiesis.

human SINGLE CELL RNA SEQ 10x Genomics Chromium

Findings

MYC is overexpressed in FA HSPCs compared to healthy donor HSPCs

FA HSPCs show proliferation-apoptosis imbalance driven by MYC dysregulation

PMID:32997960

Show evidence (1 reference)

PMID:32997960 SUPPORT Human Clinical

"MYC overexpression impairs HSPC function in FA patients and contributes to exhaustion in FA bone marrow"

scRNA-seq dataset demonstrates MYC as a key driver of HSPC dysfunction in FA patients.

Restored Hematopoietic Stem Cell Transcriptional Program in Fanconi Anemia Patients Following Gene Therapy geo:GSE180536

Single-cell RNA sequencing of chimeric corrected and uncorrected HSPC populations co-existing in bone marrow of lentiviral gene therapy-treated Fanconi anemia patients. Demonstrates that gene-corrected cells revert the FA transcriptional signature to resemble healthy donor HSPCs.

human SINGLE CELL RNA SEQ 10x Genomics Chromium

Findings

Gene therapy reverts the FA HSPC transcriptional signature to healthy donor levels

Corrected cells show downregulation of TGF-beta and p21, upregulation of DDR and telomere maintenance

PMID:37021532

Show evidence (1 reference)

PMID:37021532 SUPPORT Human Clinical

"gene therapy reverts the transcriptional signature of FA HSPC, which then resemble the transcriptional program of healthy donor HSPC"

scRNA-seq of gene therapy patients confirms molecular rescue of FA-specific transcriptomic defects.

🔬

Clinical Trials

NCT04069533 PHASE_II ACTIVE_NOT_RECRUITING

Phase II clinical trial evaluating lentiviral-mediated gene therapy for pediatric patients with Fanconi Anemia subtype A (FA-A). Autologous CD34+ hematopoietic stem cells are transduced ex vivo with a lentiviral vector carrying the FANCA gene, then reinfused with the goal of preventing bone marrow failure.

Target Phenotypes: Pancytopenia ↗ Anemia ↗

Show evidence (1 reference)

clinicaltrials:NCT04069533 SUPPORT Human Clinical

"This is an open-label Phase II clinical trial to evaluate the efficacy of a hematopoietic cell-based gene therapy for pediatric patients with Fanconi Anemia, subtype A (FA-A). Hematopoietic stem cells from mobilized peripheral blood of patients with FA-A will be transduced ex vivo (outside the..."

This Phase II gene therapy trial directly addresses the genetic defect in FA-A by correcting FANCA mutations in autologous stem cells, providing evidence for curative cell-based genetic therapy approaches.

NCT00243399 PHASE_I COMPLETED

Pilot trial evaluating oxandrolone (an androgen steroid) for treatment of bone marrow aplasia in Fanconi Anemia patients. The study assessed safety and efficacy of androgen therapy to stimulate production of red blood cells and platelets in FA patients with bone marrow failure.

Target Phenotypes: Pancytopenia ↗ Anemia ↗

Show evidence (1 reference)

clinicaltrials:NCT00243399 SUPPORT Human Clinical

"The purpose of this study is to evaluate the safety of the drug oxandrolone (a type of androgen steroid) in patients with Fanconi anemia (FA), and to determine if this drug can help in the treatment of bone marrow failure in these patients. Androgen steroids are male hormones that can stimulate..."

This Phase I trial evaluates androgen therapy as a bridge treatment for bone marrow failure in FA, providing clinical evidence for hormonal stimulation of hematopoiesis.

NCT00630253 PHASE_II COMPLETED

Phase I/II study evaluating cyclophosphamide, fludarabine, and antithymocyte globulin conditioning followed by matched sibling donor hematopoietic cell transplantation (HSCT) in patients with Fanconi Anemia. Investigates reduced-intensity conditioning regimens tailored to FA patients' increased chemotherapy sensitivity.

Target Phenotypes: Pancytopenia ↗ Anemia ↗

Show evidence (1 reference)

clinicaltrials:NCT00630253 SUPPORT Human Clinical

"Giving chemotherapy, such as cyclophosphamide and fludarabine, before a donor stem cell transplant helps to remove the patient's cells to allow for the transplant cells to take and grow. It also helps stop the patient's immune system from rejecting the donor's stem cells."

This Phase I/II trial optimizes HSCT conditioning regimens for FA patients, providing clinical evidence for the curative approach to bone marrow failure in Fanconi Anemia.

