Short stature, microcephaly, and endocrine dysfunction (SSMED) is a rare autosomal recessive microcephalic primordial dwarfism caused by biallelic hypomorphic variants in XRCC4, an obligate scaffold of the non-homologous end-joining (NHEJ) DNA double-strand-break repair pathway (the binding partner of DNA ligase IV / LIG4). Impaired NHEJ produces increased genomic instability, prenatal-onset (primordial) extreme growth failure, primary microcephaly, facial dysmorphism, and a spectrum of endocrine dysfunction (primary gonadal failure, early-onset metabolic syndrome, and in some reports hypothyroidism), with possible tumor predisposition. Unlike LIG4 syndrome and other NHEJ disorders that present with severe combined immunodeficiency, XRCC4 deficiency characteristically does NOT cause overt immunodeficiency, reflecting differential developmental requirements for NHEJ proteins.
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name: Short Stature, Microcephaly, and Endocrine Dysfunction
creation_date: "2026-08-01T00:00:00Z"
category: Mendelian
synonyms:
- SSMED
- XRCC4-related microcephalic primordial dwarfism
- XRCC4 deficiency
description: >
Short stature, microcephaly, and endocrine dysfunction (SSMED) is a rare
autosomal recessive microcephalic primordial dwarfism caused by biallelic
hypomorphic variants in XRCC4, an obligate scaffold of the non-homologous
end-joining (NHEJ) DNA double-strand-break repair pathway (the binding
partner of DNA ligase IV / LIG4). Impaired NHEJ produces increased genomic
instability, prenatal-onset (primordial) extreme growth failure, primary
microcephaly, facial dysmorphism, and a spectrum of endocrine dysfunction
(primary gonadal failure, early-onset metabolic syndrome, and in some
reports hypothyroidism), with possible tumor predisposition. Unlike LIG4
syndrome and other NHEJ disorders that present with severe combined
immunodeficiency, XRCC4 deficiency characteristically does NOT cause overt
immunodeficiency, reflecting differential developmental requirements for NHEJ
proteins.
disease_term:
preferred_term: short stature, microcephaly, and endocrine dysfunction
term:
id: MONDO:0014686
label: short stature, microcephaly, and endocrine dysfunction
parents:
- Autosomal recessive disease
- Primordial dwarfism
classifications:
isds_skeletal_category:
- classification_value: primordial_dwarfism_and_slender_bones
notes: >-
ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
PMID:36779427), group 21 "Primordial dwarfism and slender bone
dysplasias", NOS 21-0190, listed as "Microcephalic osteodysplastic
primordial dwarfism, XRCC4-related" against OMIM 616541 - the SSMED
entry this dismech file curates. As with the Seckel rows in the same
group, dyadic naming means the table carries neither "SSMED" nor "XRCC4
deficiency", so the OMIM number is what identifies the row. The
assignment is 1:1: the nosology lists exactly one XRCC4 row and this
entry curates exactly that entity. Note that the sibling NHEJ disorder
LIG4 syndrome is not in the 2023 table at all, so its absence here is
not an oversight to correct.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: NOT_YET_DOCUMENTED
notes: >-
No population prevalence or incidence estimate has been published. SSMED is
known from a small number of families reported since 2015 (biallelic XRCC4
variants identified in several consanguineous and non-consanguineous
families). Ascertainment is genotype-first, so case counts are not a
population rate.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >
Biallelic (homozygous or compound heterozygous) hypomorphic XRCC4 variants
cause the disorder; reported in multiple consanguineous families.
evidence:
- reference: PMID:25839420
reference_title: "Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "identified in three affected brothers of a consanguineous Turkish family a \nhomozygous mutation, c.482G>A, in the XRCC4 gene"
explanation: >
Homozygous XRCC4 variant in three affected brothers of a consanguineous
family, consistent with autosomal recessive inheritance.
genetic:
- name: XRCC4
gene_term:
preferred_term: XRCC4
term:
id: hgnc:12831
label: XRCC4
relationship_type: CAUSATIVE
notes: >
XRCC4 (5q14.2) encodes an obligate scaffold of the NHEJ DNA double-strand
break repair complex (the binding partner of DNA ligase IV / LIG4).
Reported biallelic hypomorphic variants include homozygous c.482G>A (a
splice-affecting variant), compound heterozygous c.25delG (p.His9Thrfs*8)
and c.823C>T (p.Arg275*), and an in-frame splice deletion of 23 amino acids.
evidence:
- reference: PMID:25728776
reference_title: "Mutations in the NHEJ component XRCC4 cause primordial dwarfism."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report the identification of biallelic mutations in XRCC4 in five families"
explanation: >
Establishes biallelic XRCC4 variants as the cause of microcephalic
primordial dwarfism across five families.
- reference: PMID:25839420
reference_title: "Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "compound heterozygous mutations c.25delG (p.His9Thrfs*8) and \nc.823C>T (p.Arg275*) in XRCC4"
explanation: >
Documents additional loss-of-function XRCC4 variants in an independent
patient.
pathophysiology:
- name: Impaired Non-Homologous End Joining
biological_scale: MOLECULAR
role: trigger
genes:
- preferred_term: XRCC4
term:
id: hgnc:12831
label: XRCC4
description: >
XRCC4 is indispensable for non-homologous end joining (NHEJ), the major
pathway repairing DNA double-strand breaks, acting as the obligate binding
partner of DNA ligase IV. Biallelic hypomorphic XRCC4 variants impair NHEJ
and defective double-strand-break repair.
biological_processes:
- preferred_term: double-strand break repair via nonhomologous end joining
term:
id: GO:0006303
label: double-strand break repair via nonhomologous end joining
modifier: DECREASED
downstream:
- target: Genomic Instability and Impaired Cell Proliferation
- target: Increased cellular sensitivity to ionizing radiation
description: >-
The direct assay readout of defective NHEJ repair of radiation-induced
double-strand breaks.
evidence:
- reference: PMID:27169690
reference_title: "Mutations in XRCC4 cause primordial dwarfism without causing immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "XRCC4 is indispensable for non-homologous end joining (NHEJ), the \nmajor pathway for repairing DNA double-strand breaks"
explanation: >
Establishes XRCC4 as an essential NHEJ component, the function lost in
disease.