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Source YAML

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name: Fanconi_Anemia
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-02-09T20:03:16Z'
description: >-
  Fanconi anemia is a rare inherited bone marrow failure syndrome characterized
  by genomic instability, congenital abnormalities, progressive bone marrow failure,
  and increased susceptibility to malignancies. Most cases result from biallelic
  pathogenic variants in genes encoding components of the Fanconi anemia/BRCA DNA
  interstrand crosslink repair pathway, with recognized exceptions including X-linked
  FANCB and autosomal dominant RAD51-associated disease (FA-R). Between 21 and
  22 complementation groups are cited depending on nomenclature and curation conventions,
  with FANCA accounting for 60-70% of cases. The phenotypic spectrum is highly
  variable even within the same complementation group, reflecting genetic modifiers
  and environmental factors.
category: Genetic
parents:
- Bone Marrow Failure
- Congenital Disorder
prevalence:
- population: Global
  percentage: Rare
inheritance:
- name: Autosomal Recessive
- name: X-linked
definitions:
- name: 2024 FA Clinical Care Guidelines Screening Indicator Set (Table 1)
  definition_type: CASE_DEFINITION
  description: >-
    Manifestations listed in Table 1 of the 5th edition Fanconi Anemia Clinical
    Care Guidelines that should raise suspicion for FA and trigger diagnostic
    screening workup.
  scope: Suspected Fanconi anemia in pediatric and adult clinical settings
  criteria_sets:
  - name: Table 1 FA screening indicators
    description: Major congenital, hematologic, and reproductive indicators associated with FA.
    core_clinical_characteristics:
    - preferred_term: Short stature
      term:
        id: HP:0004322
        label: Short stature
    - preferred_term: Microcephaly
      term:
        id: HP:0000252
        label: Microcephaly
    - preferred_term: Anterior pituitary hypoplasia
      term:
        id: HP:0010627
        label: Anterior pituitary hypoplasia
    - preferred_term: Interrupted pituitary stalk
      term:
        id: HP:0034978
        label: Interrupted pituitary stalk
    - preferred_term: Hearing impairment
      term:
        id: HP:0000365
        label: Hearing impairment
    - preferred_term: Microphthalmia
      term:
        id: HP:0000568
        label: Microphthalmia
    - preferred_term: Epicanthus
      term:
        id: HP:0000286
        label: Epicanthus
    - preferred_term: Ptosis
      term:
        id: HP:0000508
        label: Ptosis
    - preferred_term: Strabismus
      term:
        id: HP:0000486
        label: Strabismus
    - preferred_term: Cataract
      term:
        id: HP:0000518
        label: Cataract
    - preferred_term: Triangular face
      term:
        id: HP:0000325
        label: Triangular face
    - preferred_term: Micrognathia
      term:
        id: HP:0000347
        label: Micrognathia
    - preferred_term: Cleft palate
      term:
        id: HP:0000175
        label: Cleft palate
    - preferred_term: Abnormal heart morphology
      term:
        id: HP:0001627
        label: Abnormal heart morphology
    - preferred_term: Tracheoesophageal fistula
      term:
        id: HP:0002575
        label: Tracheoesophageal fistula
    - preferred_term: Esophageal atresia
      term:
        id: HP:0002032
        label: Esophageal atresia
    - preferred_term: Duodenal atresia
      term:
        id: HP:0002247
        label: Duodenal atresia
    - preferred_term: Jejunal atresia
      term:
        id: HP:0005235
        label: Jejunal atresia
    - preferred_term: Anal atresia
      term:
        id: HP:0002023
        label: Anal atresia
    - preferred_term: Annular pancreas
      term:
        id: HP:0001734
        label: Annular pancreas
    - preferred_term: Intestinal malrotation
      term:
        id: HP:0002566
        label: Intestinal malrotation
    - preferred_term: Abnormality of the genitourinary system
      term:
        id: HP:0000119
        label: Abnormality of the genitourinary system
    - preferred_term: Absent thumb
      term:
        id: HP:0009777
        label: Absent thumb
    - preferred_term: Hypoplasia of the radius
      term:
        id: HP:0002984
        label: Hypoplasia of the radius
    - preferred_term: Clinodactyly
      term:
        id: HP:0030084
        label: Clinodactyly
    - preferred_term: Aplasia/Hypoplasia of the ulna
      term:
        id: HP:0006495
        label: Aplasia/Hypoplasia of the ulna
    - preferred_term: Toe syndactyly
      term:
        id: HP:0001770
        label: Toe syndactyly
    - preferred_term: Talipes equinovarus
      term:
        id: HP:0001762
        label: Talipes equinovarus
    - preferred_term: Hemivertebrae
      term:
        id: HP:0002937
        label: Hemivertebrae
    - preferred_term: Fused cervical vertebrae
      term:
        id: HP:0002949
        label: Fused cervical vertebrae
    - preferred_term: Scoliosis
      term:
        id: HP:0002650
        label: Scoliosis
    - preferred_term: Kyphosis
      term:
        id: HP:0002808
        label: Kyphosis
    - preferred_term: Absent/hypoplastic coccyx
      term:
        id: HP:0008436
        label: Absent/hypoplastic coccyx
    - preferred_term: Cafe-au-lait spot
      term:
        id: HP:0000957
        label: Cafe-au-lait spot
    - preferred_term: Hyperpigmentation of the skin
      term:
        id: HP:0000953
        label: Hyperpigmentation of the skin
    - preferred_term: Pancytopenia
      term:
        id: HP:0001876
        label: Pancytopenia
    - preferred_term: Myelodysplasia
      term:
        id: HP:0002863
        label: Myelodysplasia
    - preferred_term: Leukemia
      term:
        id: HP:0001909
        label: Leukemia
    - preferred_term: Cryptorchidism
      term:
        id: HP:0000028
        label: Cryptorchidism
    - preferred_term: Hypospadias
      term:
        id: HP:0000047
        label: Hypospadias
    - preferred_term: Micropenis
      term:
        id: HP:0000054
        label: Micropenis
    - preferred_term: Aplasia/hypoplasia of the uterus
      term:
        id: HP:0008684
        label: Aplasia/hypoplasia of the uterus
    - preferred_term: Gonadal dysgenesis
      term:
        id: HP:0000133
        label: Gonadal dysgenesis
    - preferred_term: Vaginal atresia
      term:
        id: HP:0000148
        label: Vaginal atresia
    notes: >-
      This criteria set is intended to guide screening suspicion and referral;
      it is not a strict diagnostic-count rule.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Table 1. Manifestations that are indicators for Fanconi anemia screening."
    explanation: The FA guideline explicitly defines Table 1 manifestations as indicators that should prompt FA screening.
  notes: >-
    This is a screening definition/case-identification aid. Definitive FA
    diagnosis still requires confirmatory genetic and/or chromosome breakage
    testing.
pathophysiology:
- name: DNA Repair Deficiency
  description: Mutations in FA genes impair the body's ability to repair DNA damage, leading to increased sensitivity to crosslinking agents and propensity for chromosomal instability.
  evidence:
  - reference: PMID:35596788
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At least 22 genes are associated with Fanconi anemia, constituting the Fanconi anemia DNA repair pathway. This pathway coordinates multiple processes and proteins to facilitate the repair of DNA adducts including interstrand crosslinks (ICLs)
  downstream:
  - target: Genomic Instability
- name: Bone Marrow Failure
  description: Inability of the bone marrow to produce sufficient blood cells due to hematopoietic stem cell defects.
  evidence:
  - reference: PMID:38424108
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we identify increased protein synthesis rates in the fetal hematopoietic stem cell pool at the onset of hematopoietic failure in Fanconi Anemia, a prototypical DNA repair disorder that manifests with bone marrow failure."
    explanation: Demonstrates that bone marrow failure is a defining manifestation of Fanconi anemia, with origins in fetal HSC dysfunction.
  downstream:
  - target: Pancytopenia
  - target: Aplastic Anemia
- name: Genomic Instability
  description: Increased tendency for genomic alterations including chromosomal breaks, deletions, and rearrangements.
  evidence:
  - reference: PMID:35596788
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ICLs can interfere with DNA transactions, including replication and transcription. If not properly removed and repaired, ICLs cause DNA breaks and lead to genomic instability, a hallmark of cancer.
  downstream:
  - target: Hematopoietic Stem Cell Attrition
    description: Unrepaired genomic damage in HSCs triggers checkpoint-mediated apoptosis and senescence
  - target: Developmental Progenitor Apoptosis
    description: Genomic instability in embryonic progenitors activates p53-mediated cell death
  - target: Clonal Evolution
    description: Accumulation of somatic mutations drives malignant transformation
  - target: Epithelial Cancer Susceptibility
    description: Impaired genome maintenance in epithelial tissues promotes carcinogenesis
- name: Hematopoietic Stem Cell Attrition
  description: Progressive depletion of long-term hematopoietic stem cells in bone marrow due to replication stress, aldehyde-induced DNA damage, and chronic inflammatory signaling.
  evidence:
  - reference: PMID:38424108
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "proteostasis deregulation itself is driven by excess sterile inflammatory activity in hematopoietic and stromal cells within the fetal liver, and dampened Type I interferon signaling similarly restores fetal Fancd2-/- long-term hematopoietic stem cells to wild type-equivalent numbers."
    explanation: Demonstrates that inflammatory signaling drives HSC pool deficits in FA, and that dampening inflammation rescues HSC numbers.
  - reference: PMID:24037726
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "the FA proteins might counteract aldehyde-induced genotoxicity in hematopoietic stem cells"
    explanation: Establishes that aldehydes cause genotoxicity in HSCs and FA proteins normally protect against this damage.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  biological_processes:
  - preferred_term: response to aldehyde
    term:
      id: GO:0043437
      label: response to aldehyde
  - preferred_term: cellular response to oxidative stress
    term:
      id: GO:0034599
      label: cellular response to oxidative stress
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  downstream:
  - target: Bone Marrow Failure
- name: Translesion Synthesis Defect
  description: Impaired ability to bypass DNA lesions during replication through translesion synthesis polymerases, requiring functional FANCD2-FANCI complex and PCNA monoubiquitination.
  evidence:
  - reference: PMID:25237197
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "Establishing the interaction network involving the FA proteins and their associated partners has revealed an intersection of FA with several DNA repair pathways, including homologous recombination, DNA mismatch repair, nucleotide excision repair, and translesion DNA synthesis."
    explanation: Demonstrates that the FA pathway intersects with translesion DNA synthesis, establishing the mechanistic link.
  biological_processes:
  - preferred_term: translesion synthesis
    term:
      id: GO:0019985
      label: translesion synthesis
  downstream:
  - target: Genomic Instability
- name: Homologous Recombination Impairment
  description: Defective repair of DNA double-strand breaks following interstrand crosslink unhooking, due to mutations in FA genes involved in HR pathway including BRCA2, PALB2, and BRCA1.
  evidence:
  - reference: PMID:25237197
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "the fact that 5 FA genes are in fact familial breast cancer genes and FA gene mutations are found frequently in sporadic cancers suggest wider applicability in hematopoiesis and oncology."
    explanation: The overlap of FA genes with breast cancer genes (BRCA1, BRCA2, PALB2) establishes the connection between FA and homologous recombination repair.
  biological_processes:
  - preferred_term: homologous recombination
    term:
      id: GO:0035825
      label: homologous recombination
  downstream:
  - target: Genomic Instability
- name: Aldehyde-Induced Genotoxicity
  description: Endogenous aldehydes (acetaldehyde and formaldehyde) from normal metabolism generate DNA interstrand crosslinks and DNA-protein crosslinks; impaired detoxification by ALDH2 and ADH5 exacerbates DNA damage burden.
  evidence:
  - reference: PMID:24037726
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We examined 64 Japanese FA patients, and found that the ALDH2 variant is associated with accelerated progression of BMF"
    explanation: Human clinical data showing that impaired aldehyde detoxification (ALDH2 variant) accelerates bone marrow failure in FA patients.
  - reference: PMID:25237197
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "recent studies have shown a major involvement of the FA pathway in the tolerance of reactive aldehydes."
    explanation: Establishes that the FA pathway is required for tolerance of aldehyde-induced DNA damage.
  biological_processes:
  - preferred_term: response to aldehyde
    term:
      id: GO:0043437
      label: response to aldehyde
  downstream:
  - target: Hematopoietic Stem Cell Attrition
    description: Endogenous aldehyde-induced DNA damage preferentially depletes HSCs when FA pathway is absent
- name: Core Complex Dysfunction
  description: >-
    Mutations in FA core complex genes (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL,
    FANCM, UBE2T/FANCT) disrupt the E3 ubiquitin ligase that monoubiquitinates the
    FANCD2-FANCI complex, abolishing the central signaling step of the FA pathway.
    FANCA mutations account for 60-70% of all FA cases.
  protein_complexes:
  - preferred_term: FA nuclear complex
    term:
      id: GO:0043240
      label: Fanconi anaemia nuclear complex
  biological_processes:
  - preferred_term: protein ubiquitination
    term:
      id: GO:0016567
      label: protein ubiquitination
  genes:
  - preferred_term: FANCA
    term:
      id: hgnc:3582
      label: FANCA
  - preferred_term: FANCB
    term:
      id: hgnc:3583
      label: FANCB
  - preferred_term: FANCC
    term:
      id: hgnc:3584
      label: FANCC
  - preferred_term: FANCG
    term:
      id: hgnc:3588
      label: FANCG
  evidence:
  - reference: PMID:35596788
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "At least 22 genes are associated with Fanconi anemia, constituting the Fanconi anemia DNA repair pathway."
    explanation: Core complex genes form the upstream signaling arm of the FA pathway.
  downstream:
  - target: DNA Repair Deficiency
    description: Loss of core complex prevents FANCD2-FANCI monoubiquitination
- name: ID Complex Dysfunction
  description: >-
    Mutations in FANCD2 or FANCI disrupt the central ID2 complex whose
    monoubiquitination is the critical signaling event in FA pathway activation.
    In wild type, the core complex E3 ligase monoubiquitinates both FANCD2 and
    FANCI, causing the ID2 heterodimer to clamp onto chromatin at stalled
    replication forks and recruit downstream nucleases and HR effectors. Loss of
    either subunit abolishes this signaling hub.
  genes:
  - preferred_term: FANCD2
    term:
      id: hgnc:3585
      label: FANCD2
  - preferred_term: FANCI
    term:
      id: hgnc:25568
      label: FANCI
  biological_processes:
  - preferred_term: protein monoubiquitination
    term:
      id: GO:0006513
      label: protein monoubiquitination
  - preferred_term: interstrand cross-link repair
    term:
      id: GO:0036297
      label: interstrand cross-link repair
  evidence:
  - reference: PMID:32106311
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This reflects the indispensable role of FANCB protein in the enzymatic activation of FANCD2 monoubiquitination, an essential step in the repair of DNA interstrand crosslinks."
    explanation: FANCD2 monoubiquitination is the essential central step in ICL repair.
  downstream:
  - target: DNA Repair Deficiency
    description: Absence of functional ID2 complex prevents recruitment of downstream repair effectors
- name: Downstream Effector Dysfunction
  description: >-
    Mutations in downstream effector genes (BRCA2/FANCD1, PALB2/FANCN, BRCA1/FANCS,
    RAD51C/FANCO, XRCC2/FANCU) impair homologous recombination and translesion
    synthesis. These overlap with familial breast/ovarian cancer genes; biallelic
    mutations produce the most severe FA phenotypes with early-onset solid tumors
    and more congenital anomalies.
  genes:
  - preferred_term: BRCA2
    term:
      id: hgnc:1101
      label: BRCA2
  - preferred_term: BRCA1
    term:
      id: hgnc:1100
      label: BRCA1
  evidence:
  - reference: PMID:25237197
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "the fact that 5 FA genes are in fact familial breast cancer genes and FA gene mutations are found frequently in sporadic cancers suggest wider applicability in hematopoiesis and oncology."
    explanation: Downstream FA genes overlap with breast cancer susceptibility genes.
  downstream:
  - target: Homologous Recombination Impairment
    description: Loss of BRCA2/PALB2/BRCA1/RAD51C directly impairs HR-mediated DNA repair
- name: Inflammatory Bone Marrow Microenvironment
  description: >-
    Excess sterile inflammatory signaling (TNF-alpha, interferon-gamma, Type I
    interferons) in the bone marrow creates a hostile microenvironment for HSCs.
    Both hematopoietic and stromal cells contribute to chronic inflammation,
    driving proteostasis deregulation and accelerating stem cell attrition.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  evidence:
  - reference: PMID:38424108
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "proteostasis deregulation itself is driven by excess sterile inflammatory activity in hematopoietic and stromal cells within the fetal liver, and dampened Type I interferon signaling similarly restores fetal Fancd2-/- long-term hematopoietic stem cells to wild type-equivalent numbers."
    explanation: Inflammatory signaling in the BM microenvironment drives HSC loss in FA.
  downstream:
  - target: Hematopoietic Stem Cell Attrition
    description: Chronic inflammatory signaling drives proteostasis deregulation and HSC depletion
- name: Developmental Progenitor Apoptosis
  description: >-
    Unrepaired DNA damage in rapidly dividing embryonic progenitor cells activates
    p53-dependent apoptosis during critical developmental windows. This mechanism
    underlies the congenital malformations of FA, explaining the midline predominance
    of anomalies and correlation between pathway position and congenital abnormality
    burden.
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
  - preferred_term: embryo development
    term:
      id: GO:0009790
      label: embryo development
  evidence:
  - reference: PMID:26369989
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of central nervous system (CNS) abnormalities in FA is higher than previously reported, with a midline predominance that points to impact in the early stages of CNS development."
    explanation: Midline predominance of anomalies supports developmental progenitor loss during embryogenesis.
  downstream:
  - target: Congenital Structural Anomalies
    description: Loss of mesodermal and endodermal progenitors causes organ malformations
  - target: CNS Developmental Anomalies
    description: Loss of neural progenitors causes midline brain and pituitary defects
  - target: Endocrine Gland Dysfunction
    description: Developmental pituitary defects impair hormone production
  - target: Skin Pigmentation Changes
    description: Melanocyte progenitor defects cause pigmentary anomalies
  - target: Intrauterine Growth Retardation
- name: Clonal Evolution
  description: >-
    Progressive accumulation of somatic mutations and chromosomal aberrations in
    genomically unstable hematopoietic cells drives clonal selection and malignant
    transformation. Characteristic cytogenetic changes include gain of 1q and 3q
    and loss of 7q. Clones with selective growth advantage expand, leading to MDS
    and AML. Single-cell DNA sequencing has revealed polyclonal evolution at the
    MDS stage, with sequential acquisition of driver mutations and MDM4-mediated
    p53 dampening via chromosome 1q gain as the canonical initiating event.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  evidence:
  - reference: PMID:31558676
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "30% developed myelodysplastic syndrome (MDS), leukemia and/or solid tumors"
    explanation: 30% malignancy rate reflects ongoing clonal evolution in FA HSCs.
  - reference: PMID:36736290
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clonal hematopoiesis driven by chromosome 1q/MDM4 trisomy defines a canonical route toward leukemia in Fanconi anemia."
    explanation: Longitudinal study of 335 FA patients showing chromosome 1q gain (containing MDM4) as the most common early clonal event, dampening p53 and driving clonal hematopoiesis.
  - reference: PMID:36167633
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Polyclonal evolution of Fanconi anemia to MDS and AML revealed at single cell resolution."
    explanation: Single-cell DNA sequencing of FA patients transforming to MDS/AML revealed polyclonal patterns with sequential acquisition of UBASH3A, SF3B1, RUNX1, and IDH2 mutations.
  - reference: PMID:37391485
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "we performed multiplexed gene editing of mutational hotspots in MDS-associated genes in human induced pluripotent stem cells (iPSCs) followed by hematopoietic differentiation. We observed aberrant self-renewal and impaired differentiation of HSPCs with enrichment of RUNX1 insertions and deletions (indels)"
    explanation: iPSC-based modeling demonstrates that RUNX1 mutations blunt the G1/S cell cycle checkpoint in FA, promoting transformation.
  downstream:
  - target: Myelodysplastic Syndrome
  - target: Increased Risk of Leukemia
- name: Epithelial Cancer Susceptibility
  description: >-
    Impaired genome maintenance in epithelial tissues renders them vulnerable to
    accumulation of oncogenic mutations. Squamous epithelia of the head/neck, oral
    cavity, esophagus, and anogenital regions are particularly susceptible due to
    high proliferative turnover and exposure to environmental mutagens including HPV.
  cell_types:
  - preferred_term: epithelial cell
    term:
      id: CL:0000066
      label: epithelial cell
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA."
    explanation: Confirms epithelial tissue susceptibility to malignancy in FA.
  - reference: PMID:36912284
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "We developed the Fanconi Anemia Cancer Cell Line Resource (FA-CCLR) to foster new work on the origins, treatment and prevention of FA-associated carcinomas. The FA-CCLR consists of Fanconi-isogenic head and neck squamous cell carcinoma (HNSCC) cell line pairs generated from five individuals with FA-associated HNSCC, and five individuals with sporadic HNSCC."
    explanation: Isogenic FA/sporadic HNSCC cell line pairs provide a platform to identify FA-dependent cancer phenotypes and test therapeutic strategies.
  - reference: PMID:36450981
    supports: PARTIAL
    evidence_source: COMPUTATIONAL
    snippet: "Genomic signature of Fanconi anaemia DNA repair pathway deficiency in cancer."
    explanation: Computational genomic analysis defined the primary structural variant signature of FA pathway deficiency in squamous cancers, enabling computational classification of FA-associated vs sporadic carcinomas.
  downstream:
  - target: Squamous Cell Carcinoma
  - target: Early-Onset Solid Tumors in FANCD1/BRCA2
- name: HPV-Mediated Epithelial Damage
  description: >-
    Human papillomavirus infection compounds epithelial cancer risk in FA patients.
    HPV oncoproteins E6 and E7 degrade p53 and Rb tumor suppressors, further
    disabling the already compromised DNA damage response. HPV vaccination is
    recommended to reduce gynecologic and oropharyngeal cancer risk.
  evidence:
  - reference: PMID:20301575
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Human papilloma virus (HPV) vaccination to reduce the risk for gynecologic cancer in females"
    explanation: HPV vaccination recommendation implies HPV is a significant co-factor for epithelial cancer in FA.
  downstream:
  - target: Epithelial Cancer Susceptibility
    description: HPV oncoproteins synergize with FA pathway deficiency to accelerate carcinogenesis
- name: Endocrine Gland Dysfunction
  description: >-
    Widespread endocrine abnormalities affect approximately 73-80% of FA patients.
    Developmental pituitary/hypothalamic defects (68% have small pituitary on MRI),
    direct effects of genomic instability on endocrine cell function, and chronic
    illness contribute. Manifests as GH deficiency, hypothyroidism, glucose
    dysregulation, hypogonadism, dyslipidemia, and metabolic syndrome.
  locations:
  - preferred_term: pituitary gland
    term:
      id: UBERON:0000007
      label: pituitary gland
  evidence:
  - reference: PMID:17426088
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Endocrine abnormalities were present in 73%, including short stature and/or GH deficiency (51%), hypothyroidism (37%), midline brain abnormalities (17%)"
    explanation: Giri et al. documents 73% endocrine abnormality prevalence.
  - reference: PMID:26369989
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormalities were identified in 18 (90%) patients with FA, the commonest being a small pituitary (68%, p < 0.01 females and p < 0.001 males)"
    explanation: Small pituitary in 68% provides anatomical basis for endocrine dysfunction.
  downstream:
  - target: Growth Hormone Deficiency
  - target: Hypothyroidism
  - target: Abnormal Glucose Homeostasis
  - target: Delayed Puberty and Hypogonadism
  - target: Osteopenia and Osteoporosis
  - target: Short Stature
  - target: Impaired Fertility
- name: Congenital Structural Anomalies
  description: >-
    Developmental progenitor loss during embryogenesis causes structural malformations
    affecting limbs, heart, kidneys, GI tract, ears, and genitourinary system.
    Approximately 75% of FA patients have at least one congenital anomaly, with
    burden correlating with complementation group, mutation type, and pathway position.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies."
    explanation: 75% of FA patients have physical abnormalities.
  downstream:
  - target: Skeletal Anomalies
  - target: Radial Ray Defects
  - target: Absent or Hypoplastic Thumbs
  - target: Congenital Heart Defects
  - target: Genitourinary Malformations
  - target: Renal Anomalies
  - target: Hearing Loss
  - target: Microphthalmia
  - target: Strabismus
  - target: Structural Anomalies
  - target: Dental and Craniofacial Anomalies
  - target: Cryptorchidism
- name: CNS Developmental Anomalies
  description: >-
    Midline brain structural defects from neural progenitor loss during early CNS
    development. Includes small pituitary (68%), posterior fossa abnormalities (30%
    including Chiari I malformation and Dandy-Walker variant), and corpus callosum
    structural variation (30%).
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  - preferred_term: pituitary gland
    term:
      id: UBERON:0000007
      label: pituitary gland
  evidence:
  - reference: PMID:26369989
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormalities were identified in 18 (90%) patients with FA, the commonest being a small pituitary (68%, p < 0.01 females and p < 0.001 males)"
    explanation: 90% brain MRI abnormality rate with midline predominance.
  - reference: PMID:26369989
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Posterior fossa abnormalities were seen in six cases (30%, p = 0.01) including Chiari I malformation (n = 3), Dandy-Walker variant (n = 2) and cerebellar atrophy (n = 2)."
    explanation: Posterior fossa and corpus callosum anomalies reflect early CNS developmental impact.
  downstream:
  - target: Microcephaly
  - target: Developmental Delay
- name: Skin Pigmentation Changes
  description: >-
    Melanocyte progenitor defects during embryonic development cause characteristic
    pigmentary anomalies including café-au-lait spots and hypopigmented patches.
    Skin pigmentation changes are the most common congenital anomaly in FA,
    affecting over 50% of patients.
  evidence:
  - reference: PMID:31558676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "More than half had café-au-lait spots (52.3%) followed by renal anomalies (39.6%)."
    explanation: Café-au-lait spots are the most common congenital anomaly in the Israeli FA cohort.
  downstream:
  - target: Café-au-Lait Spots
  - target: Hypopigmentation
- name: MYC-Driven HSPC Dysfunction
  description: >-
    Single-cell RNA sequencing of primary FA patient bone marrow HSPCs revealed
    MYC overexpression as a novel pathogenic driver alongside p53 and TGF-beta
    upregulation. Distinct HSPC subpopulations co-expressing high TP53 or high
    MYC coexist in FA bone marrow. MYC-high HSPCs show downregulation of cell
    adhesion genes (including CXCR4), promoting enhanced egress from bone marrow
    to peripheral blood and contributing to HSC exhaustion and bone marrow failure.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  biological_processes:
  - preferred_term: regulation of gene expression
    term:
      id: GO:0010468
      label: regulation of gene expression
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  evidence:
  - reference: PMID:32997960
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to overexpression of p53 and TGF-β pathway genes, we identified high levels of MYC expression. We correspondingly observed coexistence of distinct HSPC subpopulations expressing high levels of TP53 or MYC in FA bone marrow (BM)."
    explanation: scRNA-seq of primary FA patient HSPCs identifies MYC as a novel driver of BMF alongside known p53/TGF-beta pathways.
  - reference: PMID:32997960
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Inhibiting MYC expression with the BET bromodomain inhibitor (+)-JQ1 reduced the clonogenic potential of FA patient HSPCs but rescued physiological and genotoxic stress in HSPCs from FA mice, showing that MYC promotes proliferation while increasing DNA damage."
    explanation: BET inhibitor targeting MYC rescues genotoxic stress in FA mouse HSPCs, validating MYC as a therapeutic target.
  downstream:
  - target: Hematopoietic Stem Cell Attrition
    description: MYC overexpression drives proliferation and DNA damage, accelerating HSC exhaustion
  - target: Bone Marrow Failure
- name: Differentiation-Induced Genotoxic Stress
  description: >-
    Transcriptional reprogramming during hematopoietic differentiation generates
    a surge of genotoxic stress from formaldehyde, an obligate by-product of
    oxidative protein demethylation during transcription regulation. In the
    absence of functional FA DNA repair, this differentiation-associated DNA
    damage causes aborted differentiation and depletion of FA progenitor cells,
    providing a mechanistic explanation for the hematopoietic-specific failure
    in FA despite it being a germline disorder.
  cell_types:
  - preferred_term: hematopoietic precursor cell
    term:
      id: CL:0008001
      label: hematopoietic precursor cell
  biological_processes:
  - preferred_term: hematopoietic progenitor cell differentiation
    term:
      id: GO:0002244
      label: hematopoietic progenitor cell differentiation
  - preferred_term: response to aldehyde
    term:
      id: GO:0043437
      label: response to aldehyde
  evidence:
  - reference: PMID:33338401
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "reprogramming transcription during hematopoietic differentiation results in an overload of genotoxic stress, which causes aborted differentiation and depletion of FA mutant progenitor cells. DNA damage onset most likely arises from formaldehyde, an obligate by-product of oxidative protein demethylation during transcription regulation."
    explanation: Demonstrates that transcriptional reprogramming during differentiation generates formaldehyde-induced DNA damage that specifically depletes FA-deficient progenitors.
  downstream:
  - target: Hematopoietic Stem Cell Attrition
    description: Differentiation-coupled DNA damage depletes progenitors, contributing to HSC pool exhaustion
  - target: Bone Marrow Failure
- name: iPSC-Revealed p53-Driven Progenitor Exhaustion
  description: >-
    Induced pluripotent stem cell modeling of FA hematopoietic differentiation
    revealed that FANCA-deficient human hematopoietic progenitor cells undergo
    accelerated terminal differentiation driven by p53/p21 activation. GAS6
    (growth arrest specific 6) was identified as a novel p53 target gene; GAS6
    signaling modulation rescues hematopoiesis. This iPSC-based new approach
    methodology overcomes the lack of faithful murine FA models and enables
    drug screening for FA therapeutics.
  cell_types:
  - preferred_term: hematopoietic precursor cell
    term:
      id: CL:0008001
      label: hematopoietic precursor cell
  biological_processes:
  - preferred_term: intrinsic apoptotic signaling pathway by p53 class mediator
    term:
      id: GO:0072332
      label: intrinsic apoptotic signaling pathway by p53 class mediator
  evidence:
  - reference: PMID:33002135
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "FANCA-deficient human HPCs underwent accelerated terminal differentiation driven by activation of p53/p21. We identified growth arrest specific 6 (GAS6) as a novel target of activated p53 in FANCA-deficient HPCs and modulate GAS6 signaling to rescue hematopoiesis in FANCA-deficient cells."
    explanation: iPSC-derived FA model reveals p53/p21/GAS6 axis driving progenitor exhaustion and validates GAS6 as a therapeutic target.
  - reference: PMID:33512438
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "disease model iPSCs displayed drastically defective cell expansion when stimulated into hematopoietic differentiation in vitro, displaying increased levels of DNA damage. The expansion defect was partially reversed by treatment with a new small molecule termed C1, which is an agonist of ALDH2"
    explanation: ADH5/ALDH2-deficient iPSCs modeling FA-like aldehyde toxicity confirm hematopoietic differentiation defects and identify ALDH2 agonism as a rescue strategy.
  downstream:
  - target: Hematopoietic Stem Cell Attrition
  - target: Bone Marrow Failure
phenotypes:
- category: Hematologic
  name: Pancytopenia
  description: Progressive decline in all blood cell lineages due to bone marrow failure.
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Decreased levels of red blood cells, white blood cells, and platelets. Over 80% of FA patients develop bone marrow failure. Typically presents in the first decade, often initially with thrombocytopenia or leukopenia. Notably, patients with FANCD1/BRCA2 mutations may not develop BMF. FA-S (biallelic BRCA1) patients also characteristically lack bone marrow failure.
  evidence:
  - reference: PMID:35596788
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Fanconi anemia is a genetic disorder that is characterized by bone marrow failure, as well as a predisposition to malignancies including leukemia and squamous cell carcinoma (SCC).
  phenotype_term:
    preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  phenotype_contexts:
  - notes: Over 80% of FA patients develop bone marrow failure.
    frequency: VERY_FREQUENT
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "82% of the patients developed BMF"
      explanation: Israeli cohort quantifies BMF prevalence at 82%.
  - genetic_context:
      gene:
        preferred_term: FANCD1/BRCA2
        term:
          id: hgnc:1101
          label: BRCA2
      complementation_group: FA-D1
    frequency: EXCLUDED
    notes: >-
      Neither FANCD1/BRCA2 patient in the Israeli cohort developed BMF.
      One was transplanted for AML before age 6 months; the other had
      no complications by age 17.
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "neither of the patients with FANCD1 mutations developed BMF"
      explanation: FANCD1/BRCA2 patients characteristically lack bone marrow failure.
  - genetic_context:
      gene:
        preferred_term: BRCA1
        term:
          id: hgnc:1100
          label: BRCA1
      complementation_group: FA-S
      zygosity: HOMOZYGOUS
    frequency: EXCLUDED
    notes: >-
      FA-S (biallelic BRCA1) patients characteristically lack bone marrow
      failure, distinguishing them from most other FA complementation groups.
    evidence:
    - reference: PMID:38146508
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Unlike most other types of FA, FA-S patients lack bone marrow failure."
      explanation: FA-S defined by absence of BMF despite other FA features.
  - population: Japanese
    notes: >-
      The ALDH2*2 dominant-negative variant (rs671), carried by nearly half
      of the Japanese population, is associated with accelerated BMF
      progression in FA patients. Birth weight and physical abnormalities
      were not affected.
    evidence:
    - reference: PMID:24037726
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the ALDH2 variant is associated with accelerated progression of BMF, while birth weight or the number of physical abnormalities was not affected"
      explanation: ALDH2*2 acts as a genetic modifier accelerating BMF in Japanese FA patients.
- category: Hematologic
  name: Increased Risk of Leukemia
  description: Significantly elevated risk of developing leukemia, predominantly acute myeloid leukemia (AML) with an incidence of 13% by age 50. Acute lymphoblastic leukemia (ALL) also reported, especially in FANCD1/BRCA2 patients.
  frequency: FREQUENT
  notes: The incidence of AML is 13% by age 50 years. Patients with FANCA mutations develop cancer at a significantly older age (mean 18.5 years) compared to non-FANCA groups (mean 5.2 years, P=0.001). Patients with FANCC mutations show a trend toward more MDS. FANCG patients may have less MDS and cancer overall. All FANCA patients in the Israeli cohort developed their first cancer after age 10, while all non-FANCA patients developed cancer by age 10.
  evidence:
  - reference: PMID:24037726
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is characterized by phenotypes including progressive bone marrow failure (BMF), developmental abnormalities, and increased occurrence of leukemia and cancer."
    explanation: Clinical description confirming that increased leukemia occurrence is a defining phenotype of FA.
  phenotype_term:
    preferred_term: Leukemia
    term:
      id: HP:0001909
      label: Leukemia
  phenotype_contexts:
  - genetic_context:
      gene:
        preferred_term: FANCA
        term:
          id: hgnc:3582
          label: FANCA
      complementation_group: FA-A
    onset:
      mean_age_years: 18.5
      min_age_years: 10.0
      notes: All FANCA patients developed cancer after age 10.
    notes: >-
      All FANCA patients in the Israeli cohort developed their first
      cancer after age 10.
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with FANCA mutations developed cancer at a significantly older age compared to patients with mutations in other Fanconi genes (mean 18.5 and 5.2 years, respectively, P=0.001)"
      explanation: FANCA patients have later onset of hematologic malignancy.
  - genetic_context:
      genes:
      - preferred_term: FANCC
        term:
          id: hgnc:3584
          label: FANCC
      - preferred_term: FANCD1/BRCA2
        term:
          id: hgnc:1101
          label: BRCA2
      - preferred_term: FANCG
        term:
          id: hgnc:3588
          label: FANCG
      - preferred_term: FANCJ/BRIP1
        term:
          id: hgnc:20473
          label: BRIP1
      description: >-
        Non-FANCA complementation groups tested in the Israeli cohort
        (FANCC, FANCD1, FANCG, FANCJ). Not exhaustive of all non-FANCA
        groups but represents the specific genes analyzed.
    onset:
      mean_age_years: 5.2
      max_age_years: 10.0
      notes: All non-FANCA patients developed cancer by age 10.
    notes: >-
      All non-FANCA patients in the Israeli cohort developed cancer
      by age 10. FANCC mutations show a trend toward more MDS.
      FANCG patients may have less MDS and cancer overall.
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with FANCA mutations developed cancer at a significantly older age compared to patients with mutations in other Fanconi genes (mean 18.5 and 5.2 years, respectively, P=0.001)"
      explanation: >-
        Same abstract sentence viewed from non-FANCA perspective;
        non-FANCA groups developed cancer significantly earlier
        (mean 5.2 years vs 18.5 years, P=0.001).
  - genetic_context:
      allele_type: nonsense
    notes: >-
      Patients with nonsense mutations developed first cancer at a
      significantly younger age than patients with deletions (P=0.011).
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "patients with nonsense and splice site mutations developed the first cancer at a significantly lower age than patients with deletions (P=0.011 and P=0.012, respectively)"
      explanation: Mutation type affects cancer onset age independent of gene identity.
  - genetic_context:
      allele_type: splice_site
    notes: >-
      Patients with splice site mutations developed first cancer at a
      significantly younger age than patients with deletions (P=0.012).
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "patients with nonsense and splice site mutations developed the first cancer at a significantly lower age than patients with deletions (P=0.011 and P=0.012, respectively)"
      explanation: Splice site mutations associated with earlier cancer onset.
  - genetic_context:
      gene:
        preferred_term: FANCG
        term:
          id: hgnc:3588
          label: FANCG
      complementation_group: FA-G
    notes: >-
      Trend toward less MDS and cancer in patients with FANCG mutations
      compared to other FA genes (not statistically significant).
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "There was a trend towards more MDS in patients with FANCC mutations and less MDS and cancer in patients with FANCG mutations, compared with patients with mutations in other genes (NS)."
      explanation: FANCG mutations may be associated with a milder malignancy phenotype.
- category: Hematologic
  name: Aplastic Anemia
  description: Bone marrow failure resulting in severely reduced production of all blood cell types.
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:24037726
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is characterized by phenotypes including progressive bone marrow failure (BMF), developmental abnormalities, and increased occurrence of leukemia and cancer."
    explanation: Progressive bone marrow failure is a cardinal feature of FA leading to aplastic anemia.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
- category: Hematologic
  name: Thrombocytopenia
  description: Low platelet count due to progressive bone marrow failure in Fanconi anemia.
  frequency: FREQUENT
  notes: Listed in FA clinical screening manifestations and commonly contributes to bleeding risk.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anemia; leukopenia; thrombocytopenia; aplastic anemia; myelodysplastic syndrome"
    explanation: FA guidelines include thrombocytopenia among core bone marrow failure manifestations.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
- category: Hematologic
  name: Leukopenia
  description: Decreased white blood cell count as part of hematopoietic failure in Fanconi anemia.
  frequency: FREQUENT
  notes: Included in the FA screening phenotype table for bone marrow failure manifestations.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anemia; leukopenia; thrombocytopenia; aplastic anemia; myelodysplastic syndrome"
    explanation: FA guidelines include leukopenia as a characteristic hematologic manifestation.
  phenotype_term:
    preferred_term: Decreased total leukocyte count
    term:
      id: HP:0001882
      label: Decreased total leukocyte count
- category: Developmental
  name: Short Stature
  description: Growth deficiency present from birth, affecting approximately 60% of patients.
  frequency: FREQUENT
  notes: In the Israeli cohort, 57% met criteria for short stature. Patients with downstream FA gene mutations (FANCD1, FANCJ) were significantly shorter than core complex patients (P=0.003). Patients with deletion mutations were shorter than those with nonsense mutations (P=0.018). Contributing factors include GH deficiency, hypothyroidism, and constitutional factors.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies."
    explanation: GeneReviews confirms short stature as one of the common physical abnormalities in FA.
  phenotype_term:
    preferred_term: Short Stature
    term:
      id: HP:0004322
      label: Short stature
  phenotype_contexts:
  - notes: 57% met criteria for short stature in the Israeli cohort (n=111).
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "57% fit criteria for short stature"
      explanation: Quantitative frequency data from Israeli FA cohort of 111 patients.
  - genetic_context:
      genes:
      - preferred_term: FANCD1/BRCA2
        term:
          id: hgnc:1101
          label: BRCA2
      - preferred_term: FANCJ/BRIP1
        term:
          id: hgnc:20473
          label: BRIP1
      description: Downstream FA pathway genes
    severity: More severe
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with mutations in the downstream genes FANCD1 and FANCJ were significantly shorter compared with the others (P=0.003)"
      explanation: Downstream pathway gene mutations associated with more severe growth deficiency.
  - genetic_context:
      allele_type: deletion
    severity: More severe
    notes: Deletion mutations associated with shorter stature than nonsense mutations.
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with deletions were shorter than patients with nonsense mutations (P=0.018)"
      explanation: Mutation type affects severity of growth phenotype.
- category: Skeletal
  name: Skeletal Anomalies
  description: Upper limb malformations including absent or hypoplastic thumbs, radial ray defects, and hip abnormalities.
  frequency: FREQUENT
  notes: Includes areas such as the radius, thumb, and hips
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies"
  phenotype_term:
    preferred_term: Skeletal Anomalies
    term:
      id: HP:0005775
      label: Multiple skeletal anomalies
  phenotype_contexts:
  - genetic_context:
      gene:
        preferred_term: FANCC
        term:
          id: hgnc:3584
          label: FANCC
      complementation_group: FA-C
    notes: >-
      Rib abnormalities were observed only in patients with FANCC
      mutations in the Israeli cohort — exclusive to this complementation
      group.
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Rib abnormalities were observed only in patients with FANCC mutations."
      explanation: FANCC-exclusive rib anomaly pattern.