- reference: PMID:25728776
reference_title: "Mutations in the NHEJ component XRCC4 cause primordial dwarfism."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "immunoglobulin levels are normal, and individuals \nlack overt signs of immunodeficiency"
explanation: >
Although XRCC4 NHEJ deficiency impairs immunoglobulin junctional
diversification, immunoglobulin levels remain normal and patients lack
overt immunodeficiency — the differential developmental requirement for
NHEJ proteins that distinguishes XRCC4 deficiency from SCID-causing NHEJ
disorders (e.g. LIG4 syndrome), as asserted in the entry description.
- name: Genomic Instability and Impaired Cell Proliferation
biological_scale: CELLULAR
description: >
Defective NHEJ leaves DNA double-strand breaks unrepaired, causing
hypersensitivity to DSB-inducing agents, increased cell death, and genomic
instability. Impaired proliferation and survival of progenitor cells during
development is proposed to drive the prenatal-onset growth failure and
primary microcephaly.
biological_processes:
- preferred_term: DNA repair
term:
id: GO:0006281
label: DNA repair
modifier: DECREASED
downstream:
- target: Prenatal-onset growth failure
description: >-
Impaired progenitor proliferation and survival during development is the
proposed route to prenatal growth failure.
- target: Short stature
description: >-
The postnatal growth endpoint.
- target: Primary microcephaly
description: >-
Reduced proliferation and survival of neural progenitors is the proposed
route to the microcephaly.
- target: Facial dysmorphism
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Craniofacial consequence of the same developmental proliferation
deficit; no specific route established.
- target: Increased genomic instability
description: >-
The cellular readout of this node, measured directly in patient cells.
- target: Endocrine dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The "E" of SSMED, grouped here as a developmental consequence of the
proliferation defect.
- target: Hypergonadotropic hypogonadism
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Primary gonadal failure; germ cells are among the most
replication-dependent lineages, which is the plausible route.
- target: Insulin resistance / metabolic syndrome
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Early-onset metabolic syndrome reported in affected siblings; grouped
with the endocrine arm, with no established mechanism.
- target: Tumor predisposition
description: >-
Unrepaired double-strand breaks and genomic instability are the expected
route to malignancy; the human evidence is a single case.
evidence:
- reference: PMID:25839420
reference_title: "Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "XRCC4 deficiency leads to hypersensitivity to \nDSB-inducing agents and defective DSB repair, which results in increased cell \ndeath after exposure to genotoxic agents"
explanation: >
Patient-cell studies show defective DSB repair and increased cell death,
the cellular basis of genomic instability and impaired proliferation.
- reference: PMID:25839420
reference_title: "Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "autosomal recessive mutations in XRCC4 induce increased genomic instability and cause a NHEJ-related syndrome defined by facial dysmorphism, primary microcephaly and short stature"
explanation: >
Links XRCC4-driven genomic instability to the core clinical syndrome.
phenotypes:
- name: Short stature
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
frequency: VERY_FREQUENT
evidence:
- reference: PMID:25839420
reference_title: "Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a NHEJ-related syndrome defined by facial dysmorphism, primary microcephaly and short stature"
explanation: >
Short stature is a defining feature of the XRCC4 NHEJ-related syndrome.
- name: Primary microcephaly
phenotype_term:
preferred_term: Primary microcephaly
term:
id: HP:0000252
label: Microcephaly
frequency: VERY_FREQUENT
evidence:
- reference: PMID:25839420
reference_title: "Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a NHEJ-related syndrome defined by facial dysmorphism, primary microcephaly and short stature"
explanation: >
Primary microcephaly is a defining feature of the syndrome.
- name: Prenatal-onset growth failure
phenotype_term:
preferred_term: Prenatal-onset (primordial) growth failure
term:
id: HP:0001511
label: Intrauterine growth retardation
evidence:
- reference: PMID:25728776
reference_title: "Mutations in the NHEJ component XRCC4 cause primordial dwarfism."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "microcephalic primordial \ndwarfism (MPD), a phenotype characterized by prenatal-onset extreme global \ngrowth failure"
explanation: >
XRCC4 deficiency causes microcephalic primordial dwarfism with
prenatal-onset growth failure.
- name: Endocrine dysfunction
phenotype_term:
preferred_term: Endocrine dysfunction
term:
id: HP:0000818
label: Abnormality of the endocrine system
evidence:
- reference: PMID:25742519
reference_title: "An XRCC4 splice mutation associated with severe short stature, gonadal failure, and early-onset metabolic syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "XRCC4 deficiency causing severe postnatal growth failure, microcephaly, \ngonadal failure, metabolic syndrome, and possibly tumor predisposition"
explanation: >
Endocrine dysfunction (gonadal failure, metabolic syndrome) is part of the
XRCC4 phenotype and the defining "E" of SSMED.
- name: Hypergonadotropic hypogonadism
phenotype_term:
preferred_term: Primary gonadal failure
term:
id: HP:0000815
label: Hypergonadotropic hypogonadism
evidence:
- reference: PMID:25742519
reference_title: "An XRCC4 splice mutation associated with severe short stature, gonadal failure, and early-onset metabolic syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "microcephaly, primary gonadal failure, and early-onset metabolic syndrome in late adolescence"
explanation: >
Primary gonadal failure was documented in two adult siblings with XRCC4
deficiency.
- name: Insulin resistance / metabolic syndrome
phenotype_term:
preferred_term: Early-onset metabolic syndrome
term:
id: HP:0000855
label: Insulin resistance
evidence:
- reference: PMID:25742519
reference_title: "An XRCC4 splice mutation associated with severe short stature, gonadal failure, and early-onset metabolic syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "microcephaly, primary gonadal failure, and early-onset metabolic syndrome in late adolescence"
explanation: >
Early-onset metabolic syndrome (insulin resistance) was documented in
affected siblings.