  - genetic_context:
      gene:
        preferred_term: FANCD1/BRCA2
        term:
          id: hgnc:1101
          label: BRCA2
      complementation_group: FA-D1
    notes: >-
      Cleft lip was significantly more common in patients with FANCD1
      mutations compared with other FA genes (P<0.001).
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cleft lip was more common in patients with FANCD1 mutations, compared with other FA genes (P<0.001)."
      explanation: FANCD1/BRCA2 specifically enriched for cleft lip.
  - genetic_context:
      gene:
        preferred_term: FANCB
        term:
          id: hgnc:3583
          label: FANCB
      complementation_group: FA-B
      allele_type: truncating
    severity: Severe
    notes: >-
      FANCB deletion or truncation variants produce earlier-than-average onset
      of bone marrow failure and more severe congenital abnormalities. Missense
      variants with residual FANCD2 monoubiquitination activity are associated
      with more favorable outcome. FANCB is X-linked, so only males are affected.
    evidence:
    - reference: PMID:32106311
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Those with FANCB deletion or truncation demonstrate earlier-than-average onset of bone marrow failure and more severe congenital abnormalities compared with a large series of FA individuals in published reports."
      explanation: Jung et al. 19-child FANCB cohort shows truncating variants produce severe congenital abnormality phenotype.
  - genetic_context:
      gene:
        preferred_term: FANCI
        term:
          id: hgnc:25568
          label: FANCI
      complementation_group: FA-I
    notes: >-
      44% of FA patients with FANCI mutations (7/16) met criteria for VACTERL
      association (at least 3 features), significantly overrepresented compared
      to ~5% in FA overall.
    evidence:
    - reference: PMID:26590883
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "There are now 16 reported cases of FA due to FANCI of whom 7 have at least 3 features of the VACTERL association (44%)."
      explanation: FANCI mutations are disproportionately associated with VACTERL phenotype in FA.
- category: Dermatologic
  name: Café-au-Lait Spots
  description: Hyperpigmented skin macules commonly seen in FA patients.
  frequency: FREQUENT
  notes: One of the abnormal skin pigmentation findings in FA
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies"
    explanation: Abnormal skin pigmentation, including café-au-lait spots, is among the physical abnormalities present in ~75% of FA patients.
  phenotype_term:
    preferred_term: Café-au-lait Spot
    term:
      id: HP:0000957
      label: Cafe-au-lait spot
  phenotype_contexts:
  - frequency: FREQUENT
    notes: 52.3% of patients in the Israeli cohort had café-au-lait spots, the most common congenital anomaly.
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "More than half had café-au-lait spots (52.3%) followed by renal anomalies (39.6%)."
      explanation: Quantitative frequency from Israeli FA cohort (n=111).
- category: Oncologic
  name: Squamous Cell Carcinoma
  description: Markedly increased risk of early-onset squamous cell carcinomas, particularly of the head and neck, oral cavity, esophagus, and anogenital regions.
  frequency: FREQUENT
  notes: Cancer surveillance is critical due to genomic instability and persistent epithelial cancer risk. Solid tumors in the Israeli cohort appeared at a mean age of 26.6 years, significantly later than MDS/leukemia. All solid tumors in that cohort were in patients with FANCA mutations or undiagnosed patients. HPV vaccination is recommended to reduce risk. Oral examination every 6 months from age 9-10 years and annual nasolaryngoscopy from age 10 years are recommended.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA."
    explanation: GeneReviews confirms elevated risk of solid tumors including head/neck and skin squamous cell carcinomas.
  phenotype_term:
    preferred_term: Squamous cell carcinoma
    term:
      id: HP:0002860
      label: Squamous cell carcinoma
  phenotype_contexts:
  - onset:
      mean_age_years: 26.6
      notes: Solid tumors appear significantly later than hematologic malignancies.
    notes: >-
      All solid tumors in the Israeli cohort were in patients with FANCA
      mutations or undiagnosed patients. Mean age of solid tumor onset
      was 26.6 years, significantly later than MDS/leukemia.
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "for solid tumors 26.6 years (SD 4.9)"
      explanation: Mean solid tumor onset at 26.6 years, significantly later than MDS (13.3y) and leukemia (10.8y).
  - sex: FEMALE
    notes: >-
      Female FA patients have elevated risk of gynecologic squamous cell
      carcinomas (vulvar, cervical) at young ages. HPV vaccination is
      recommended. Gynecologic assessment annually from age 13; Pap smear
      annually from age 18.
    evidence:
    - reference: PMID:20301575
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Human papilloma virus (HPV) vaccination to reduce the risk for gynecologic cancer in females"
      explanation: GeneReviews specifically highlights gynecologic cancer risk in female FA patients and recommends HPV vaccination.
  - genetic_context:
      gene:
        preferred_term: BRCA1
        term:
          id: hgnc:1100
          label: BRCA1
      complementation_group: FA-S
      zygosity: HOMOZYGOUS
    notes: >-
      FA-S (biallelic BRCA1) patients have predisposition to breast/ovarian
      cancer and/or childhood cancers, distinct from the typical FA SCC
      spectrum.
    evidence:
    - reference: PMID:38146508
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "predisposition to breast/ovarian cancer and/or childhood cancers"
      explanation: FA-S cancer spectrum includes breast/ovarian cancer rather than the typical SCC pattern.
- category: Gastrointestinal
  name: Structural Anomalies
  description: Congenital malformations of the gastrointestinal tract.
  frequency: OCCASIONAL
  notes: Includes esophageal atresia, duodenal atresia, and other malformations
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical abnormalities, present in approximately 75% of affected individuals"
    explanation: GeneReviews confirms congenital abnormalities are present in ~75% of FA patients.
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Atresias: esophageal, duodenal, jejunal"
    explanation: FA guidelines list GI atresias as part of the congenital anomaly spectrum used for FA screening.
- category: Gastrointestinal
  name: Esophageal Atresia
  description: Congenital interruption of the esophagus reported among Fanconi anemia gastrointestinal manifestations.
  frequency: OCCASIONAL
  notes: Included in the FA guideline atresia spectrum used for diagnostic screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Atresias: esophageal, duodenal, jejunal"
    explanation: FA guidelines explicitly list esophageal atresia among congenital gastrointestinal findings.
  phenotype_term:
    preferred_term: Esophageal atresia
    term:
      id: HP:0002032
      label: Esophageal atresia
- category: Gastrointestinal
  name: Duodenal Atresia
  description: Congenital obstruction of the duodenum reported among Fanconi anemia gastrointestinal manifestations.
  frequency: OCCASIONAL
  notes: Included in the FA guideline atresia spectrum used for diagnostic screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Atresias: esophageal, duodenal, jejunal"
    explanation: FA guidelines explicitly include duodenal atresia among congenital gastrointestinal findings.
  phenotype_term:
    preferred_term: Duodenal atresia
    term:
      id: HP:0002247
      label: Duodenal atresia
- category: Gastrointestinal
  name: Jejunal Atresia
  description: Congenital jejunal occlusion reported among Fanconi anemia gastrointestinal manifestations.
  frequency: OCCASIONAL
  notes: Included in the FA guideline atresia spectrum used for diagnostic screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Atresias: esophageal, duodenal, jejunal"
    explanation: FA guidelines explicitly list jejunal atresia among congenital gastrointestinal abnormalities.
  phenotype_term:
    preferred_term: Jejunal atresia
    term:
      id: HP:0005235
      label: Jejunal atresia
- category: Gastrointestinal
  name: Anal Atresia
  description: Congenital anorectal malformation reported in Fanconi anemia screening manifestations.
  frequency: OCCASIONAL
  notes: Included in FA guideline diagnostic manifestations as imperforate or bifurcated anus.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anal malformations: imperforate or bifurcated anus"
    explanation: FA guidelines list anal malformations among congenital features prompting FA screening.
  phenotype_term:
    preferred_term: Anal atresia
    term:
      id: HP:0002023
      label: Anal atresia
- category: Gastrointestinal
  name: Intestinal Malrotation
  description: Congenital abnormal rotation/fixation of the intestine occurring in a subset of FA patients.
  frequency: OCCASIONAL
  notes: Included in FA guideline gastrointestinal screening manifestations.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intestinal malrotation"
    explanation: FA guidelines include intestinal malrotation in the congenital GI anomaly spectrum.
  phenotype_term:
    preferred_term: Intestinal malrotation
    term:
      id: HP:0002566
      label: Intestinal malrotation
- category: Gastrointestinal
  name: Annular Pancreas
  description: Congenital ring of pancreatic tissue encircling the duodenum, reported among FA screening manifestations.
  frequency: OCCASIONAL
  notes: Listed in the FA guideline gastrointestinal anomaly table.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Annular pancreas"
    explanation: FA guidelines include annular pancreas among congenital gastrointestinal findings that should trigger FA evaluation.
  phenotype_term:
    preferred_term: Annular pancreas
    term:
      id: HP:0001734
      label: Annular pancreas
- category: Gastrointestinal
  name: Tracheoesophageal Fistula
  description: Congenital fistulous connection between trachea and esophagus in a subset of FA patients.
  frequency: OCCASIONAL
  notes: Included as a diagnostic screening manifestation in FA clinical care guidelines.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tracheoesophageal fistula"
    explanation: FA guidelines list tracheoesophageal fistula within gastrointestinal congenital anomalies.
  phenotype_term:
    preferred_term: Tracheoesophageal fistula
    term:
      id: HP:0002575
      label: Tracheoesophageal fistula
- category: Reproductive
  name: Genitourinary Malformations
  description: Congenital abnormalities of the kidneys and reproductive organs.
  frequency: OCCASIONAL
  notes: Genitourinary anomalies were significantly more common in patients with downstream FA gene mutations (FANCD1, FANCJ) compared to core complex mutations (P=0.03) in the Israeli cohort.
  phenotype_term:
    preferred_term: Genitourinary Abnormality
    term:
      id: HP:0000119
      label: Abnormality of the genitourinary system
  phenotype_contexts:
  - genetic_context:
      genes:
      - preferred_term: FANCD1/BRCA2
        term:
          id: hgnc:1101
          label: BRCA2
      - preferred_term: FANCJ/BRIP1
        term:
          id: hgnc:20473
          label: BRIP1
      description: Downstream FA pathway genes
    frequency: FREQUENT
    notes: >-
      Genitourinary anomalies were significantly more common in patients
      with downstream FA gene mutations compared to core complex mutations
      (P=0.03).
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with downstream mutations were found to have significantly more skull anomalies (P<0.001), central nervous system (CNS) abnormalities (P=0.005) and genitourinary anomalies (P=0.03), compared with patients with core complex mutations."
      explanation: Downstream FA pathway mutations enriched for genitourinary anomalies.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies"
- category: Neurologic
  name: Microcephaly
  description: Abnormally small head circumference, present in a subset of FA patients as part of congenital anomalies.
  frequency: OCCASIONAL
  notes: Part of the congenital anomaly spectrum. Skull anomalies were significantly more common in patients with downstream FA gene mutations (FANCD1, FANCJ) compared to core complex mutations (P<0.001). FA-S (biallelic BRCA1) patients also frequently present with microcephaly.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies"
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  phenotype_contexts:
  - genetic_context:
      genes:
      - preferred_term: FANCD1/BRCA2
        term:
          id: hgnc:1101
          label: BRCA2
      - preferred_term: FANCJ/BRIP1
        term:
          id: hgnc:20473
          label: BRIP1
      description: Downstream FA pathway genes
    frequency: VERY_FREQUENT
    notes: >-
      Skull anomalies were significantly more common in patients
      with downstream FA gene mutations compared to core complex
      mutations (P<0.001).
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with downstream mutations were found to have significantly more skull anomalies (P<0.001), central nervous system (CNS) abnormalities (P=0.005) and genitourinary anomalies (P=0.03), compared with patients with core complex mutations."
      explanation: Downstream pathway mutations associated with significantly more skull anomalies including microcephaly.
  - genetic_context:
      gene:
        preferred_term: BRCA1
        term:
          id: hgnc:1100
          label: BRCA1
      complementation_group: FA-S
      zygosity: HOMOZYGOUS
    frequency: VERY_FREQUENT
    notes: FA-S (biallelic BRCA1) patients frequently present with microcephaly.
    evidence:
    - reference: PMID:38146508
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "this FA-S cohort phenotype includes short stature, microcephaly, facial dysmorphisms"
      explanation: Microcephaly is a characteristic feature of the FA-S phenotype.
  - frequency: VERY_FREQUENT
    notes: >-
      90% of FA patients (18/20) had brain MRI abnormalities including small
      pituitary (68%), posterior fossa abnormalities (30%), and corpus callosum
      structural variation (30%). The high incidence of midline CNS anomalies
      points to impact in early stages of CNS development.
    evidence:
    - reference: PMID:26369989
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Abnormalities were identified in 18 (90%) patients with FA, the commonest being a small pituitary (68%, p < 0.01 females and p < 0.001 males)"
      explanation: Stivaros et al. found 90% of FA patients have brain MRI abnormalities, much higher than previously recognized.
- category: Neurologic
  name: Anterior Pituitary Hypoplasia
  description: Small anterior pituitary as part of the central nervous system anomaly spectrum in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in FA guideline CNS screening manifestations as small pituitary/stalk anomalies.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Small pituitary and stalk interruption; agenesis of corpus callosum; cerebellar hypoplasia; hydrocephalus ; dilated ventricles; developmental delay"
    explanation: FA guidelines include small pituitary as a CNS manifestation prompting FA screening.
  phenotype_term:
    preferred_term: Anterior pituitary hypoplasia
    term:
      id: HP:0010627
      label: Anterior pituitary hypoplasia
- category: Neurologic
  name: Interrupted Pituitary Stalk
  description: Interruption of the pituitary stalk reported among central nervous system manifestations in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in FA guideline CNS screening manifestations as stalk interruption.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Small pituitary and stalk interruption; agenesis of corpus callosum; cerebellar hypoplasia; hydrocephalus ; dilated ventricles; developmental delay"
    explanation: FA guidelines explicitly include pituitary stalk interruption among CNS abnormalities.
  phenotype_term:
    preferred_term: Interrupted pituitary stalk
    term:
      id: HP:0034978
      label: Interrupted pituitary stalk
- category: Developmental
  name: Micrognathia
  description: Congenital mandibular hypoplasia reported within the facial anomaly spectrum of Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in the FA guideline facial manifestations that should raise suspicion for FA.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Facial FA facies; triangular face; micrognathia; pointed chin; mid -face hypoplasia; facial nerve palsy; microsomia; hypertelorism; hypotelorism; cleft palate"
    explanation: FA guidelines explicitly list micrognathia among facial abnormalities in the screening table.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
- category: Developmental
  name: Cleft Palate
  description: Orofacial clefting reported as part of the congenital facial phenotype in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Listed in FA guideline facial manifestations used for diagnostic screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Facial FA facies; triangular face; micrognathia; pointed chin; mid -face hypoplasia; facial nerve palsy; microsomia; hypertelorism; hypotelorism; cleft palate"
    explanation: FA guidelines include cleft palate in the facial anomaly spectrum.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
- category: Developmental
  name: Triangular Face
  description: Triangular facial shape reported among congenital facial manifestations in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in FA guideline facial manifestations used for diagnostic screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Facial FA facies; triangular face; micrognathia; pointed chin; mid -face hypoplasia; facial nerve palsy; microsomia; hypertelorism; hypotelorism; cleft palate"
    explanation: FA guidelines list triangular face among characteristic facial findings.
  phenotype_term:
    preferred_term: Triangular face
    term:
      id: HP:0000325
      label: Triangular face
- category: Developmental
  name: Midface Retrusion
  description: Retruded or hypoplastic midface reported among congenital facial manifestations in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in FA guideline facial manifestations as mid-face hypoplasia.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Facial FA facies; triangular face; micrognathia; pointed chin; mid -face hypoplasia; facial nerve palsy; microsomia; hypertelorism; hypotelorism; cleft palate"
    explanation: FA guidelines include mid-face hypoplasia among facial abnormalities.
  phenotype_term:
    preferred_term: Midface retrusion
    term:
      id: HP:0011800
      label: Midface retrusion
- category: Developmental
  name: Pointed Chin
  description: Pointed chin morphology reported among congenital facial manifestations in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in FA guideline facial manifestations used for diagnostic screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Facial FA facies; triangular face; micrognathia; pointed chin; mid -face hypoplasia; facial nerve palsy; microsomia; hypertelorism; hypotelorism; cleft palate"
    explanation: FA guidelines list pointed chin among characteristic facial findings.
  phenotype_term:
    preferred_term: Pointed chin
    term:
      id: HP:0000307
      label: Pointed chin
- category: Developmental
  name: Facial Palsy
  description: Congenital facial nerve weakness or palsy reported among facial manifestations in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in FA guideline facial manifestations used for diagnostic screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Facial FA facies; triangular face; micrognathia; pointed chin; mid -face hypoplasia; facial nerve palsy; microsomia; hypertelorism; hypotelorism; cleft palate"
    explanation: FA guidelines explicitly include facial nerve palsy among congenital facial abnormalities.
  phenotype_term:
    preferred_term: Facial palsy
    term:
      id: HP:0010628
      label: Facial palsy
- category: Developmental
  name: Hypertelorism
  description: Increased interpupillary and/or interorbital distance reported among facial anomalies in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in FA guideline facial manifestations used for diagnostic screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Facial FA facies; triangular face; micrognathia; pointed chin; mid -face hypoplasia; facial nerve palsy; microsomia; hypertelorism; hypotelorism; cleft palate"
    explanation: FA guidelines list hypertelorism within the congenital facial anomaly spectrum.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
- category: Developmental
  name: Hypotelorism
  description: Decreased interpupillary and/or interorbital distance reported among facial anomalies in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in FA guideline facial manifestations used for diagnostic screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Facial FA facies; triangular face; micrognathia; pointed chin; mid -face hypoplasia; facial nerve palsy; microsomia; hypertelorism; hypotelorism; cleft palate"
    explanation: FA guidelines include hypotelorism among listed facial abnormalities.
  phenotype_term:
    preferred_term: Hypotelorism
    term:
      id: HP:0000601
      label: Hypotelorism
- category: Neurologic
  name: Agenesis of Corpus Callosum
  description: Absence of corpus callosum as part of the CNS developmental anomaly spectrum in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Listed in FA guideline CNS screening manifestations.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "agenesis of corpus callosum"
    explanation: FA guidelines include corpus callosum agenesis among central nervous system anomalies.
  phenotype_term:
    preferred_term: Agenesis of corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
- category: Neurologic
  name: Cerebellar Hypoplasia
  description: Underdevelopment of the cerebellum reported among FA central nervous system anomalies.
  frequency: OCCASIONAL
  notes: Included in FA guideline CNS screening manifestations.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cerebellar hypoplasia"
    explanation: FA guidelines list cerebellar hypoplasia among central nervous system abnormalities.
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
- category: Skeletal
  name: Radial Ray Defects
  description: Upper limb malformations affecting the radius and thumb, including hypoplasia or aplasia of the radius and thumb abnormalities.
  frequency: FREQUENT
  notes: Common skeletal manifestation in FA; can include absent or hypoplastic thumbs
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skeletal malformations of the upper and/or lower limbs"
    explanation: GeneReviews confirms upper limb skeletal malformations as a common feature of FA.
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radius: absent, hypoplastic"
    explanation: FA guidelines enumerate radial hypoplasia/aplasia among screening manifestations.
  phenotype_term:
    preferred_term: Hypoplasia of the radius
    term:
      id: HP:0002984
      label: Hypoplasia of the radius
- category: Skeletal
  name: Absent or Hypoplastic Thumbs
  description: Absent thumbs, hypoplastic thumbs, or supernumerary thumbs are common upper limb anomalies in FA, frequently accompanied by radial ray defects.
  frequency: FREQUENT
  notes: Part of the radial ray anomaly spectrum. More prevalent in core complex complementation groups (FANCA, FANCC, FANCG). The VACTERL phenotype is overrepresented in FA complementation groups D1, E, and F.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skeletal malformations of the upper and/or lower limbs"