- name: Facial dysmorphism
phenotype_term:
preferred_term: Facial dysmorphism
term:
id: HP:0001999
label: Abnormal facial shape
evidence:
- reference: PMID:25839420
reference_title: "Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a NHEJ-related syndrome defined by facial dysmorphism, primary microcephaly and short stature"
explanation: >
Facial dysmorphism is a defining feature of the syndrome.
- name: Tumor predisposition
phenotype_term:
preferred_term: Neoplasm (possible tumor predisposition)
term:
id: HP:0002664
label: Neoplasm
evidence:
- reference: PMID:25742519
reference_title: "An XRCC4 splice mutation associated with severe short stature, gonadal failure, and early-onset metabolic syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "P2 developed a malignant gastrointestinal stromal tumor at age 28"
explanation: >
A single affected individual developed a malignancy, raising the
possibility of tumor predisposition; the evidence is limited to one case,
hence PARTIAL support.
- category: Cellular
name: Increased genomic instability
phenotype_term:
preferred_term: Increased genomic instability
term:
id: HP:0003220
label: Abnormality of chromosome stability
evidence:
- reference: PMID:25839420
reference_title: "Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "autosomal recessive mutations in XRCC4 induce increased genomic instability"
explanation: >
Patient cells show increased genomic instability due to defective NHEJ.
- category: Cellular
name: Increased cellular sensitivity to ionizing radiation
phenotype_term:
preferred_term: Increased sensitivity to ionizing radiation
term:
id: HP:0011133
label: Increased sensitivity to ionizing radiation
evidence:
- reference: PMID:25728776
reference_title: "Mutations in the NHEJ component XRCC4 cause primordial dwarfism."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "NHEJ-dependent repair of ionizing-radiation-induced DNA double-strand breaks is \ncompromised in XRCC4 cells"
explanation: >
Patient-derived XRCC4 cells show compromised repair of
ionizing-radiation-induced DNA double-strand breaks, i.e. increased
cellular radiosensitivity — the assay basis of the DNA-repair defect.
references:
- reference: PMID:25728776
title: "Mutations in the NHEJ component XRCC4 cause primordial dwarfism."
- reference: PMID:25839420
title: "Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability."
- reference: PMID:25742519
title: "An XRCC4 splice mutation associated with severe short stature, gonadal failure, and early-onset metabolic syndrome."
- reference: PMID:27169690
title: "Mutations in XRCC4 cause primordial dwarfism without causing immunodeficiency."
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Short stature, microcephaly, and endocrine dysfunction is an exceptionally rare, autosomal-recessive developmental DNA-repair disorder caused by biallelic pathogenic variants in XRCC4, encoding X-ray repair cross-complementing protein 4. The disease overlaps strongly with XRCC4-related microcephalic primordial dwarfism, also called XRCC4 deficiency or X4 syndrome. Its best-established manifestations are prenatal-onset growth restriction, severe postnatal short stature, congenital microcephaly that becomes disproportionately severe after birth, variable developmental delay, and marked cellular sensitivity to ionizing radiation. Gonadal failure and early-onset metabolic syndrome were reported in a separate XRCC4 splice-variant family but have not been established as universal features. Most reported patients do not have overt immunodeficiency despite measurable abnormalities of V(D)J junction formation. (OpenTargets Search: Short stature, microcephaly, and endocrine dysfunction, lee2016dnadamageto pages 12-13, murray2015mutationsinthe pages 10-11)
The evidence base is very small and dominated by two 2015 human studies. Consequently, prevalence, penetrance, long-term survival, cancer risk, quality of life, and treatment-response statistics are unknown. No disease-specific clinical trial or approved disease-modifying therapy was identified.
| Domain | Established finding | Quantitative/clinical detail | Ontology suggestions | Evidence strength/key source |
|---|---|---|---|---|
| Disease identity | Short stature, microcephaly, and endocrine dysfunction corresponds to an XRCC4-related Mendelian disorder | MONDO:0014686; Open Targets links the disease to XRCC4 as the associated target | MONDO:0014686; XRCC4 (HGNC:12831) | Strong disease-target mapping (OpenTargets Search: Short stature, microcephaly, and endocrine dysfunction) |
| Core molecular cause | Biallelic XRCC4 defects impair canonical non-homologous end joining (NHEJ) DNA double-strand break repair | XRCC4 is a core NHEJ factor acting with LIG4/XLF; human disease established by multiple affected individuals with pathogenic XRCC4 variants causing primordial dwarfism/microcephaly | GO:0006302 DNA ligation involved in DNA repair; GO:0006974 cellular response to DNA damage stimulus; GO:0000724 double-strand break repair via NHEJ | Strong primary human genetic + cellular evidence, Murray 2015 (murray2015mutationsinthe pages 2-3, murray2015mutationsinthe pages 10-11) |
| Inheritance | Autosomal recessive inheritance is established | Affected families include consanguineous pedigrees and homozygous/compound heterozygous XRCC4 variants in the 2015 cohort; endocrine pedigree also reported as familial recessive in reviews | HP:0000007 Autosomal recessive inheritance | Strong primary/review support (lee2016dnadamageto pages 12-13, murray2015mutationsinthe pages 2-3) |
| Prenatal/postnatal growth failure | Prenatal and postnatal growth retardation are core features | Murray cohort: “all XRCC4-MPD-affected individuals demonstrated in utero and postnatal growth retardation”; severe short stature/dwarfism recurrent across reports | HP:0001511 Growth delay; HP:0000252 Microcephaly-associated primordial dwarfism phenotype; UBERON:0002101 limb/long bone growth context | Strong primary cohort evidence (murray2015mutationsinthe pages 8-9, murray2015mutationsinthe pages 4-5) |
| Progressive microcephaly | Microcephaly is present at birth and becomes more pronounced postnatally | Murray cohort: microcephaly at birth with disproportionate worsening after birth; brain growth appears especially sensitive to unrepaired DNA damage | HP:0000252 Microcephaly; HP:0011451 Progressive microcephaly; UBERON:0000955 brain | Strong primary cohort evidence (murray2015mutationsinthe pages 8-9) |
| Neurodevelopment | Developmental delay is variable, not universal | Murray cohort included none to severe developmental delay; mechanism inferred to involve impaired neurogenesis and apoptosis of developing neural cells | HP:0001263 Global developmental delay; HP:0011344 Severe global developmental delay; CL:0000034 neural stem cell; CL:0000540 neuron | Moderate-strong human cohort + mechanistic support (murray2015mutationsinthe pages 4-5, ribeiro2023dnadamageand pages 9-10) |
| Endocrine dysfunction | Endocrine manifestations are part of the named disease entity but appear limited in the published XRCC4 literature | Review evidence cites a family with severe short stature, gonadal failure, and early-onset metabolic syndrome due to an XRCC4 splice mutation; these findings are not described as common in the larger Murray cohort | HP:0008209 Premature ovarian insufficiency/gonadal dysfunction (approximate); HP:0000824 Abnormality of the gonad; HP:0001943 Metabolic syndrome | Limited/heterogeneous evidence; mainly de Bruin 2015 as summarized in review, not broadly replicated (lee2016dnadamageto pages 12-13) |
| Gonadal failure/metabolic syndrome | Likely real but currently narrow phenotype extension rather than universally established core feature | Reported in a single family in review text; should be treated as limited evidence and possibly allelic/variant-specific until additional cases are published | HP:0000135 Hypogonadism/gonadal failure related term; HP:0001956 Metabolic abnormality | Limited evidence/inference from cited pedigree summary (lee2016dnadamageto pages 12-13) |
| Immune phenotype | Overt immunodeficiency is usually absent despite NHEJ deficiency | Most individuals had normal blood counts, T/B-cell subsets, and immunoglobulins; one patient had chronic non-progressive lymphopenia; normal vaccine responses documented in P1 | HP:0002721 Immunodeficiency (not typical/usually absent); HP:0001888 Lymphopenia | Strong primary cohort evidence (murray2015mutationsinthe pages 5-6) |
| V(D)J recombination | Adaptive immunity is functionally preserved but junctional diversity is perturbed | Deep sequencing showed large numbers of unique productive IGH rearrangements, but significantly reduced random nucleotide insertions at V(D)J junctions | GO:0033151 V(D)J recombination; GO:0043966 histone H2AX phosphorylation (damage response marker context) | Strong primary mechanistic evidence (murray2015mutationsinthe pages 5-6, murray2015mutationsinthe pages 10-11) |
| Radiosensitivity | Patient cells are hypersensitive to ionizing radiation | After irradiation, 99.4% of P1 and 62.3% of P5 asynchronous cells retained >5 γ-H2AX foci at 24 h versus 9.2% of controls; 58% ± 6.0% of DSBs remained unresolved in P1 cells versus 5.4% ± 2.6% in controls | HP:0011297 Increased cellular sensitivity to ionizing radiation; GO:0000785 chromatin, GO:0006974 response to DNA damage | Strong quantitative primary cellular evidence (murray2015mutationsinthe pages 5-6, murray2015mutationsinthe pages 8-9) |
| Environmental information | No environmental cause is established, but ionizing radiation is a clinically important hazard | Authors recommend minimizing clinical X-ray exposure because of marked cellular radiosensitivity | CHEBI:36927 ionizing radiation (exposure concept); NCIT:C16548 Radiation Exposure | Strong management implication from primary cellular data (murray2015mutationsinthe pages 8-9) |
| Anatomy affected | Primary affected systems are developing brain and generalized somatic growth; secondary/occasional involvement may include gonads, kidneys, genital tract | Human cohort includes brain growth failure, proportionate small body size, variable developmental delay; occasional additional features in tables/reviews include renal/genital anomalies | UBERON:0000955 brain; UBERON:0002103 kidney; UBERON:0000991 gonad; UBERON:0000473 neuroepithelium | Moderate evidence; primary for brain/growth, limited for gonadal/renal extensions (murray2015mutationsinthe pages 8-9, murray2015mutationsinthe pages 5-6, lee2016dnadamageto pages 12-13) |
| Diagnosis | Diagnosis is molecular, supported by phenotype plus sequencing and functional interpretation | Exome sequencing/cohort resequencing identified XRCC4 variants; supportive findings include prenatal/postnatal growth failure, microcephaly, variable delay, and cellular radiosensitivity; differential includes other NHEJ disorders such as LIG4, NHEJ1/XLF, DCLRE1C/Artemis, PRKDC | NCIT:C101294 Whole Exome Sequencing; NCIT:C47809 Molecular Diagnosis; HP:0000252; HP:0001511 | Strong primary diagnostic framework (murray2015mutationsinthe pages 2-3) |
| Differential diagnosis | Closest differentials are DNA repair/NHEJ syndromes and primordial dwarfism disorders | XRCC4 differs from LIG4/NHEJ1 by often lacking overt SCID; other microcephalic dwarfism syndromes remain differential diagnoses | MONDO terms for DNA repair disorders; HP:0002721; HP:0001511 | Moderate evidence/inference from comparative discussion (murray2015mutationsinthe pages 10-11, lee2016dnadamageto pages 12-13) |
| Treatment/management | No disease-modifying therapy is established; management is supportive and preventive | Current care is developmental support, surveillance of growth and neurologic status, endocrine replacement if endocrine failure is documented, infection/hematology monitoring as indicated, and avoidance/minimization of diagnostic radiation; no disease-specific clinical trial identified in prior tool search | NCIT:C15783 Supportive Care; NCIT:C15604 Physical Therapy; NCIT:C15220 Hormone Replacement Therapy; NCIT:C94626 Genetic Counseling | Moderate evidence: supportive management inferred from phenotype and radiosensitivity; no approved targeted therapy (murray2015mutationsinthe pages 8-9, murray2015mutationsinthe pages 5-6) |