    explanation: GeneReviews confirms upper limb skeletal malformations as common in FA.
  - reference: PMID:16015582
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all have radial ray anomalies and 12 of these 13 subjects show at least 1 other feature of FA"
    explanation: In FA patients with VACTERL phenotype, all had radial ray anomalies including thumb abnormalities.
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thumb: absent, hypoplastic, triphalangeal, polydactyly"
    explanation: FA guidelines list thumb malformation subtypes as characteristic upper-limb findings.
  phenotype_term:
    preferred_term: Absent thumb
    term:
      id: HP:0009777
      label: Absent thumb
- category: Skeletal
  name: Small Thenar Eminence
  description: Hypoplastic or absent thenar eminence as part of the upper-limb anomaly spectrum in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in the FA guideline upper-limb diagnostic manifestations.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thenar-eminence: hypoplastic, absent"
    explanation: FA guidelines list thenar eminence hypoplasia or absence among characteristic upper-limb abnormalities.
  phenotype_term:
    preferred_term: Small thenar eminence
    term:
      id: HP:0001245
      label: Small thenar eminence
- category: Skeletal
  name: First Metacarpal Aplasia or Hypoplasia
  description: Absent or hypoplastic first metacarpal reported among upper-limb manifestations in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in the FA guideline upper-limb diagnostic manifestations.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Others: absent first metacarpal, clinodactyly"
    explanation: FA guidelines explicitly include absent first metacarpal among upper-limb anomalies.
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia of the 1st metacarpal
    term:
      id: HP:0010026
      label: Aplasia/Hypoplasia of the 1st metacarpal
- category: Skeletal
  name: Clinodactyly
  description: Curvature deformity of digits reported among upper-limb anomalies in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in the FA guideline upper-limb diagnostic manifestations.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Others: absent first metacarpal, clinodactyly"
    explanation: FA guidelines list clinodactyly in the upper-limb anomaly profile.
  phenotype_term:
    preferred_term: Clinodactyly
    term:
      id: HP:0030084
      label: Clinodactyly
- category: Skeletal
  name: Ulnar Aplasia or Hypoplasia
  description: Short or dysplastic ulna as part of the upper-limb congenital anomaly spectrum in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in the FA guideline upper-limb diagnostic manifestations.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ulna: short, dysplastic"
    explanation: FA guidelines list short and dysplastic ulna among characteristic upper-limb findings.
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia of the ulna
    term:
      id: HP:0006495
      label: Aplasia/Hypoplasia of the ulna
- category: Skeletal
  name: Hip Dysplasia
  description: Congenital hip dislocation or dysplasia reported among lower-limb anomalies in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in the FA guideline lower-limb diagnostic manifestations.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lower limb Hips: congenital dislocation/dysplasia, malrotation"
    explanation: FA guidelines include congenital hip dislocation or dysplasia among lower-limb abnormalities.
  phenotype_term:
    preferred_term: Hip dysplasia
    term:
      id: HP:0001385
      label: Hip dysplasia
- category: Skeletal
  name: Hemivertebrae
  description: Vertebral segmentation defect present in a subset of FA patients.
  frequency: OCCASIONAL
  notes: Included within vertebral anomalies listed in FA diagnostic manifestation tables.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hemivertebrae; Klippel -Feil; scoliosis; kyphosis"
    explanation: FA guidelines enumerate hemivertebrae and related spinal anomalies as part of vertebral involvement.
  phenotype_term:
    preferred_term: Hemivertebrae
    term:
      id: HP:0002937
      label: Hemivertebrae
- category: Skeletal
  name: Scoliosis
  description: Abnormal lateral curvature of the spine reported among vertebral manifestations in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in the FA guideline vertebral anomaly manifestations.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Web, hemivertebrae; Klippel -Feil; scoliosis; kyphosis; coccygeal apl asia"
    explanation: FA guidelines list scoliosis among vertebral abnormalities in the screening table.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
- category: Skeletal
  name: Kyphosis
  description: Excessive posterior spinal curvature reported among vertebral anomalies in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in the FA guideline vertebral anomaly manifestations.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Web, hemivertebrae; Klippel -Feil; scoliosis; kyphosis; coccygeal apl asia"
    explanation: FA guidelines list kyphosis among vertebral abnormalities in the screening table.
  phenotype_term:
    preferred_term: Kyphosis
    term:
      id: HP:0002808
      label: Kyphosis
- category: Skeletal
  name: Fused Cervical Vertebrae
  description: Cervical vertebral fusion consistent with Klippel-Feil pattern reported among vertebral anomalies in Fanconi anemia.
  frequency: OCCASIONAL
  notes: FA guideline vertebral manifestations list Klippel-Feil among spinal findings.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Web, hemivertebrae; Klippel -Feil; scoliosis; kyphosis; coccygeal apl asia"
    explanation: FA guidelines include Klippel-Feil in vertebral abnormalities, represented by fused cervical vertebrae.
  phenotype_term:
    preferred_term: Fused cervical vertebrae
    term:
      id: HP:0002949
      label: Fused cervical vertebrae
- category: Skeletal
  name: Absent or Hypoplastic Coccyx
  description: Coccygeal aplasia or hypoplasia reported among vertebral anomalies in Fanconi anemia.
  frequency: OCCASIONAL
  notes: FA guideline vertebral manifestations include coccygeal aplasia.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Web, hemivertebrae; Klippel -Feil; scoliosis; kyphosis; coccygeal apl asia"
    explanation: FA guidelines include coccygeal aplasia in the vertebral anomaly profile.
  phenotype_term:
    preferred_term: Absent/hypoplastic coccyx
    term:
      id: HP:0008436
      label: Absent/hypoplastic coccyx
- category: Skeletal
  name: Toe Syndactyly
  description: Congenital fusion of toes reported as part of lower-limb anomalies in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in FA guideline lower-limb manifestations.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Feet: toe syndactyly, abnormal toes, club feet"
    explanation: FA guidelines explicitly include toe syndactyly among lower-limb anomalies.
  phenotype_term:
    preferred_term: Toe syndactyly
    term:
      id: HP:0001770
      label: Toe syndactyly
- category: Skeletal
  name: Clubfoot
  description: Congenital foot deformity listed among lower-limb manifestations in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in FA guideline lower-limb manifestations as club feet.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Feet: toe syndactyly, abnormal toes, club feet"
    explanation: FA guidelines include club feet among lower-limb findings used in FA screening.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
- category: Skeletal
  name: Abnormal Toe Morphology
  description: Structural toe abnormalities reported among lower-limb manifestations in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in FA guideline lower-limb manifestations as abnormal toes.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Feet: toe syndactyly, abnormal toes, club feet"
    explanation: FA guidelines explicitly list abnormal toes among lower-limb anomalies.
  phenotype_term:
    preferred_term: Abnormal toe morphology
    term:
      id: HP:0001780
      label: Abnormal toe morphology
- category: Ophthalmologic
  name: Microphthalmia
  description: Abnormally small eyes, part of the spectrum of ophthalmic anomalies seen in FA patients.
  frequency: OCCASIONAL
  notes: Ophthalmic anomalies are listed among the congenital features present in approximately 75% of FA patients. Microphthalmia may be more common in patients with higher congenital abnormality burden scores.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ophthalmic and genitourinary tract anomalies"
    explanation: GeneReviews lists ophthalmic anomalies including microphthalmia among FA congenital features.
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
- category: Ophthalmologic
  name: Strabismus
  description: Misalignment of the eyes, a relatively common ophthalmic finding in FA patients.
  frequency: OCCASIONAL
  notes: Part of the ophthalmic anomaly spectrum in FA.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ophthalmic and genitourinary tract anomalies"
    explanation: GeneReviews lists ophthalmic anomalies as part of the FA congenital phenotype spectrum.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
- category: Ophthalmologic
  name: Epicanthus
  description: Medial canthal skin fold reported among ocular manifestations in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in FA guideline eye manifestations used for diagnostic screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eyes Microphthalmia; epicanthal folds; almond -shaped fissures; ptosis; strabismus; cataracts"
    explanation: FA guidelines list epicanthal folds as part of the ophthalmic phenotype spectrum.
  phenotype_term:
    preferred_term: Epicanthus
    term:
      id: HP:0000286
      label: Epicanthus
- category: Ophthalmologic
  name: Almond-Shaped Palpebral Fissures
  description: Almond-shaped eye fissures reported among ocular manifestations in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in FA guideline eye manifestations used for diagnostic screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eyes Microphthalmia; epicanthal folds; almond -shaped fissures; ptosis; strabismus; cataracts"
    explanation: FA guidelines list almond-shaped fissures in the ophthalmic manifestation profile.
  phenotype_term:
    preferred_term: Almond-shaped palpebral fissure
    term:
      id: HP:0007874
      label: Almond-shaped palpebral fissure
- category: Ophthalmologic
  name: Cataract
  description: Lens opacity reported among ophthalmic anomalies in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in the FA guideline diagnostic manifestation table under eye abnormalities.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microphthalmia; epicanthal folds; almond -shaped fissures; ptosis; strabismus; cataracts"
    explanation: FA guidelines enumerate cataracts among ocular manifestations associated with FA.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
- category: Ophthalmologic
  name: Ptosis
  description: Drooping upper eyelid reported among ophthalmic manifestations of Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in FA guideline eye-abnormality screening manifestations.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ptosis"
    explanation: FA guidelines list ptosis among ocular abnormalities associated with FA.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
- category: Cardiac
  name: Congenital Heart Defects
  description: Structural heart anomalies including ventricular septal defects, atrial septal defects, patent ductus arteriosus, and other cardiac malformations.
  frequency: OCCASIONAL
  notes: Part of the VACTERL association overlap with FA. Heart abnormalities contribute to the congenital abnormality burden score (CABS). Patients with missense mutations had significantly less congenital heart disease (P=0.022) in the Israeli cohort. Downstream FA genes (FANCD1, FANCJ) may be associated with more severe congenital anomalies.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of growth deficiency, limb anomalies, ocular anomalies, renal malformations, genital anomalies, hypothyroidism, cardiac anomalies, and dermatologic manifestations as recommended by the subspecialty care provider."
    explanation: GeneReviews lists cardiac anomalies as part of the FA clinical spectrum requiring subspecialty management.
  - reference: PMID:31558676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with missense mutations had significantly less congenital heart disease (P=0.022)."
    explanation: Israeli cohort study found genotype-phenotype correlation for cardiac defects and mutation type.
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patent ductus arteriosus; atrial septal defect; ventri cular septal defect; coarctation; situs inversus; truncus arteriosus"
    explanation: FA guidelines enumerate specific congenital heart defects within the diagnostic manifestation table.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  phenotype_contexts:
  - genetic_context:
      allele_type: missense
    frequency: OCCASIONAL
    notes: >-
      Missense mutations associated with significantly less congenital
      heart disease (P=0.022) in the Israeli cohort.
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with missense mutations had significantly less congenital heart disease (P=0.022)."
      explanation: Missense mutations are protective relative to other mutation types for cardiac defects.
- category: Cardiac
  name: Patent Ductus Arteriosus
  description: Persistent patency of the ductus arteriosus reported among congenital cardiac anomalies in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Listed in FA guideline cardiac manifestations used for FA screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patent ductus arteriosus; atrial septal defect; ventri cular septal defect; coarctation; situs inversus; truncus arteriosus"
    explanation: FA guidelines explicitly enumerate patent ductus arteriosus in the cardiac anomaly list.
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
- category: Cardiac
  name: Atrial Septal Defect
  description: Congenital interatrial septal defect included in the Fanconi anemia cardiac phenotype spectrum.
  frequency: OCCASIONAL
  notes: Listed in FA guideline cardiac manifestations used for FA screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patent ductus arteriosus; atrial septal defect; ventri cular septal defect; coarctation; situs inversus; truncus arteriosus"
    explanation: FA guidelines list atrial septal defect among congenital cardiac anomalies.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
- category: Cardiac
  name: Ventricular Septal Defect
  description: Congenital interventricular septal defect included in the Fanconi anemia cardiac anomaly spectrum.
  frequency: OCCASIONAL
  notes: Listed in FA guideline cardiac manifestations used for FA screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patent ductus arteriosus; atrial septal defect; ventri cular septal defect; coarctation; situs inversus; truncus arteriosus"
    explanation: FA guidelines include ventricular septal defect among congenital heart findings.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
- category: Cardiac
  name: Coarctation of Aorta
  description: Congenital narrowing of the aorta reported in Fanconi anemia cardiac manifestations.
  frequency: OCCASIONAL
  notes: Listed in FA guideline cardiac manifestations used for FA screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patent ductus arteriosus; atrial septal defect; ventri cular septal defect; coarctation; situs inversus; truncus arteriosus"
    explanation: FA guidelines list coarctation among congenital cardiovascular defects.
  phenotype_term:
    preferred_term: Coarctation of aorta
    term:
      id: HP:0001680
      label: Coarctation of aorta
- category: Cardiac
  name: Truncus Arteriosus
  description: Persistent common arterial trunk reported among congenital cardiac manifestations in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Listed in FA guideline cardiac manifestations used for FA screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patent ductus arteriosus; atrial septal defect; ventri cular septal defect; coarctation; situs inversus; truncus arteriosus"
    explanation: FA guidelines include truncus arteriosus among congenital cardiac anomalies.
  phenotype_term:
    preferred_term: Truncus arteriosus
    term:
      id: HP:0001660
      label: Truncus arteriosus
- category: Cardiac
  name: Situs Inversus
  description: Reversal of thoracoabdominal organ laterality reported among FA-associated congenital cardiovascular anomalies.
  frequency: OCCASIONAL
  notes: Listed in FA guideline cardiac manifestations used for FA screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patent ductus arteriosus; atrial septal defect; ventri cular septal defect; coarctation; situs inversus; truncus arteriosus"
    explanation: FA guidelines list situs inversus in the congenital cardiac manifestation table.
  phenotype_term:
    preferred_term: Situs inversus totalis
    term:
      id: HP:0001696
      label: Situs inversus totalis
- category: Audiologic
  name: Hearing Loss
  description: Conductive and/or sensorineural hearing loss, often associated with external ear anomalies or middle ear malformations.
  frequency: OCCASIONAL
  notes: In the Israeli FA cohort, 18% of patients had hearing loss, all with a conductive component. Hearing loss contributes to the congenital abnormality burden score (CABS). Hearing aids may be helpful per otolaryngology evaluation.
  evidence:
  - reference: PMID:31558676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 18% of the patients with hearing loss, all had a conductive component"
    explanation: Israeli cohort documents 18% hearing loss prevalence with conductive component in FA patients.
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing aids may be helpful for hearing loss as per otolaryngologist"
    explanation: GeneReviews recommends hearing evaluation and hearing aids as part of FA management.
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of hearing loss and congenital ear malformation is much higher in patients with FA than previously reported"
    explanation: Fanconi Anemia Clinical Care Guidelines report hearing-loss prevalence and associated congenital ear anomalies.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
- category: Audiologic
  name: Abnormal Pinna Morphology
  description: Congenital pinna malformations reported in Fanconi anemia with structural ear abnormalities.
  frequency: OCCASIONAL
  notes: Included in FA guideline otologic manifestations and supported by dedicated ear-phenotype sections.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Otology Hearing loss (conductive, sensorineural, or mixed); abnormal pinna; atretic,"
    explanation: FA guidelines list abnormal pinna as part of otologic manifestations.
  phenotype_term:
    preferred_term: Abnormal pinna morphology
    term:
      id: HP:0000377
      label: Abnormal pinna morphology
- category: Audiologic
  name: External Auditory Canal Atresia
  description: Congenital absence or atresia of the external auditory canal in a subset of Fanconi anemia patients.
  frequency: OCCASIONAL
  notes: Described in FA guideline otologic sections as part of structural ear anomalies.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an absent ear canal, an anomaly known as aural atresia."
    explanation: Guidelines directly describe absent ear canal (aural atresia) in FA patients.
  phenotype_term:
    preferred_term: Atresia of the external auditory canal
    term:
      id: HP:0000413
      label: Atresia of the external auditory canal
- category: Audiologic
  name: External Auditory Canal Stenosis
  description: Narrow external auditory canal reported among structural ear manifestations in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in FA guideline otologic manifestations as a narrow/atretic canal.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "atretic, narrow canal; and abnormal middle e ar bones"
    explanation: FA guidelines include narrow ear canal in the otologic anomaly profile.
  phenotype_term:
    preferred_term: Stenosis of the external auditory canal
    term:
      id: HP:0000402
      label: Stenosis of the external auditory canal
- category: Audiologic
  name: Middle Ear Ossicle Abnormalities
  description: Structural anomalies of middle ear ossicles reported among Fanconi anemia otologic findings.
  frequency: OCCASIONAL
  notes: Included in FA guideline otologic manifestations as abnormal middle ear bones.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "narrow canal; and abnormal middle e ar bones"
    explanation: FA guidelines include abnormal middle ear bones in the otologic anomaly profile.
  phenotype_term:
    preferred_term: Abnormality of the middle ear ossicles
    term:
      id: HP:0004452
      label: Abnormality of the middle ear ossicles
- category: Endocrine
  name: Hypothyroidism
  description: Thyroid hormone deficiency requiring monitoring and potentially replacement therapy.
  frequency: FREQUENT
  notes: About 80% of FA patients have at least one endocrine abnormality. Hypothyroidism is one of the most common endocrine manifestations. Annual TSH and free T4 screening is recommended.
  evidence:
  - reference: PMID:25575015
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility."
    explanation: Consensus review documents hypothyroidism as a common endocrine abnormality in FA.
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  phenotype_contexts:
  - frequency: FREQUENT
    notes: >-
      37% prevalence in the NCI cohort (n=45, Giri et al. 2007). Annual TSH
      and free T4 screening is recommended.
    evidence:
    - reference: PMID:17426088
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "short stature and/or GH deficiency (51%), hypothyroidism (37%)"
      explanation: Giri et al. NCI cohort quantifies hypothyroidism at 37% in FA patients.
- category: Endocrine
  name: Growth Hormone Deficiency
  description: Insufficient growth hormone production contributing to short stature beyond what is expected from the underlying condition alone.
  frequency: FREQUENT
  notes: GH deficiency affects approximately 51% of FA patients (Giri et al. 2007, NCI cohort). Patients with GH deficiency were significantly shorter than those without (P=0.01). Growth hormone therapy may be used but requires careful monitoring given cancer predisposition. Ninety-two percent of FA patients aged 18 or older had osteopenia or osteoporosis.
  evidence:
  - reference: PMID:17426088
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short stature and/or GH deficiency (51%)"
    explanation: NCI cohort study of 45 FA patients found GH deficiency in 51%, establishing it as a frequent phenotype.
  - reference: PMID:25575015
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility."
    explanation: Consensus review identifies GH deficiency as a recognized endocrine abnormality in FA.
  phenotype_term:
    preferred_term: Secondary growth hormone deficiency
    term:
      id: HP:0008240
      label: Secondary growth hormone deficiency
  phenotype_contexts:
  - frequency: FREQUENT
    notes: >-
      51% of FA patients had short stature and/or GH deficiency in the NCI
      cohort (n=45). Only GH deficiency correlated significantly with short
      stature (P=0.01). Midline brain abnormalities were found in 17% of
      patients, and 60% of those were GH-deficient.
    evidence:
    - reference: PMID:17426088
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "short stature and/or GH deficiency (51%), hypothyroidism (37%), midline brain abnormalities (17%) (these patients had very short stature and 60% were GH-deficient)"