| Prognosis | Natural history is incompletely defined; childhood survival is compatible, but long-term cancer risk is uncertain | Murray cohort was young and had no observed tumors, yet authors note cancer risk is probably elevated because of radiosensitivity and analogy to other NHEJ disorders | HP:0000006 Autosomal recessive disease course context; NCIT:C17021 Disease Progression | Limited evidence/important uncertainty (murray2015mutationsinthe pages 8-9, murray2015mutationsinthe pages 4-5) |
| Population/epidemiology | Extremely rare disorder; prevalence/incidence unavailable | Only a small number of families/patients are reported in the literature; no robust population estimate located | MONDO:0014686 | Unavailable data; rarity inferred from case-based literature (lee2016dnadamageto pages 12-13, murray2015mutationsinthe pages 2-3) |
| Mouse models | Mouse data support neurodevelopmental vulnerability and explain preserved immunity in residual-function states | Xrcc4-null mice are embryonic lethal because of apoptosis of post-mitotic neurons; Xrcc4M61R separation-of-function mice are DNA-repair deficient with minor adaptive immune impact, while combined deficiency with Xlf/Paxx/Atm causes severe immunodeficiency | MGI:Xrcc4; GO:0006915 apoptosis; CL:0000540 neuron; CL:0000813 memory B cell/T-cell lineage context | Strong model-organism evidence (roch2021anxrcc4mutant pages 1-2) |
| 2023-2024 research context | Recent work reinforces DDR-linked microcephaly mechanisms rather than introducing XRCC4-specific therapy | 2023 review emphasizes that DNA repair defects trigger reduced proliferation, premature differentiation, and apoptosis of neural progenitors causing microcephaly; 2024 ovarian DNA-repair work supports biologic plausibility for gonadal vulnerability but is not XRCC4-syndrome-specific | GO:0008283 cell proliferation; GO:0072331 signal transduction involved in DNA integrity checkpoint; CL:0000047 oocyte | Moderate contextual evidence; mechanistic relevance but partly indirect (ribeiro2023dnadamageand pages 9-10) |
Table: This table compacts the strongest available human, cellular, and mouse evidence for XRCC4-related short stature, microcephaly, and endocrine dysfunction. It highlights which features are well established, which remain limited or inferred, and which data are currently unavailable.
The disease is a Mendelian, syndromic growth and neurodevelopmental disorder arising from defective canonical non-homologous end joining (c-NHEJ). Open Targets maps the exact disease name to MONDO:0014686 and identifies XRCC4 as its sole associated target, citing PMID 25728776 and PMID 24389050. (OpenTargets Search: Short stature, microcephaly, and endocrine dysfunction)
Key identifiers and nomenclature are:
The knowledge summarized here is aggregated disease-level evidence from published pedigrees, primary fibroblast experiments, and mouse studies, not individual EHR data.
The primary cause is germline biallelic XRCC4 dysfunction. XRCC4 forms part of the XRCC4–DNA ligase IV complex and cooperates with XLF/NHEJ1 in ligating DNA double-strand breaks. Disease-associated variants reduce XRCC4 and/or LIG4 abundance or activity and impair NHEJ. (murray2015mutationsinthe pages 2-3, murray2015mutationsinthe pages 10-11, murray2015mutationsinthe pages 4-5)
Reported classes include missense, frameshift/truncating, and splice-altering variants. Explicit examples in the retrieved primary study include p.Trp43Arg and a frameshift/splice-associated allele described as p.His9fs/ss. Exact HGVS descriptions and current ACMG classifications should be verified against the patient’s transcript and ClinVar record before clinical use. (murray2015mutationsinthe pages 2-3, murray2015mutationsinthe pages 8-8)
No validated protective XRCC4 allele, modifier gene, diet, drug, or lifestyle intervention has been reported. Functional redundancy with XLF, PAXX, ATM, and other DNA-damage-response proteins may modify immune and developmental severity, but this is supported principally by mouse genetics rather than proven human modifiers. (roch2021anxrcc4mutant pages 1-2)
| Phenotype | Course and frequency in available evidence | Suggested HPO terms |
|---|---|---|
| Prenatal growth restriction | Present across the definitive XRCC4-MPD cohort; congenital and persistent | HP:0001511 Intrauterine growth retardation |
| Postnatal short stature/primordial dwarfism | Core, severe, chronic, lifelong | HP:0004322 Short stature; HP:0003510 Severe short stature; HP:0001510 Growth delay |
| Congenital microcephaly | Present at birth in all described XRCC4-MPD individuals and becomes more evident postnatally | HP:0000252 Microcephaly; HP:0011451 Progressive microcephaly |
| Developmental delay | Variable from absent to severe in the original cohort | HP:0001263 Global developmental delay; HP:0001249 Intellectual disability |
| Facial/dysmorphic features | Fine or sparse hair, small chin and broad nasal tip were noted across patients, but specificity is uncertain | HP:0008070 Sparse hair; HP:0000347 Micrognathia |
| Gonadal failure | Reported in the endocrine pedigree; frequency unknown | HP:0000135 Hypogonadism; HP:0008209 Premature ovarian insufficiency where applicable |
| Early-onset metabolic syndrome | Reported in the same pedigree; not established in the broader cohort | HP:0001943 Metabolic syndrome |
| Lymphopenia | One individual had chronic, non-progressive depletion; overt infection susceptibility usually absent | HP:0001888 Lymphopenia |
| Renal/genital anomalies | Occasional unilateral renal agenesis, ectopic kidney, bilateral small kidneys, or cryptorchidism in cohort tables; not core | HP:0000104 Renal agenesis; HP:0000085 Horseshoe/ectopic kidney as phenotype-specific; HP:0000028 Cryptorchidism |
The Murray cohort showed “in utero and postnatal growth retardation,” with microcephaly “present at birth, becoming more evident postnatally.” Developmental delay ranged from none to severe. (murray2015mutationsinthe pages 5-6, murray2015mutationsinthe pages 8-9, murray2015mutationsinthe pages 4-5)
Quality-of-life instruments such as EQ-5D, SF-36, or PROMIS have not been reported. Likely functional burdens include small adult stature, learning or developmental needs, endocrine/fertility consequences in affected patients, repeated specialist surveillance, and constraints on radiologic care; these are clinically reasonable inferences rather than measured disease-specific outcomes.
XRCC4 is the established causal gene. The disorder is germline and autosomal recessive; it is not a somatic cancer syndrome. The variants reported in affected people are rare enough to be compatible with a recessive ultrarare disorder, but variant-by-variant gnomAD frequencies were not recoverable from the available papers. No validated modifier gene, reproducible epigenetic signature, recurrent chromosomal rearrangement, anticipation, or common susceptibility locus has been established. (OpenTargets Search: Short stature, microcephaly, and endocrine dysfunction, murray2015mutationsinthe pages 2-3)
Functional evidence is unusually strong. Patient fibroblasts were hypersensitive to ionizing radiation and showed persistent DNA-damage markers. At 24 hours after irradiation, 99.4% of P1 cells and 62.3% of P5 cells retained more than five γ-H2AX foci, versus 9.2% of control cells. Pulse-field electrophoresis showed 58% ± 6.0% of breaks unresolved in p.Trp43Arg cells after 24 hours, versus 5.4% ± 2.6% in controls. Increased micronuclei provided additional evidence of genome instability. (murray2015mutationsinthe pages 5-6, murray2015mutationsinthe pages 8-9)
Suggested annotations include:
No environmental, nutritional, behavioral, infectious, or lifestyle factor is known to initiate XRCC4 disease. There is no evidence for smoking, alcohol, exercise, diet, pollution, radiation exposure in pregnancy, or infectious agents as necessary causal factors.
However, medical ionizing radiation is a significant avoidable hazard after diagnosis. The primary investigators concluded that “clinical exposure to X-rays should be minimized” because XRCC4-mutant fibroblasts were markedly radiosensitive. MRI and ultrasonography are preferable when diagnostically equivalent. This does not imply that clinically essential imaging should be withheld; decisions should involve radiology and genetics specialists and use the lowest reasonable dose. (murray2015mutationsinthe pages 8-9)
The 2023 review of DNA-repair-associated microcephaly describes the current broader model: unrepaired lesions induce cell death, reduced proliferation, and premature differentiation of neural stem/progenitor cells, reducing final brain size. This is authoritative mechanistic context, although it is not an XRCC4-specific patient experiment. DOI: 10.3389/fcell.2023.1268565, published October 2023. (ribeiro2023dnadamageand pages 9-10)
Suggested cell types are neural stem cell (CL:0000047/appropriate current CL descendant), neural progenitor cell, post-mitotic neuron (CL:0000540), B lymphocyte, T lymphocyte, oocyte, and granulosa cell. Relevant processes include apoptosis (GO:0006915), neurogenesis (GO:0022008), cell proliferation (GO:0008283), DNA ligation, and immune-receptor diversification.
There is no disease-specific human transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, or multi-omics signature. The endocrine mechanism is incompletely resolved. Gonadal germ cells may be especially vulnerable to accumulated DNA breaks, but direct proof in XRCC4-syndrome gonadal tissue is lacking.
The primary systems are:
At the subcellular level, the relevant compartment is the nucleus/chromatin at DNA double-strand breaks, where XRCC4 scaffolds LIG4-dependent ligation.
Onset is prenatal and insidious, with fetal growth restriction and congenital microcephaly. Growth restriction persists throughout childhood. Microcephaly becomes disproportionately more severe postnatally, consistent with continuing vulnerability during postnatal brain growth. Developmental outcomes are variable rather than uniformly progressive. Endocrine and metabolic abnormalities may emerge in childhood, puberty, or adulthood, but the available evidence is insufficient to define a standard timeline. (murray2015mutationsinthe pages 8-9, murray2015mutationsinthe pages 4-5)
The condition is chronic and lifelong. No spontaneous remission is expected because the constitutional DNA-repair defect persists. Critical windows likely include fetal neurogenesis, early postnatal brain growth, and pubertal gonadal maturation; only the first two are directly supported by the clinical pattern.
Inheritance is autosomal recessive. For two confirmed heterozygous parents, each pregnancy has a 25% probability of an affected child, 50% probability of a carrier child, and 25% probability of a child inheriting neither familial variant. Penetrance for clearly deleterious biallelic variants appears high, but the number of families is too small for a numerical estimate. Expressivity is variable, particularly for developmental delay, immune findings, and endocrine disease.
Prevalence, incidence, carrier frequency, sex ratio, age distribution, and geographic distribution are unknown. Reported disease is confined to a small number of families, precluding cases-per-100,000 estimates. A possible population founder allele was discussed in the original cohort, but no broadly validated founder effect or population carrier estimate is available. (murray2015mutationsinthe pages 8-9)
There is no evidence of anticipation. Germline mosaicism is theoretically possible but has not been quantified. Consanguinity can enrich homozygous rare alleles but is not necessary for disease.
CMA is useful when a copy-number disorder remains plausible but will miss most sequence-level XRCC4 variants. Karyotyping, FISH, mitochondrial testing, and repeat-expansion testing are not first-line unless other findings indicate them. No validated metabolomic, proteomic, liquid-biopsy, or epigenomic diagnostic exists.
Important alternatives include LIG4 syndrome, NHEJ1/XLF deficiency, PRKDC deficiency, DCLRE1C/Artemis deficiency, Seckel syndrome, microcephalic osteodysplastic primordial dwarfism, PCNT-related MOPD II, and replication-origin disorders such as Meier-Gorlin syndrome. XRCC4 disease is distinguished by strong cellular NHEJ/radiation-sensitivity evidence with severe microcephalic growth failure but usually no overt SCID. (murray2015mutationsinthe pages 2-3, murray2015mutationsinthe pages 10-11)
There are no consensus disease-specific diagnostic criteria, newborn screening program, or population screening recommendation. Cascade testing is appropriate for adult relatives of reproductive age.