      explanation: Giri et al. NCI cohort quantifies GH deficiency at 51% with pituitary abnormality association.
- category: Endocrine
  name: Abnormal Glucose Homeostasis
  description: Abnormal glucose and insulin metabolism including insulin resistance, impaired glucose tolerance, and diabetes mellitus.
  frequency: OCCASIONAL
  notes: Part of the metabolic/endocrine abnormalities seen in up to 80% of FA patients. Two-hour glucose tolerance testing and insulin levels are recommended as part of annual endocrine surveillance.
  evidence:
  - reference: PMID:25575015
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility."
    explanation: Consensus review identifies abnormal glucose/insulin metabolism as part of the FA endocrine phenotype.
  phenotype_term:
    preferred_term: Abnormal glucose homeostasis
    term:
      id: HP:0011014
      label: Abnormal glucose homeostasis
  phenotype_contexts:
  - frequency: FREQUENT
    notes: >-
      39% of FA patients had abnormal glucose/insulin metabolism in the NCI
      cohort (Giri et al. 2007). 21% met criteria for metabolic syndrome.
    evidence:
    - reference: PMID:17426088
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "abnormal glucose/insulin metabolism (39%)"
      explanation: Giri et al. NCI cohort quantifies glucose/insulin abnormalities at 39%.
- category: Endocrine
  name: Delayed Puberty and Hypogonadism
  description: Delayed onset of puberty and hypogonadism affecting both sexes, with males commonly showing cryptorchidism and females showing ovarian insufficiency.
  frequency: FREQUENT
  notes: Pubertal delay and hypogonadism are among the most common endocrine abnormalities in FA (present in up to 80% of patients with at least one endocrine abnormality). Pubertal staging and hormone levels should be assessed at puberty and every two years until complete.
  evidence:
  - reference: PMID:25575015
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility."
    explanation: Consensus review identifies pubertal delay and hypogonadism as prominent endocrine features of FA.
  phenotype_term:
    preferred_term: Delayed puberty
    term:
      id: HP:0000823
      label: Delayed puberty
  phenotype_contexts:
  - frequency: VERY_FREQUENT
    notes: >-
      65% of peripubertal or postpubertal FA patients had gonadal dysfunction
      in the NCI cohort (Giri et al. 2007).
    evidence:
    - reference: PMID:17426088
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "65% of peripubertal or postpubertal patients had gonadal dysfunction"
      explanation: Giri et al. NCI cohort quantifies gonadal dysfunction at 65% in peripubertal/postpubertal FA patients.
- category: Reproductive
  name: Impaired Fertility
  description: Reduced fertility in both sexes, with males often showing azoospermia or oligospermia due to gonadal failure, and females showing diminished ovarian reserve and premature menopause.
  frequency: FREQUENT
  notes: Male infertility is very common due to primary gonadal failure. Female fertility is reduced but pregnancies have been reported. Fertility preservation counseling should be offered early.
  evidence:
  - reference: PMID:25575015
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility."
    explanation: Impaired fertility is listed as a key endocrine abnormality in FA patients.
  phenotype_term:
    preferred_term: Infertility
    term:
      id: HP:0000789
      label: Infertility
  phenotype_contexts:
  - sex: MALE
    frequency: VERY_FREQUENT
    notes: Near-universal azoospermia due to primary gonadal failure.
    evidence:
    - reference: PMID:25575015
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility."
      explanation: Male infertility in FA is near-universal due to gonadal failure and azoospermia.
  - sex: FEMALE
    frequency: FREQUENT
    notes: Reduced fertility with diminished ovarian reserve and premature menopause, but pregnancies have been reported.
    evidence:
    - reference: PMID:25575015
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility."
      explanation: Female fertility is reduced but not absent; successful pregnancies have been documented.
- category: Reproductive
  name: Cryptorchidism
  description: Undescended testes, a common genitourinary malformation in male FA patients.
  frequency: OCCASIONAL
  notes: Part of the genitourinary anomaly spectrum. Genital anomalies were significantly more common in patients with downstream FA gene mutations (FANCD1, FANCJ) compared to core complex mutations in the Israeli cohort.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ophthalmic and genitourinary tract anomalies"
    explanation: GeneReviews lists genitourinary anomalies including genital anomalies as part of FA.
  - reference: PMID:31558676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with downstream mutations were found to have significantly more skull anomalies (P<0.001), central nervous system (CNS) abnormalities (P=0.005) and genitourinary anomalies (P=0.03), compared with patients with core complex mutations."
    explanation: Israeli cohort found genitourinary anomalies enriched in downstream FA gene mutations (FANCD1, FANCJ).
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  phenotype_contexts:
  - genetic_context:
      genes:
      - preferred_term: FANCD1/BRCA2
        term:
          id: hgnc:1101
          label: BRCA2
      - preferred_term: FANCJ/BRIP1
        term:
          id: hgnc:20473
          label: BRIP1
      description: Downstream FA pathway genes
    frequency: FREQUENT
    notes: >-
      Genitourinary anomalies including cryptorchidism were significantly
      more common in downstream FA gene mutations (P=0.03).
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with downstream mutations were found to have significantly more skull anomalies (P<0.001), central nervous system (CNS) abnormalities (P=0.005) and genitourinary anomalies (P=0.03), compared with patients with core complex mutations."
      explanation: Downstream pathway mutations enriched for genitourinary anomalies including cryptorchidism.
- category: Reproductive
  name: Testicular Aplasia or Hypoplasia
  description: Small or absent testes reported among male genital manifestations in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in FA guideline male genital manifestations used for diagnostic screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Undescended, small or absent testis; microphalus; hypospadias; micropenis; absent testis; infertility"
    explanation: FA guidelines list small or absent testis among male genital abnormalities.
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia of the testes
    term:
      id: HP:0010468
      label: Aplasia/Hypoplasia of the testes
- category: Reproductive
  name: Hypospadias
  description: Ventral displacement of the urethral meatus as part of male genital anomalies in FA.
  frequency: OCCASIONAL
  notes: Listed in FA guideline male genital manifestations used for diagnostic screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Undescended, small or absent testis; microphalus; hypospadias; micropenis; absent testis; infertility"
    explanation: FA guidelines include hypospadias among recognized male genital anomalies.
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
- category: Reproductive
  name: Micropenis
  description: Congenital small phallus reported among male genital manifestations in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in FA guideline male genital manifestations used for diagnostic screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Undescended, small or absent testis; microphalus; hypospadias; micropenis; absent testis; infertility"
    explanation: FA guidelines include micropenis among male genital anomalies associated with FA.
  phenotype_term:
    preferred_term: Micropenis
    term:
      id: HP:0000054
      label: Micropenis
- category: Reproductive
  name: Bicornuate Uterus
  description: Congenital uterine malformation reported among female genital manifestations in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in the FA guideline female-genital manifestations used for FA screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypoplastic, absent or bicornuate uterus;  gonadal dysgenesis; small ovaries;"
    explanation: FA guidelines list bicornuate uterus in the female genital anomaly spectrum.
  phenotype_term:
    preferred_term: Bicornuate uterus
    term:
      id: HP:0000813
      label: Bicornuate uterus
- category: Reproductive
  name: Uterine Aplasia or Hypoplasia
  description: Hypoplastic or absent uterus reported among female genital manifestations in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in the FA guideline female-genital manifestations used for FA screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypoplastic, absent or bicornuate uterus;  gonadal dysgenesis; small ovaries;"
    explanation: FA guidelines explicitly include hypoplastic or absent uterus among female genital anomalies.
  phenotype_term:
    preferred_term: Aplasia/hypoplasia of the uterus
    term:
      id: HP:0008684
      label: Aplasia/hypoplasia of the uterus
- category: Reproductive
  name: Gonadal Dysgenesis
  description: Gonadal developmental abnormality reported among female genital manifestations in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in the FA guideline female-genital manifestations used for FA screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypoplastic, absent or bicornuate uterus;  gonadal dysgenesis; small ovaries;"
    explanation: FA guidelines include gonadal dysgenesis among female genital abnormalities.
  phenotype_term:
    preferred_term: Gonadal dysgenesis
    term:
      id: HP:0000133
      label: Gonadal dysgenesis
- category: Reproductive
  name: Ovarian Hypoplasia
  description: Small or underdeveloped ovaries reported in female Fanconi anemia manifestations.
  frequency: OCCASIONAL
  notes: Included in the FA guideline female-genital manifestations as small ovaries.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypoplastic, absent or bicornuate uterus;  gonadal dysgenesis; small ovaries;"
    explanation: FA guidelines report small ovaries within the female reproductive anomaly profile.
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia of the ovary
    term:
      id: HP:0010462
      label: Aplasia/Hypoplasia of the ovary
- category: Reproductive
  name: Rectovaginal Fistula
  description: Congenital fistulous communication between rectum and vagina reported in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in the FA guideline female-genital manifestations used for FA screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "rectovaginal fistula; vaginal atresia; late menarche; early menopause;"
    explanation: FA guidelines include rectovaginal fistula in the female genital anomaly spectrum.
  phenotype_term:
    preferred_term: Rectovaginal fistula
    term:
      id: HP:0000143
      label: Rectovaginal fistula
- category: Reproductive
  name: Vaginal Atresia
  description: Congenital vaginal canal atresia reported among female genital manifestations in Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in the FA guideline female-genital manifestations used for FA screening.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "rectovaginal fistula; vaginal atresia; late menarche; early menopause;"
    explanation: FA guidelines list vaginal atresia among congenital female genital findings.
  phenotype_term:
    preferred_term: Vaginal atresia
    term:
      id: HP:0000148
      label: Vaginal atresia
- category: Reproductive
  name: Delayed Menarche
  description: Later-than-expected onset of menarche reported in female Fanconi anemia manifestations.
  frequency: OCCASIONAL
  notes: Included in the FA guideline female-genital and endocrine-reproductive manifestation spectrum.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "rectovaginal fistula; vaginal atresia; late menarche; early menopause;"
    explanation: FA guidelines include late menarche among female reproductive manifestations.
  phenotype_term:
    preferred_term: Delayed menarche
    term:
      id: HP:0012569
      label: Delayed menarche
- category: Reproductive
  name: Premature Ovarian Insufficiency
  description: Early loss of ovarian function corresponding to early menopause in female Fanconi anemia.
  frequency: OCCASIONAL
  notes: Included in the FA guideline female-genital manifestations as early menopause.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "rectovaginal fistula; vaginal atresia; late menarche; early menopause;"
    explanation: FA guidelines list early menopause among female reproductive manifestations.
  phenotype_term:
    preferred_term: Premature ovarian insufficiency
    term:
      id: HP:0008209
      label: Premature ovarian insufficiency
- category: Renal
  name: Renal Anomalies
  description: Congenital kidney malformations including ectopic kidneys, horseshoe kidneys, renal agenesis, or hypoplastic kidneys.
  frequency: FREQUENT
  notes: In the Israeli FA cohort, 39.6% of patients had renal anomalies, making it the second most common congenital anomaly after skin pigmentation changes. Renal anomalies contribute to the congenital abnormality burden score.
  evidence:
  - reference: PMID:31558676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "More than half had café-au-lait spots (52.3%) followed by renal anomalies (39.6%)."
    explanation: Israeli cohort found renal anomalies in nearly 40% of FA patients.
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ophthalmic and genitourinary tract anomalies"
    explanation: GeneReviews lists genitourinary tract anomalies as part of the FA congenital spectrum.
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Horseshoe, ectopic, hypoplastic, dysplastic, absent, hydronephrosis, hydroureter"
    explanation: FA guidelines list common renal malformation patterns in affected patients.
  phenotype_term:
    preferred_term: Abnormality of the genitourinary system
    term:
      id: HP:0000119
      label: Abnormality of the genitourinary system
- category: Developmental
  name: Intrauterine Growth Retardation
  description: Low birth weight for gestational age, reflecting prenatal growth restriction.
  frequency: OCCASIONAL
  notes: In the Israeli cohort, 20% of FA patients were born small for gestational age. Growth deficiency often begins prenatally and continues postnatally.
  evidence:
  - reference: PMID:31558676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "20% were born small for the gestational age, and 57% fit criteria for short stature."
    explanation: Israeli cohort documents 20% small for gestational age prevalence in FA.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  phenotype_contexts:
  - frequency: OCCASIONAL
    notes: >-
      20% born SGA in the Israeli cohort. ALDH2*2 variant did not affect
      birth weight in Japanese FA patients, suggesting prenatal growth
      restriction is independent of aldehyde-mediated damage.
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "20% were born small for the gestational age, and 57% fit criteria for short stature."
      explanation: 20% SGA prevalence in Israeli FA cohort.
    - reference: PMID:24037726
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the ALDH2 variant is associated with accelerated progression of BMF, while birth weight or the number of physical abnormalities was not affected"
      explanation: Birth weight unaffected by ALDH2 status, suggesting different mechanism for prenatal growth restriction.
- category: Neurologic
  name: Developmental Delay
  description: Cognitive and/or motor developmental delays present in a subset of FA patients.
  frequency: OCCASIONAL
  notes: Developmental delay contributes to the congenital abnormality burden score. Patients with splice site mutations had significantly more CNS anomalies and developmental delay (P=0.038) compared with other mutation types. Patients with downstream FA gene mutations (FANCD1, FANCJ) had significantly more CNS abnormalities (P=0.005). FA-S (biallelic BRCA1) patients frequently present with intellectual disability.
  evidence:
  - reference: PMID:31558676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with splice site mutations had significantly more CNS anomalies and developmental delay, compared with the other patients (P=0.03 and P=0.038, respectively)."
    explanation: Israeli cohort found developmental delay associated with splice site mutations in FA.
  - reference: PMID:38146508
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this FA-S cohort phenotype includes short stature, microcephaly, facial dysmorphisms, hypo/hyperpigmented lesions, intellectual disability, chromosomal sensitivity to crosslinking agents and predisposition to breast/ovarian cancer and/or childhood cancers"
    explanation: FA-S (BRCA1 biallelic) patients commonly present with intellectual disability.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  phenotype_contexts:
  - genetic_context:
      allele_type: splice_site
    frequency: FREQUENT
    notes: >-
      Patients with splice site mutations had significantly more CNS
      anomalies and developmental delay (P=0.038) compared with other
      mutation types.
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with splice site mutations had significantly more CNS anomalies and developmental delay, compared with the other patients (P=0.03 and P=0.038, respectively)."
      explanation: Splice site mutations specifically associated with developmental delay in FA.
  - genetic_context:
      genes:
      - preferred_term: FANCD1/BRCA2
        term:
          id: hgnc:1101
          label: BRCA2
      - preferred_term: FANCJ/BRIP1
        term:
          id: hgnc:20473
          label: BRIP1
      description: Downstream FA pathway genes
    frequency: FREQUENT
    notes: >-
      Downstream FA gene mutations associated with significantly more
      CNS abnormalities (P=0.005) compared to core complex mutations.
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with downstream mutations were found to have significantly more skull anomalies (P<0.001), central nervous system (CNS) abnormalities (P=0.005) and genitourinary anomalies (P=0.03), compared with patients with core complex mutations."
      explanation: Downstream pathway mutations enriched for CNS abnormalities.
  - genetic_context:
      gene:
        preferred_term: BRCA1
        term:
          id: hgnc:1100
          label: BRCA1
      complementation_group: FA-S
      zygosity: HOMOZYGOUS
    frequency: VERY_FREQUENT
    notes: >-
      FA-S (biallelic BRCA1) patients frequently present with intellectual
      disability as part of the characteristic FA-S phenotypic spectrum.
    evidence:
    - reference: PMID:38146508
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "this FA-S cohort phenotype includes short stature, microcephaly, facial dysmorphisms, hypo/hyperpigmented lesions, intellectual disability"
      explanation: Intellectual disability is a defining feature of the FA-S subtype.
- category: Neurologic
  name: Hydrocephalus
  description: Ventricular enlargement and cerebrospinal fluid accumulation reported among FA CNS anomalies.
  frequency: OCCASIONAL
  notes: Included in the FA guideline central nervous system screening manifestations.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Small pituitary and stalk interruption; agenesis of corpus callosum; cerebellar hypoplasia; hydrocephalus ; dilated ventricles; developmental delay"
    explanation: FA guidelines list hydrocephalus in the CNS anomaly spectrum used for screening.
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
- category: Neurologic
  name: Ventriculomegaly
  description: Dilatation of the cerebral ventricles reported in the FA central nervous system anomaly spectrum.
  frequency: OCCASIONAL
  notes: Included in the FA guideline CNS screening manifestations as dilated ventricles.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dilated ventricles"
    explanation: FA guidelines list dilated ventricles among CNS manifestations warranting FA screening.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
- category: Dermatologic
  name: Hypopigmentation
  description: Areas of decreased skin pigmentation, often in combination with hyperpigmented lesions such as café-au-lait spots.
  frequency: FREQUENT
  notes: The combination of hypo- and hyperpigmented skin lesions is characteristic of FA. In the Israeli cohort, skin pigmentation changes (café-au-lait spots) were the most common congenital anomaly (52.3%).
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abnormal skin pigmentation"
    explanation: GeneReviews lists abnormal skin pigmentation among the physical abnormalities present in ~75% of FA patients.
  phenotype_term:
    preferred_term: Abnormality of the skin
    term:
      id: HP:0000951
      label: Abnormality of the skin
- category: Dermatologic
  name: Hyperpigmentation
  description: Generalized or patchy increased skin pigmentation in the Fanconi anemia congenital anomaly spectrum.
  frequency: FREQUENT
  notes: Included in FA guideline skin findings and commonly co-occurs with hypopigmented lesions.
  evidence:
  - reference: file:research/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.extracted.md
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin Café au lait macules; generalized hypo - or hyperpigmentation"
    explanation: FA guidelines list generalized hyperpigmentation among characteristic skin findings.
  phenotype_term:
    preferred_term: Hyperpigmentation of the skin
    term:
      id: HP:0000953
      label: Hyperpigmentation of the skin
- category: Skeletal
  name: Osteopenia and Osteoporosis
  description: Reduced bone mineral density affecting the majority of adult FA patients, likely related to endocrine dysfunction, chronic illness, and potentially direct effects of FA pathway deficiency on osteoblast function.
  frequency: VERY_FREQUENT
  notes: 92% of FA patients aged 18 or older had osteopenia or osteoporosis in the NCI cohort (Giri et al. 2007). May be compounded by GH deficiency, hypogonadism, and post-HSCT conditioning effects.
  evidence:
  - reference: PMID:17426088
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ninety-two percent of the patients 18 yr or older had osteopenia or osteoporosis."
    explanation: Near-universal bone density loss in adult FA patients.
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
- category: Dental
  name: Dental and Craniofacial Anomalies
  description: Dental anomalies including tooth agenesis, root abnormalities, tooth rotation, enamel defects, and craniofacial dysmorphisms.
  frequency: FREQUENT
  notes: In a systematic review with 46 additional Brazilian cases, 93.5% of FA patients exhibited dental/craniofacial anomalies. Root abnormalities (69.6%), tooth rotation (54.3%), and tooth agenesis (26%) were most common. Anomalies in tooth size and shape were more prevalent in patients who underwent HSCT at age 14 or older.
  evidence:
  - reference: PMID:39568270
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our cohort, 93.5% of patients exhibited anomalies, primarily root abnormalities (69.6%), tooth rotation (54.3%), and tooth agenesis (26%)."
    explanation: Systematic review demonstrates very high prevalence of dental anomalies in FA patients.
  phenotype_term:
    preferred_term: Abnormality of the dentition
    term:
      id: HP:0000164
      label: Abnormality of the dentition
- category: Hematologic
  name: Myelodysplastic Syndrome
  description: Clonal hematopoietic disorder with dysplastic bone marrow and cytopenias, frequently preceding progression to acute myeloid leukemia.
  frequency: FREQUENT