Survival rates and life expectancy have not been measured. The published cohort included surviving children and adults, showing compatibility with survival beyond childhood, but the sample is insufficient for actuarial conclusions.
Major morbidity arises from severe stature reduction, microcephaly, variable neurodevelopmental disability, possible gonadal failure/infertility, metabolic disease, and the practical implications of radiation hypersensitivity. The original cohort had no observed tumors, but it was young; investigators considered cancer risk “probably elevated” by analogy with other NHEJ disorders and cellular genomic instability. This remains a precautionary hypothesis, not a quantified syndrome-specific risk. (murray2015mutationsinthe pages 8-9)
No prognostic biomarker is validated. Residual XRCC4/LIG4 activity, growth severity, head-circumference trajectory, developmental status, cytopenias, endocrine abnormalities, and recurrent infection are reasonable clinical surveillance variables.
There is no curative or disease-modifying treatment and no identified XRCC4-specific interventional clinical trial. Current implementation is individualized supportive care:
Growth-hormone efficacy and safety have not been established specifically for XRCC4 disease. Because short stature is primarily developmental/genomic rather than proven GH deficiency, treatment should follow endocrine testing and specialist risk–benefit assessment. Radiotherapy or DNA-damaging chemotherapy would require exceptional caution and specialist dose planning.
Suggested NCIT intervention concepts are Genetic Counseling, Supportive Care, Physical Therapy, Occupational Therapy, Speech Therapy, and Hormone Replacement Therapy. No genotype-guided pharmacotherapy, approved gene replacement, CRISPR therapy, ASO, siRNA, cell therapy, or immunotherapy is available.
Primary prevention through lifestyle change or vaccination is not applicable. Reproductive prevention options include carrier testing, cascade testing, genetic counseling, prenatal diagnosis, and preimplantation genetic testing for a known familial variant.
Secondary prevention consists of early molecular diagnosis, developmental intervention, endocrine/metabolic surveillance, and avoidance of unnecessary radiation. Tertiary prevention includes treatment of hormone deficiencies, metabolic risk, developmental disability, and any hematologic or immune complication.
No disease-specific immunization is needed. Routine vaccines remain appropriate unless an individual immunologic evaluation indicates otherwise; one studied patient had normal vaccine responses. (murray2015mutationsinthe pages 5-6)
No naturally occurring veterinary syndrome confidently attributable to orthologous XRCC4 variants was identified. There is no infectious transmission, zoonotic potential, or cross-species contagion. The mechanism is evolutionarily conserved but studied predominantly in engineered mice and cultured cells.
Relevant taxonomy includes Homo sapiens, NCBI Taxon 9606, and Mus musculus, NCBI Taxon 10090. Veterinary breed ontology annotations are not applicable on present evidence.
Complete Xrcc4 knockout in mice causes late embryonic lethality driven by apoptosis of post-mitotic neurons, making it a strong mechanistic model of nervous-system vulnerability but a poor viable model of the hypomorphic human syndrome. (roch2021anxrcc4mutant pages 1-2)
Roch et al. developed an Xrcc4M61R separation-of-function mouse that cannot interact normally with XLF but can stabilize DNA ligase IV. These mice are DNA-repair deficient yet have only a minor adaptive-immune phenotype. Combining Xrcc4M61R with Paxx, Nhej1/Xlf, or Atm deficiency produces severe immunocompromise, while Xrcc4M61R/Nhej1 double mutants undergo massive post-mitotic neuronal apoptosis and embryonic death. The paper was published 14 September 2021 in eLife, DOI: 10.7554/eLife.69353. Its abstract states that the model provides insight into human XRCC4 deficiency, “in particular its absence of immune deficiency.” (roch2021anxrcc4mutant pages 1-2)
These models are useful for studying NHEJ redundancy, neurodevelopmental apoptosis, V(D)J recombination, radiosensitivity, and genotype–phenotype relationships. Their principal limitation is that complete or combined loss is substantially more severe than most surviving human genotypes. No validated zebrafish, Drosophila, organoid, patient-iPSC, or CRISPR-screen model specific to this syndrome was identified.
The strongest evidence supports biallelic XRCC4 causality, defective NHEJ, radiation hypersensitivity, primordial dwarfism, congenital/progressive microcephaly, and usually preserved clinical immunity. Endocrine dysfunction is credible but rests mainly on one pedigree and should not be assumed in every XRCC4-deficient patient. (lee2016dnadamageto pages 12-13, murray2015mutationsinthe pages 2-3, murray2015mutationsinthe pages 5-6)
Major priorities are an international natural-history registry, systematic endocrine and fertility phenotyping, variant-level ClinVar curation, cancer-risk ascertainment, longitudinal quality-of-life measurement, and development of viable human neural and gonadal cell models. The lack of substantial new XRCC4-specific patient cohorts in 2023–2024 is itself important: recent literature mainly refines the general DNA-damage/neurogenesis framework rather than changing diagnosis or therapy.
References
(OpenTargets Search: Short stature, microcephaly, and endocrine dysfunction): Open Targets Query (Short stature, microcephaly, and endocrine dysfunction, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(lee2016dnadamageto pages 12-13): Youngsoo Lee, Inseo Choi, Jusik Kim, and Keeeun Kim. Dna damage to human genetic disorders with neurodevelopmental defects. Journal of genetic medicine, 13:1-13, Jun 2016. URL: https://doi.org/10.5734/jgm.2016.13.1.1, doi:10.5734/jgm.2016.13.1.1. This article has 21 citations.
(murray2015mutationsinthe pages 10-11): Jennie E. Murray, Mirjam van der Burg, Hanna IJspeert, Paula Carroll, Qian Wu, Takashi Ochi, Andrea Leitch, Edward S. Miller, Boris Kysela, Alireza Jawad, Armand Bottani, Francesco Brancati, Marco Cappa, Valerie Cormier-Daire, Charu Deshpande, Eissa A. Faqeih, Gail E. Graham, Emmanuelle Ranza, Tom L. Blundell, Andrew P. Jackson, Grant S. Stewart, and Louise S. Bicknell. Mutations in the nhej component xrcc4 cause primordial dwarfism. American journal of human genetics, 96 3:412-24, Mar 2015. URL: https://doi.org/10.1016/j.ajhg.2015.01.013, doi:10.1016/j.ajhg.2015.01.013. This article has 67 citations and is from a highest quality peer-reviewed journal.