  notes: In the Israeli cohort, 30% of patients developed MDS, leukemia, and/or solid tumors. Patients with non-FANCA mutations (FANCC, FANCD1, FANCG, FANCJ) developed first cancer (including MDS) significantly earlier than FANCA patients (mean 5.2 vs 18.5 years, P=0.001). There was a trend toward more MDS in FANCC patients.
  evidence:
  - reference: PMID:31558676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "30% developed myelodysplastic syndrome (MDS), leukemia and/or solid tumors"
    explanation: Israeli cohort documents that 30% of FA patients developed MDS, leukemia, and/or solid tumors.
  - reference: PMID:31558676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean age of the first cancer was 18.5 years (SD 6.3 years) for patients with FANCA, relative to 5.2 years (SD 3.7 years) for patients with FANCC, FANCD1, FANCG and FANCJ mutations, with a statistically significant difference (P=0.001)."
    explanation: Demonstrates significantly earlier cancer onset in non-FANCA complementation groups.
  phenotype_term:
    preferred_term: Myelodysplasia
    term:
      id: HP:0002863
      label: Myelodysplasia
  phenotype_contexts:
  - onset:
      mean_age_years: 13.3
    notes: >-
      Mean age of first MDS event was 13.3 years in the Israeli cohort.
      There was a trend toward more MDS in FANCC patients.
    evidence:
    - reference: PMID:31558676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "30% developed myelodysplastic syndrome (MDS), leukemia and/or solid tumors"
      explanation: Israeli cohort documents MDS as part of the 30% cancer rate in FA patients.
- category: Oncologic
  name: Early-Onset Solid Tumors in FANCD1/BRCA2
  description: Patients with biallelic FANCD1/BRCA2 mutations have a uniquely severe cancer predisposition with early-onset solid tumors in childhood, including medulloblastoma, Wilms tumor, and neuroblastoma, distinct from the typical FA tumor spectrum.
  frequency: VERY_FREQUENT
  subtype: FANCD1/BRCA2
  notes: FANCD1/BRCA2 and FANCN/PALB2 patients have the most severe cancer phenotype with near-invariable early-onset malignancy. In the Israeli cohort, one FANCD1 patient developed medulloblastoma at age 3. These patients require cancer screening from a very young age. Neither FANCD1 patient in the Israeli cohort developed BMF, distinguishing this subtype. FA-S (biallelic BRCA1) patients also lack bone marrow failure but have cancer predisposition.
  evidence:
  - reference: PMID:31558676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with FANCD1 mutations have been previously described as uniquely developing solid tumors early in life"
    explanation: Confirms early-onset solid tumor predisposition unique to FANCD1/BRCA2 subtype.
  - reference: PMID:38146508
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unlike most other types of FA, FA-S patients lack bone marrow failure."
    explanation: FA-S (biallelic BRCA1) patients have cancer predisposition but lack BMF, similar to FANCD1.
biochemical:
- name: Chromosomal Breakage Test
  presence: Positive
  context: Diagnostic indicator
- name: Crosslinking Sensitivity
  presence: Increased
  context: Diagnostic indicator (often using diepoxybutane (DEB) or mitomycin C (MMC))
genetic:
- name: FANCA
  association: Pathogenic Variants
  notes: Most common FA gene, accounting for approximately 60-70% of cases.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms FANCA is one of the 21 genes causing autosomal recessive Fanconi anemia.
- name: FANCB
  association: Pathogenic Variants
  inheritance:
  - name: X-linked
  notes: Component of FA core complex; X-linked inheritance pattern.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a hemizygous pathogenic variant in FANCB known to cause X-linked FA"
    explanation: GeneReviews confirms FANCB causes X-linked Fanconi anemia.
- name: FANCC
  association: Pathogenic Variants
  notes: Second most common FA gene in certain populations.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms FANCC is one of the 21 genes causing autosomal recessive Fanconi anemia.
- name: FANCE
  association: Pathogenic Variants
  notes: Component of FA core complex.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms FANCE is one of the 21 genes causing autosomal recessive Fanconi anemia.
- name: FANCF
  association: Pathogenic Variants
  notes: Component of FA core complex.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms FANCF is one of the 21 genes causing autosomal recessive Fanconi anemia.
- name: FANCG
  association: Pathogenic Variants
  notes: Associated with more severe phenotype requiring earlier intervention.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms FANCG is one of the 21 genes causing autosomal recessive Fanconi anemia.
- name: FANCL
  association: Pathogenic Variants
  notes: E3 ubiquitin ligase component of FA core complex that monoubiquitinates FANCD2-FANCI complex.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms FANCL is one of the 21 genes causing autosomal recessive Fanconi anemia.
- name: FANCM
  association: Pathogenic Variants
  notes: >-
    DNA translocase that recognizes stalled replication forks and recruits the FA
    core complex. FANCM has historically been proposed as FA-M in some sources,
    but classification differs across curation resources.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews lists FANCM among FA-associated genes; some ontology resources classify FANCM-related disease separately from canonical FA complementation groups.
- name: UBE2T
  association: Pathogenic Variants
  notes: Also known as FANCT; E2 ubiquitin-conjugating enzyme that works with FANCL to monoubiquitinate FANCD2-FANCI.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms UBE2T (FANCT) is one of the 21 genes causing autosomal recessive Fanconi anemia.
- name: FANCD2
  association: Pathogenic Variants
  notes: Forms complex with FANCI; monoubiquitination is central to FA pathway activation and DNA repair.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms FANCD2 is one of the 21 genes causing autosomal recessive Fanconi anemia.
- name: FANCI
  association: Pathogenic Variants
  notes: Forms complex with FANCD2; phosphorylation and monoubiquitination regulate ICL repair.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms FANCI is one of the 21 genes causing autosomal recessive Fanconi anemia.
- name: SLX4
  association: Pathogenic Variants
  notes: Also known as FANCP; nuclease scaffold protein that coordinates multiple nucleases for DNA unhooking.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms SLX4 (FANCP) is one of the 21 genes causing autosomal recessive Fanconi anemia.
- name: BRCA2
  association: Pathogenic Variants
  notes: Also known as FANCD1; essential for homologous recombination repair downstream of ICL unhooking.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms BRCA2 (FANCD1) is one of the 21 genes causing autosomal recessive Fanconi anemia.
- name: PALB2
  association: Pathogenic Variants
  notes: Also known as FANCN; partner and localizer of BRCA2, required for HR repair.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms PALB2 (FANCN) is one of the 21 genes causing autosomal recessive Fanconi anemia.
- name: BRCA1
  association: Pathogenic Variants
  notes: Also known as FANCS; involved in homologous recombination and DNA damage response.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms BRCA1 (FANCS) is one of the 21 genes causing autosomal recessive Fanconi anemia.
- name: BRIP1
  association: Pathogenic Variants
  notes: Also known as FANCJ/BACH1; BRCA1-interacting helicase involved in homologous recombination.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms BRIP1 (FANCJ) is one of the 21 genes causing autosomal recessive Fanconi anemia.
- name: ERCC4
  association: Pathogenic Variants
  notes: Also known as FANCQ/XPF; structure-specific nuclease with roles in interstrand crosslink and nucleotide excision repair.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms ERCC4 (FANCQ) is one of the 21 genes causing autosomal recessive Fanconi anemia.
- name: RAD51C
  association: Pathogenic Variants
  notes: Also known as FANCO; RAD51 paralog essential for homologous recombination.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms RAD51C (FANCO) is one of the 21 genes causing autosomal recessive Fanconi anemia.
- name: RAD51
  association: Pathogenic Variants
  inheritance:
  - name: Autosomal dominant
  notes: Also known as FANCR; dominant-negative heterozygous variants cause the autosomal dominant FA-R subtype.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a heterozygous pathogenic variant in RAD51 known to cause autosomal dominant FA"
    explanation: GeneReviews confirms RAD51 (FANCR) as the autosomal dominant FA subtype gene.
- name: XRCC2
  association: Pathogenic Variants
  notes: Also known as FANCU; involved in homologous recombination repair.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms XRCC2 (FANCU) is one of the 21 genes causing autosomal recessive Fanconi anemia.
- name: MAD2L2
  association: Pathogenic Variants
  notes: Also known as REV7 and FANCV; component of DNA polymerase zeta for translesion synthesis.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms MAD2L2/REV7 (FANCV) is one of the 21 genes causing autosomal recessive Fanconi anemia.
- name: RFWD3
  association: Pathogenic Variants
  notes: Also known as FANCW; E3 ubiquitin ligase active at stalled replication forks that supports homologous recombination.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms RFWD3 (FANCW) is one of the 21 genes causing autosomal recessive Fanconi anemia.
- name: ALDH2
  association: Risk Modifier
  notes: Aldehyde dehydrogenase 2; detoxifies acetaldehyde. ALDH2*2 variant accelerates bone marrow failure progression in FA patients.
  evidence:
  - reference: PMID:24037726
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the ALDH2 variant is associated with accelerated progression of BMF"
    explanation: Study of 64 Japanese FA patients showed ALDH2 deficiency accelerates bone marrow failure progression.
- name: ADH5
  association: Risk Modifier
  notes: Alcohol dehydrogenase 5; detoxifies formaldehyde, providing tier-1 protection against aldehyde-induced DNA damage.
  evidence:
  - reference: PMID:22081012
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "a synthetic lethal interaction in avian cells between ADH5, encoding the main formaldehyde-detoxifying enzyme, and the Fanconi anemia (FA) DNA-repair pathway"
    explanation: Demonstrates that ADH5 formaldehyde catabolism is essential in FA-deficient cells.
- name: KMT2D
  association: Disease Modifier
  notes: Histone methyltransferase; loss in squamous cell carcinomas can epigenetically suppress FA/BRCA gene expression under metabolic stress.
diagnosis:
- name: Chromosomal Breakage Test
  notes: Measures sensitivity to DNA crosslinking agents
- name: Genetic Testing
  notes: Identifies pathogenic variants in FA genes
- name: Bone Marrow Examination
  notes: Assesses degree of bone marrow failure
environmental:
- name: Protections from DNA-damaging Agents
  description: Avoid exposure to agents that can cause DNA damage, such as radiation and certain chemicals.
  notes: Broad recommendation spanning both ionizing radiation and chemical genotoxins; no single specific ECTO term is used here to avoid a mismatched mapping.
treatments:
- name: Hematopoietic Stem Cell Transplantation (HSCT)
  description: The only curative treatment for the hematologic manifestations of FA, using reduced-intensity conditioning regimens due to patient sensitivity to chemotherapy and radiation.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematologic manifestations of FA
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: MAXO:0000747
      label: hematopoietic stem cell transplantation
- name: Androgen Therapy
  description: Can stimulate erythropoiesis and improve blood counts, often used as a bridge to transplantation.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Administration of oral androgens (e.g., oxymetholone) improves blood counts (red cell and platelets) in approximately 50% of individuals with FA
  treatment_term:
    preferred_term: hormone modifying therapy
    term:
      id: MAXO:0000283
      label: hormone modifying therapy
- name: Growth Hormone Therapy
  description: May be used to improve growth in affected children with short stature.
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of growth deficiency, limb anomalies, ocular anomalies, renal malformations, genital anomalies, hypothyroidism, cardiac anomalies, and dermatologic manifestations as recommended by the subspecialty care provider."
    explanation: GeneReviews recommends treatment of growth deficiency as part of comprehensive FA management.
  treatment_term:
    preferred_term: hormone modifying therapy
    term:
      id: MAXO:0000283
      label: hormone modifying therapy
- name: Supportive Care
  description: Treatment of cytopenias with transfusions, antibiotics, and monitoring for malignancy.
  notes: Includes blood transfusions, growth factor support, and infection prophylaxis
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "granulocyte colony-stimulating factor improves the neutrophil count in some individuals"
    explanation: GeneReviews confirms use of growth factors as part of supportive care for cytopenias.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
- name: Cancer Surveillance
  description: Regular screenings for early detection of cancers, particularly acute myeloid leukemia and squamous cell carcinomas of the head and neck, oral cavity, and anogenital regions.
  notes: Required due to markedly increased risk of developing malignancies, especially squamous cell carcinomas at young ages
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "oral examinations for tumors every six months beginning at age nine to ten years; annual nasolaryngoscopy beginning at age ten years"
    explanation: GeneReviews recommends regular oral and nasolaryngoscopic surveillance for early cancer detection.
  treatment_term:
    preferred_term: cancer screening
    term:
      id: MAXO:0000126
      label: cancer screening
- name: Genetic Counseling
  description: Counseling for patients and families regarding inheritance patterns, recurrence risks, carrier testing, and prenatal diagnosis options.
  notes: Essential for family planning and understanding autosomal recessive and X-linked inheritance patterns
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Carrier testing for at-risk relatives (for autosomal recessive and X-linked FA) and prenatal and preimplantation genetic testing are possible if the pathogenic variant(s) in the family are known."
    explanation: GeneReviews confirms the importance of genetic counseling for carrier testing and prenatal diagnosis.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
- name: Lentiviral Gene Therapy (FA-A)
  description: >-
    Ex vivo lentiviral-mediated gene correction of autologous CD34+ hematopoietic stem cells
    with a FANCA-expressing vector, followed by reinfusion without conditioning. Single-cell
    RNA sequencing of gene therapy-treated patients demonstrates that corrected HSPCs revert
    the FA transcriptional signature, including downregulation of TGF-beta and p21 and
    upregulation of DNA damage response and telomere maintenance pathways.
  evidence:
  - reference: PMID:37021532
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gene therapy reverts the transcriptional signature of FA HSPC, which then resemble the transcriptional program of healthy donor HSPC"
    explanation: Single-cell RNA-seq of gene therapy-treated FA patients demonstrates molecular rescue of the FA HSPC transcriptional program.
  - reference: PMID:37021532
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a down-regulated expression of TGF-β and p21, typically up-regulated in FA HSPC, and upregulation of DNA damage response and telomere maintenance pathways"
    explanation: Gene therapy corrects specific molecular defects in FA HSPCs as confirmed by scRNA-seq.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: MAXO:0001001
      label: gene therapy
- name: Adenine Base Editing (ABE8e)
  description: >-
    Precision base editing approach using optimized adenine base editors (ABE8e) to correct
    prevalent FANCA point mutations in patient hematopoietic stem and progenitor cells
    without relying on double-strand breaks or homology-directed repair, which are impaired
    in FA cells. Restores FANCA expression and FA pathway function.
  evidence:
  - reference: PMID:36371486
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "optimizing adenine base editor construct, vector type, guide RNA format, and delivery conditions leads to very effective genetic modification in multiple FA patient backgrounds"
    explanation: ABE8e base editing achieves effective correction across multiple FANCA mutation backgrounds.
  - reference: PMID:36371486
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Optimized base editing restored FANCA expression, molecular function of the FA pathway, and phenotypic resistance to crosslinking agents"
    explanation: Base editing restores functional FA pathway activity in patient-derived HSPCs.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: MAXO:0001001
      label: gene therapy
clinical_trials:
- name: NCT04069533
  phase: PHASE_II
  status: ACTIVE_NOT_RECRUITING
  description: Phase II clinical trial evaluating lentiviral-mediated gene therapy for pediatric patients with Fanconi Anemia subtype A (FA-A). Autologous CD34+ hematopoietic stem cells are transduced ex vivo with a lentiviral vector carrying the FANCA gene, then reinfused with the goal of preventing bone marrow failure.
  target_phenotypes:
  - preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  - preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: clinicaltrials:NCT04069533
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is an open-label Phase II clinical trial to evaluate the efficacy of a hematopoietic cell-based gene therapy for pediatric patients with Fanconi Anemia, subtype A (FA-A). Hematopoietic stem cells from mobilized peripheral blood of patients with FA-A will be transduced ex vivo (outside the body) with a lentiviral vector carrying the FANCA gene."
    explanation: This Phase II gene therapy trial directly addresses the genetic defect in FA-A by correcting FANCA mutations in autologous stem cells, providing evidence for curative cell-based genetic therapy approaches.
- name: NCT00243399
  phase: PHASE_I
  status: COMPLETED
  description: Pilot trial evaluating oxandrolone (an androgen steroid) for treatment of bone marrow aplasia in Fanconi Anemia patients. The study assessed safety and efficacy of androgen therapy to stimulate production of red blood cells and platelets in FA patients with bone marrow failure.
  target_phenotypes:
  - preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  - preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: clinicaltrials:NCT00243399
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The purpose of this study is to evaluate the safety of the drug oxandrolone (a type of androgen steroid) in patients with Fanconi anemia (FA), and to determine if this drug can help in the treatment of bone marrow failure in these patients. Androgen steroids are male hormones that can stimulate the production of red blood cells (the cells which carry oxygen in the blood) and platelets (cells that help blood clot)."
    explanation: This Phase I trial evaluates androgen therapy as a bridge treatment for bone marrow failure in FA, providing clinical evidence for hormonal stimulation of hematopoiesis.
- name: NCT00630253
  phase: PHASE_II
  status: COMPLETED
  description: Phase I/II study evaluating cyclophosphamide, fludarabine, and antithymocyte globulin conditioning followed by matched sibling donor hematopoietic cell transplantation (HSCT) in patients with Fanconi Anemia. Investigates reduced-intensity conditioning regimens tailored to FA patients' increased chemotherapy sensitivity.
  target_phenotypes:
  - preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  - preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: clinicaltrials:NCT00630253
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Giving chemotherapy, such as cyclophosphamide and fludarabine, before a donor stem cell transplant helps to remove the patient's cells to allow for the transplant cells to take and grow. It also helps stop the patient's immune system from rejecting the donor's stem cells."
    explanation: This Phase I/II trial optimizes HSCT conditioning regimens for FA patients, providing clinical evidence for the curative approach to bone marrow failure in Fanconi Anemia.
datasets:
- accession: geo:GSE157591
  title: MYC Promotes Bone Marrow Stem Cell Dysfunction in Fanconi Anemia
  description: >-
    Single-cell RNA sequencing of bone marrow CD34+ hematopoietic stem and progenitor cells
    from Fanconi anemia patients and healthy donors. Reveals aberrant MYC overexpression
    in FA HSPCs driving proliferation-apoptosis imbalance, with transcriptomic signatures
    distinct from normal hematopoiesis.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  platform: 10x Genomics Chromium
  publication: PMID:32997960
  findings:
  - statement: MYC is overexpressed in FA HSPCs compared to healthy donor HSPCs
  - statement: FA HSPCs show proliferation-apoptosis imbalance driven by MYC dysregulation
  evidence:
  - reference: PMID:32997960
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MYC overexpression impairs HSPC function in FA patients and contributes to exhaustion in FA bone marrow"
    explanation: scRNA-seq dataset demonstrates MYC as a key driver of HSPC dysfunction in FA patients.
- accession: geo:GSE180536
  title: Restored Hematopoietic Stem Cell Transcriptional Program in Fanconi Anemia Patients Following Gene Therapy
  description: >-
    Single-cell RNA sequencing of chimeric corrected and uncorrected HSPC populations
    co-existing in bone marrow of lentiviral gene therapy-treated Fanconi anemia patients.
    Demonstrates that gene-corrected cells revert the FA transcriptional signature to
    resemble healthy donor HSPCs.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  platform: 10x Genomics Chromium
  publication: PMID:37021532
  findings:
  - statement: Gene therapy reverts the FA HSPC transcriptional signature to healthy donor levels
  - statement: Corrected cells show downregulation of TGF-beta and p21, upregulation of DDR and telomere maintenance
  evidence:
  - reference: PMID:37021532
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gene therapy reverts the transcriptional signature of FA HSPC, which then resemble the transcriptional program of healthy donor HSPC"
    explanation: scRNA-seq of gene therapy patients confirms molecular rescue of FA-specific transcriptomic defects.
computational_models:
- name: Boolean Network Model of FA/BRCA Pathway
  description: >-
    A Boolean network model incorporating the FA/BRCA DNA repair pathway, checkpoint proteins,
    and alternative DNA repair pathways. Simulates ICL repair, checkpoint activation, and
    predicts which alternative repair pathways become active when the FA/BRCA pathway is
    defective. The largest network model incorporating a DNA repair pathway at time of publication.
  model_type: BOOLEAN_NETWORK
  publication: PMID:22267503
  findings:
  - statement: The model simulates ICL repair mediated by the FA/BRCA pathway
  - statement: Alternative DNA repair pathways are predicted to become active when FA/BRCA is defective
  - statement: Checkpoint protein activation patterns emerge from recurrent DNA damage
  evidence:
  - reference: PMID:22267503