(murray2015mutationsinthe pages 2-3): Jennie E. Murray, Mirjam van der Burg, Hanna IJspeert, Paula Carroll, Qian Wu, Takashi Ochi, Andrea Leitch, Edward S. Miller, Boris Kysela, Alireza Jawad, Armand Bottani, Francesco Brancati, Marco Cappa, Valerie Cormier-Daire, Charu Deshpande, Eissa A. Faqeih, Gail E. Graham, Emmanuelle Ranza, Tom L. Blundell, Andrew P. Jackson, Grant S. Stewart, and Louise S. Bicknell. Mutations in the nhej component xrcc4 cause primordial dwarfism. American journal of human genetics, 96 3:412-24, Mar 2015. URL: https://doi.org/10.1016/j.ajhg.2015.01.013, doi:10.1016/j.ajhg.2015.01.013. This article has 67 citations and is from a highest quality peer-reviewed journal.
(murray2015mutationsinthe pages 8-9): Jennie E. Murray, Mirjam van der Burg, Hanna IJspeert, Paula Carroll, Qian Wu, Takashi Ochi, Andrea Leitch, Edward S. Miller, Boris Kysela, Alireza Jawad, Armand Bottani, Francesco Brancati, Marco Cappa, Valerie Cormier-Daire, Charu Deshpande, Eissa A. Faqeih, Gail E. Graham, Emmanuelle Ranza, Tom L. Blundell, Andrew P. Jackson, Grant S. Stewart, and Louise S. Bicknell. Mutations in the nhej component xrcc4 cause primordial dwarfism. American journal of human genetics, 96 3:412-24, Mar 2015. URL: https://doi.org/10.1016/j.ajhg.2015.01.013, doi:10.1016/j.ajhg.2015.01.013. This article has 67 citations and is from a highest quality peer-reviewed journal.
(murray2015mutationsinthe pages 4-5): Jennie E. Murray, Mirjam van der Burg, Hanna IJspeert, Paula Carroll, Qian Wu, Takashi Ochi, Andrea Leitch, Edward S. Miller, Boris Kysela, Alireza Jawad, Armand Bottani, Francesco Brancati, Marco Cappa, Valerie Cormier-Daire, Charu Deshpande, Eissa A. Faqeih, Gail E. Graham, Emmanuelle Ranza, Tom L. Blundell, Andrew P. Jackson, Grant S. Stewart, and Louise S. Bicknell. Mutations in the nhej component xrcc4 cause primordial dwarfism. American journal of human genetics, 96 3:412-24, Mar 2015. URL: https://doi.org/10.1016/j.ajhg.2015.01.013, doi:10.1016/j.ajhg.2015.01.013. This article has 67 citations and is from a highest quality peer-reviewed journal.
(ribeiro2023dnadamageand pages 9-10): Jessica Honorato Ribeiro, Nazlican Altinisik, Nicholas Rajan, Mieke Verslegers, Sarah Baatout, Jay Gopalakrishnan, and Roel Quintens. Dna damage and repair: underlying mechanisms leading to microcephaly. Frontiers in Cell and Developmental Biology, Oct 2023. URL: https://doi.org/10.3389/fcell.2023.1268565, doi:10.3389/fcell.2023.1268565. This article has 31 citations.
(murray2015mutationsinthe pages 5-6): Jennie E. Murray, Mirjam van der Burg, Hanna IJspeert, Paula Carroll, Qian Wu, Takashi Ochi, Andrea Leitch, Edward S. Miller, Boris Kysela, Alireza Jawad, Armand Bottani, Francesco Brancati, Marco Cappa, Valerie Cormier-Daire, Charu Deshpande, Eissa A. Faqeih, Gail E. Graham, Emmanuelle Ranza, Tom L. Blundell, Andrew P. Jackson, Grant S. Stewart, and Louise S. Bicknell. Mutations in the nhej component xrcc4 cause primordial dwarfism. American journal of human genetics, 96 3:412-24, Mar 2015. URL: https://doi.org/10.1016/j.ajhg.2015.01.013, doi:10.1016/j.ajhg.2015.01.013. This article has 67 citations and is from a highest quality peer-reviewed journal.
(roch2021anxrcc4mutant pages 1-2): Benoit Roch, Vincent Abramowski, Olivier Etienne, Stefania Musilli, Pierre David, Jean-Baptiste Charbonnier, Isabelle Callebaut, François D Boussin, and Jean-Pierre de Villartay. An xrcc4 mutant mouse, a model for human x4 syndrome, reveals interplays with xlf, paxx, and atm in lymphoid development. eLife, Sep 2021. URL: https://doi.org/10.7554/elife.69353, doi:10.7554/elife.69353. This article has 7 citations and is from a domain leading peer-reviewed journal.
(murray2015mutationsinthe pages 8-8): Jennie E. Murray, Mirjam van der Burg, Hanna IJspeert, Paula Carroll, Qian Wu, Takashi Ochi, Andrea Leitch, Edward S. Miller, Boris Kysela, Alireza Jawad, Armand Bottani, Francesco Brancati, Marco Cappa, Valerie Cormier-Daire, Charu Deshpande, Eissa A. Faqeih, Gail E. Graham, Emmanuelle Ranza, Tom L. Blundell, Andrew P. Jackson, Grant S. Stewart, and Louise S. Bicknell. Mutations in the nhej component xrcc4 cause primordial dwarfism. American journal of human genetics, 96 3:412-24, Mar 2015. URL: https://doi.org/10.1016/j.ajhg.2015.01.013, doi:10.1016/j.ajhg.2015.01.013. This article has 67 citations and is from a highest quality peer-reviewed journal.