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Our model is able to simulate the ICL repair process mediated by the FA/BRCA pathway, the activation of Checkpoint proteins observed by recurrent DNA damage, as well as the repair of DNA double-strand breaks and DNA adducts"
    explanation: Boolean network model successfully recapitulates FA/BRCA pathway behavior and predicts compensatory repair mechanisms.
- name: Multi-level Dynamical Modelling of SCC in FA
  description: >-
    A conceptual framework for multi-level dynamical modelling of squamous cell carcinoma
    development in Fanconi anemia, integrating longitudinal genome, proteome, and transcriptome
    data from a database of over 750 FA individuals. Proposes mechanistic models trained on
    multi-omic data from healthy and diseased tissue to detect early SCC signatures and
    predict tumorigenesis.
  publication: PMID:38028610
  findings:
  - statement: Defines hallmarks of cancer specific to FA for model training
  - statement: Proposes using multi-omic data for early SCC signature detection
  - statement: Framework designed to predict experimentally testable tumorigenesis mechanisms
  evidence:
  - reference: PMID:38028610
    supports: PARTIAL
    evidence_source: COMPUTATIONAL
    snippet: "we introduce here the concept of multi-level dynamical modelling using large, longitudinally collected genome, proteome- and transcriptome-wide data sets from a small number of FA individuals"
    explanation: Proposes a multi-level modeling approach for understanding SCC development in FA using multi-omic data.
- name: Machine Learning Drug Repurposing (drexml)
  description: >-
    Machine learning framework using multi-output regression and mechanistic signal transduction
    models to identify drug targets capable of regulating FA-related cell functionalities.
    The drexml tool predicts potential therapeutic targets by mapping external proteins to
    signaling circuits that trigger FA-related phenotypes, identifying over 20 potential
    drug targets and successfully predicting previously validated repurposed drugs.
  model_type: MACHINE_LEARNING
  repository_url: https://github.com/loucerac/drexml
  publication: PMID:31266445
  findings:
  - statement: Over 20 potential therapeutic drug targets identified around the FA pathway
  - statement: Framework validated by successfully predicting previously known repurposed drugs in FA
  evidence:
  - reference: PMID:31266445
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "The application of multi-output regression machine learning methodologies to predict the potential effect of external proteins over the signaling circuits that trigger Fanconi anemia related cell functionalities, inferred with a mechanistic model, allowed us to detect over 20 potential therapeutic targets"
    explanation: ML approach identifies novel drug targets for FA using mechanistic pathway modeling.
  - reference: PMID:38510973
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "In the Fanconi Anemia case, the model successfully predicts previously validated repurposed drugs"
    explanation: The drexml tool package validates the ML drug repurposing approach in FA.
- name: Deep Learning FA Core Complex Structure
  description: >-
    Integration of deep-learned residue distance predictions with Rosetta folding and automated
    cryo-EM map-guided assembly to determine the near-complete atomic structure of the Fanconi
    Anemia core complex (FAcc) E3 ubiquitin ligase from a 4.6 angstrom resolution cryo-EM map.
    Placed 5182 of 6557 residues, greatly expanding the structural model and enabling
    interpretation of disease-related mutations.
  model_type: MACHINE_LEARNING
  publication: PMID:32939280
  findings:
  - statement: Near-complete atomic model of FA core complex determined (5182 of 6557 residues placed)
  - statement: Deep learning overcame limitations of homology modeling for 4795 previously unmodeled residues
  - statement: Structure facilitates interpretation of disease-related mutational data
  evidence:
  - reference: PMID:32939280
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "we are able to determine an almost-complete atomic model of FAcc, in which 5182 of the 6557 residues were placed"
    explanation: Deep learning-guided structure determination provides structural context for understanding FA-causing mutations.
- name: DNA Methylation Episignature Classifier
  description: >-
    Machine learning classifier trained on genome-wide DNA methylation profiles from peripheral
    blood of FA patients. Identifies 82 differentially methylated CpG sites that distinguish
    FA from healthy individuals and other genetic disorders. The episignature is robust across
    complementation groups and tissue types, and can detect FA even in individuals with
    reverted phenotype due to gene conversion.
  model_type: MACHINE_LEARNING
  publication: PMID:37865086
  findings:
  - statement: 82 CpG sites define an FA-specific DNA methylation signature
  - statement: Episignature validated across multiple complementation groups
  - statement: Can diagnose FA even in mosaic/reverted patients with normalized chromosome breakage
  evidence:
  - reference: PMID:37865086
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "We identified 82 differentially methylated CpG sites that allow to distinguish subjects with FA from healthy individuals and subjects with other genetic disorders, defining an FA-specific DNAm signature"
    explanation: ML-based episignature provides a complementary diagnostic tool for FA.
  - reference: PMID:37865086
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "the generated episignature includes CpG sites that do not undergo functional selective pressure, allowing diagnosis of FA in individuals with reverted phenotype due to gene conversion"
    explanation: The episignature overcomes a key diagnostic challenge in FA patients with somatic mosaicism.
- name: REPAIR-FANC High Content Screening Platform
  description: >-
    Cell-based high content screening platform using TALEN-mediated FANCA-deficient U2OS cells
    stably expressing YFP-FANCD2 to monitor FA/BRCA pathway activity via fluorescent FANCD2
    foci formation. Screened 3802 compounds including 1200 FDA-approved drugs for potential
    FA pathway rescue.
  publication: PMID:32605631
  findings:
  - statement: None of the 3802 compounds tested were able to rescue FANCA-dependent FANCD2 foci formation
  - statement: Platform demonstrates feasibility for high-throughput screening in FA therapeutics
  - statement: Some compounds showed mild reduction in chromosomal instability markers
  evidence:
  - reference: PMID:32605631
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "we developed a novel high-content cell-based screening assay to identify drugs with therapeutic potential in FA"
    explanation: Establishes an optimized platform for screening drug candidates in FA, though no pathway-rescuing compounds were identified.
has_subtypes:
# Pathway tier classification
- name: Core Complex Subtypes
  classification: pathway_tier
  description: >-
    FA core complex genes (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FANCT/UBE2T) encode
    the E3 ubiquitin ligase complex that monoubiquitinates the FANCD2-FANCI heterodimer. Patients with
    core complex mutations generally have a later age of cancer onset compared to downstream pathway
    defects.
  children:
  - FA-A
  - FA-B
  - FA-C
  - FA-E
  - FA-F
  - FA-G
  - FA-L
  - FA-T
  evidence:
  - reference: PMID:31558676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with FANCA mutations developed cancer at a significantly older age compared to patients with mutations in other Fanconi genes (mean 18.5 and 5.2 years, respectively, P=0.001)"
    explanation: Israeli cohort demonstrates later cancer onset in core complex (FANCA) vs downstream gene mutations.
- name: ID Complex Subtypes
  classification: pathway_tier
  description: >-
    The FANCD2-FANCI heterodimer is monoubiquitinated by the core complex and recruited to DNA damage
    sites. Mutations in these genes cause intermediate-severity FA phenotypes.
  children:
  - FA-D2
  - FA-I
- name: Downstream Effector Subtypes
  classification: pathway_tier
  description: >-
    Downstream effector genes (BRCA2/FANCD1, BRIP1/FANCJ, PALB2/FANCN, RAD51C/FANCO, RAD51/FANCR,
    BRCA1/FANCS, SLX4/FANCP, ERCC4/FANCQ, XRCC2/FANCU, MAD2L2/FANCV, RFWD3/FANCW) mediate
    homologous recombination repair downstream of FANCD2-FANCI. Patients with FANCD1/BRCA2 and
    FANCN/PALB2 mutations have notably earlier cancer onset and increased risk of childhood solid tumors
    including medulloblastoma and Wilms tumor.
  children:
  - FA-D1
  - FA-J
  - FA-N
  - FA-O
  - FA-P
  - FA-Q
  - FA-R
  - FA-S
  - FA-U
  - FA-V
  - FA-W
  evidence:
  - reference: PMID:31558676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with downstream mutations were found to have significantly more skull anomalies (P<0.001), central nervous system (CNS) abnormalities (P=0.005) and genitourinary anomalies (P=0.03), compared with patients with core complex mutations."
    explanation: Israeli cohort demonstrates more severe congenital anomaly profile in downstream pathway gene mutations.
# Complementation group classification
- name: FA-A
  classification: complementation_group
  description: >-
    Most common complementation group, accounting for 60-70% of all FA cases. FANCA is a component of
    the FA core complex. Patients tend to develop cancer at a later age compared to other FA subtypes.
  subtype_term:
    preferred_term: Fanconi anemia complementation group A
    term:
      id: MONDO:0009215
      label: Fanconi anemia complementation group A
  genes:
  - preferred_term: FANCA
    term:
      id: hgnc:3582
      label: FANCA
  subtype_frequency: "60-70%"
  evidence:
  - reference: PMID:31558676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two-thirds of genetically diagnosed patients had biallelic FANCA mutations. These numbers are similar to the International Fanconi Anemia Registry, in which 60% of the diagnosed patients had FANCA mutations"
    explanation: Israeli cohort confirms FANCA accounts for approximately 60-70% of FA cases.
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms FANCA causes autosomal recessive FA.
- name: FA-B
  classification: complementation_group
  description: >-
    X-linked FA subtype caused by hemizygous FANCB mutations. FANCB is part of the FA core complex.
    Affected males may have more severe congenital anomalies including VACTERL association.
  subtype_term:
    preferred_term: Fanconi anemia complementation group B
    term:
      id: MONDO:0010351
      label: Fanconi anemia complementation group B
  genes:
  - preferred_term: FANCB
    term:
      id: hgnc:3583
      label: FANCB
  subtype_frequency: "<1%"
  inheritance:
  - name: X-linked recessive
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a hemizygous pathogenic variant in FANCB known to cause X-linked FA"
    explanation: GeneReviews confirms FANCB causes X-linked Fanconi anemia.
- name: FA-C
  classification: complementation_group
  description: >-
    Second or third most common FA complementation group depending on population. FANCC is a component
    of the FA core complex. Common Ashkenazi Jewish founder mutation (IVS4+4A>T).
  subtype_term:
    preferred_term: Fanconi anemia complementation group C
    term:
      id: MONDO:0009213
      label: Fanconi anemia complementation group C
  genes:
  - preferred_term: FANCC
    term:
      id: hgnc:3584
      label: FANCC
  subtype_frequency: "~10-15%"
  evidence:
  - reference: PMID:31558676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FANCA (67%), FANCC (13%), FANCG (14%), FANCJ (3%) and FANCD1 (2%)"
    explanation: Israeli cohort shows FANCC accounts for 13% of genetically diagnosed FA cases.
- name: FA-D1
  classification: complementation_group
  description: >-
    Caused by biallelic BRCA2 mutations. Associated with very early-onset malignancies including
    medulloblastoma, Wilms tumor, and AML, typically before age 5. Distinct from heterozygous
    BRCA2 carriers who develop breast/ovarian cancer.
  subtype_term:
    preferred_term: Fanconi anemia complementation group D1
    term:
      id: MONDO:0011584
      label: Fanconi anemia complementation group D1
  genes:
  - preferred_term: BRCA2
    term:
      id: hgnc:1101
      label: BRCA2
  subtype_frequency: "~2%"
  evidence:
  - reference: PMID:31558676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "one patient with a FANCD1 mutation developed medulloblastoma at the age of 3 years. Patients with FANCD1 mutations have been previously described as uniquely developing solid tumors early in life"
    explanation: Confirms early-onset solid tumors in FANCD1/BRCA2 patients.
- name: FA-D2
  classification: complementation_group
  description: >-
    FANCD2 is one of two components of the ID complex that is monoubiquitinated by the core complex.
    FANCD2 mutations cause a moderate FA phenotype.
  subtype_term:
    preferred_term: Fanconi anemia complementation group D2
    term:
      id: MONDO:0009214
      label: Fanconi anemia complementation group D2
  genes:
  - preferred_term: FANCD2
    term:
      id: hgnc:3585
      label: FANCD2
  subtype_frequency: "~3%"
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms FANCD2 causes autosomal recessive FA.
- name: FA-E
  classification: complementation_group
  description: >-
    FANCE is a component of the FA core complex that directly interacts with FANCD2.
  subtype_term:
    preferred_term: Fanconi anemia complementation group E
    term:
      id: MONDO:0010953
      label: Fanconi anemia complementation group E
  genes:
  - preferred_term: FANCE
    term:
      id: hgnc:3586
      label: FANCE
  subtype_frequency: "<1%"
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms FANCE causes autosomal recessive FA.
- name: FA-F
  classification: complementation_group
  description: >-
    FANCF is a core complex adaptor protein required for complex assembly and stability.
  subtype_term:
    preferred_term: Fanconi anemia complementation group F
    term:
      id: MONDO:0011325
      label: Fanconi anemia complementation group F
  genes:
  - preferred_term: FANCF
    term:
      id: hgnc:3587
      label: FANCF
  subtype_frequency: "<1%"
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms FANCF causes autosomal recessive FA.
- name: FA-G
  classification: complementation_group
  description: >-
    Third most common complementation group in some populations, accounting for up to 14% of cases.
    FANCG/XRCC9 is a component of the FA core complex.
  subtype_term:
    preferred_term: Fanconi anemia complementation group G
    term:
      id: MONDO:0013565
      label: Fanconi anemia complementation group G
  genes:
  - preferred_term: FANCG
    term:
      id: hgnc:3588
      label: FANCG
  subtype_frequency: "~10%"
  evidence:
  - reference: PMID:31558676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FANCA (67%), FANCC (13%), FANCG (14%), FANCJ (3%) and FANCD1 (2%)"
    explanation: Israeli cohort shows FANCG accounts for 14% of genetically diagnosed FA cases.
- name: FA-I
  classification: complementation_group
  description: >-
    FANCI forms the ID heterodimer with FANCD2. The complex is monoubiquitinated by the core complex
    and recruited to sites of DNA interstrand crosslinks.
  subtype_term:
    preferred_term: Fanconi anemia complementation group I
    term:
      id: MONDO:0012186
      label: Fanconi anemia complementation group I
  genes:
  - preferred_term: FANCI
    term:
      id: hgnc:25568
      label: FANCI
  subtype_frequency: "<1%"
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms FANCI causes autosomal recessive FA.
- name: FA-J
  classification: complementation_group
  description: >-
    Caused by biallelic mutations in BRIP1 (BACH1), a BRCA1-interacting helicase involved in
    homologous recombination repair. Heterozygous BRIP1 mutations confer increased breast cancer risk.
  subtype_term:
    preferred_term: Fanconi anemia complementation group J
    term:
      id: MONDO:0012187
      label: Fanconi anemia complementation group J
  genes:
  - preferred_term: BRIP1
    term:
      id: hgnc:20473
      label: BRIP1
  subtype_frequency: "~3%"
  evidence:
  - reference: PMID:31558676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FANCA (67%), FANCC (13%), FANCG (14%), FANCJ (3%) and FANCD1 (2%)"
    explanation: Israeli cohort shows FANCJ accounts for 3% of genetically diagnosed FA cases.
- name: FA-L
  classification: complementation_group
  description: >-
    FANCL is the E3 ubiquitin ligase of the FA core complex responsible for monoubiquitinating
    FANCD2 and FANCI.
  subtype_term:
    preferred_term: Fanconi anemia complementation group L
    term:
      id: MONDO:0013566
      label: Fanconi anemia complementation group L
  genes:
  - preferred_term: FANCL
    term:
      id: hgnc:20748
      label: FANCL
  subtype_frequency: "<1%"
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms FANCL causes autosomal recessive FA.
- name: FA-N
  classification: complementation_group
  description: >-
    Caused by biallelic PALB2 mutations. Like FA-D1 (BRCA2), associated with very early-onset
    childhood malignancies. Heterozygous PALB2 mutations are a moderate-penetrance breast cancer
    susceptibility allele.
  subtype_term:
    preferred_term: Fanconi anemia complementation group N
    term:
      id: MONDO:0012565
      label: Fanconi anemia complementation group N
  genes:
  - preferred_term: PALB2
    term:
      id: hgnc:26144
      label: PALB2
  subtype_frequency: "<1%"
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms PALB2/FANCN causes autosomal recessive FA.
- name: FA-O
  classification: complementation_group
  description: >-
    Caused by biallelic RAD51C mutations. RAD51C functions in homologous recombination downstream
    of FANCD2. Heterozygous RAD51C mutations confer ovarian cancer susceptibility.
  subtype_term:
    preferred_term: Fanconi anemia complementation group O
    term:
      id: MONDO:0013248
      label: Fanconi anemia complementation group O
  genes:
  - preferred_term: RAD51C
    term:
      id: hgnc:9820
      label: RAD51C
  subtype_frequency: "<1%"
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms RAD51C/FANCO causes autosomal recessive FA.
- name: FA-P
  classification: complementation_group
  description: >-
    Caused by biallelic SLX4 mutations. SLX4 is a scaffold protein that coordinates multiple
    structure-specific endonucleases for interstrand crosslink repair.
  subtype_term:
    preferred_term: Fanconi anemia complementation group P
    term:
      id: MONDO:0013499
      label: Fanconi anemia complementation group P
  genes:
  - preferred_term: SLX4
    term:
      id: hgnc:23845
      label: SLX4
  subtype_frequency: "<1%"
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms SLX4/FANCP causes autosomal recessive FA.
- name: FA-Q
  classification: complementation_group
  description: >-
    Caused by biallelic ERCC4/XPF mutations. ERCC4 is a structure-specific endonuclease also
    implicated in nucleotide excision repair, creating a phenotypic overlap with xeroderma
    pigmentosum and Cockayne syndrome.
  subtype_term:
    preferred_term: Fanconi anemia complementation group Q
    term:
      id: MONDO:0014108
      label: Fanconi anemia complementation group Q
  genes:
  - preferred_term: ERCC4
    term:
      id: hgnc:3436
      label: ERCC4
  subtype_frequency: "<1%"
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms ERCC4/FANCQ causes autosomal recessive FA.
- name: FA-R
  classification: complementation_group
  description: >-
    Caused by heterozygous dominant-negative RAD51 mutations. The only autosomal dominant form of FA.
    All reported cases arise de novo.
  subtype_term:
    preferred_term: Fanconi anemia complementation group R
    term:
      id: MONDO:0014986
      label: Fanconi anemia complementation group R
  genes:
  - preferred_term: RAD51
    term:
      id: hgnc:9817
      label: RAD51
  subtype_frequency: "<1%"
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a heterozygous pathogenic variant in RAD51 known to cause autosomal dominant FA"
    explanation: GeneReviews confirms RAD51/FANCR causes autosomal dominant FA via de novo mutations.
- name: FA-S
  classification: complementation_group
  description: >-
    Caused by biallelic BRCA1 mutations. Extremely rare, with phenotypic overlap with both FA and
    hereditary breast/ovarian cancer syndrome. Heterozygous BRCA1 carriers have high breast and
    ovarian cancer risk.
  subtype_term:
    preferred_term: Fanconi anemia, complementation group S
    term:
      id: MONDO:0054748
      label: Fanconi anemia, complementation group S
  genes:
  - preferred_term: BRCA1
    term:
      id: hgnc:1100
      label: BRCA1
  subtype_frequency: "<1%"
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms BRCA1/FANCS causes autosomal recessive FA.
- name: FA-T
  classification: complementation_group
  description: >-
    Caused by biallelic UBE2T mutations. UBE2T is the E2 ubiquitin-conjugating enzyme that works
    with the FANCL E3 ligase to monoubiquitinate the ID complex.
  subtype_term:
    preferred_term: Fanconi anemia complementation group T
    term:
      id: MONDO:0014638
      label: Fanconi anemia complementation group T
  genes:
  - preferred_term: UBE2T
    term:
      id: hgnc:25009
      label: UBE2T
  subtype_frequency: "<1%"
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms UBE2T/FANCT causes autosomal recessive FA.
- name: FA-U
  classification: complementation_group
  description: >-
    Caused by biallelic XRCC2 mutations. XRCC2 is a RAD51 paralog involved in homologous
    recombination repair.
  subtype_term:
    preferred_term: Fanconi anemia complementation group U
    term:
      id: MONDO:0014987
      label: Fanconi anemia complementation group U
  genes:
  - preferred_term: XRCC2
    term:
      id: hgnc:12829
      label: XRCC2
  subtype_frequency: "<1%"
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms XRCC2/FANCU causes autosomal recessive FA.
- name: FA-V
  classification: complementation_group
  description: >-
    Caused by biallelic MAD2L2/REV7 mutations. MAD2L2 functions in translesion synthesis and
    also plays roles in mitotic checkpoint signaling.
  subtype_term:
    preferred_term: Fanconi anemia complementation group V
    term:
      id: MONDO:0014985
      label: Fanconi anemia complementation group V
  genes:
  - preferred_term: MAD2L2
    term:
      id: hgnc:6764
      label: MAD2L2
  subtype_frequency: "<1%"
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms MAD2L2/FANCV causes autosomal recessive FA.
- name: FA-W
  classification: complementation_group
  description: >-
    Caused by biallelic RFWD3 mutations. RFWD3 is an E3 ubiquitin ligase that ubiquitinates
    RPA at stalled replication forks to promote homologous recombination.
  subtype_term:
    preferred_term: Fanconi anemia, complementation group W
    term:
      id: MONDO:0044325
      label: Fanconi anemia, complementation group W
  genes:
  - preferred_term: RFWD3
    term:
      id: hgnc:25539
      label: RFWD3
  subtype_frequency: "<1%"
  evidence:
  - reference: PMID:20301575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA"
    explanation: GeneReviews confirms RFWD3/FANCW causes autosomal recessive FA.
notes: Fanconi Anemia is a complex condition that requires multidisciplinary management and regular monitoring to address both hematologic and systemic complications.
disease_term:
  preferred_term: Fanconi anemia
  term:
    id: MONDO:0019391
    label: Fanconi anemia
classifications:
  harrisons_chapter:
  - classification_value: hematologic disorder
  - classification_value: hereditary disease