8p Inverted Duplication Deletion Syndrome

Chromosomal MONDO:0019876 Pathograph 62 Show in embeddings browser Chromosomal Disorder

8p inverted duplication/deletion syndrome combines a terminal loss of 8p with an inverted duplication of a more proximal segment on the same chromosome. Many recurrent rearrangements retain a copy-neutral spacer, whereas some nonrecurrent forms lack it or acquire additional chromosomal material during stabilization. The phenotype includes developmental and speech delay, intellectual disability, hypotonia, callosal anomalies, seizures and variable congenital malformations. Gene content and clinical severity vary. Common spacer-containing rearrangements preserve GATA4 and SOX7; their deletion is relevant only to particular larger deletions. Most studied cases are sporadic, but transmission of the unbalanced rearrangement across generations has been documented.

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Inheritance

Usually sporadic structural rearrangement HP:0003745

The common inversion-associated pathway was characterized in sporadic cases with maternal origin. Alternative architectures and familial unbalanced transmission prevent a universal de novo or exclusively maternal rule.

Sporadic

Show evidence (2 references)

url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"all ﬁve mothers were heterozygous inv(8)(p23) carriers (inversion heterozygotes)"

Observed in five selected Japanese families. This does not establish that all affected individuals require a maternal inversion.

url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"all deletions in the ﬁve patients had arisen in the maternally derived chromosomes 8"

STRP analysis establishes parent of origin independently of the maternal inversion FISH result. The observation is confined to the five studied families.

Familial transmission of the unbalanced chromosome HP:0000006

Autosomal transmission was documented in a two-generation family with variable intellectual disability. Reproductive counseling depends on the actual rearrangement and parental studies; the small family cannot establish a numerical recurrence risk.

Autosomal dominant inheritance

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Patients 16, 17, 18, 19, and 20 were from the same family and included two sibs and their children (Figure 1). All five individuals pres- ented with mild to moderate ID without any major associated malforma- tion."

Five affected relatives in two generations carried the rearrangement; all had mild to moderate intellectual disability. This is direct transmission of the unbalanced chromosome, not just inheritance of a benign inversion.

◆

Subtypes

Spacer-containing invdupdel(8p)

Terminal deletion and inverted duplication are separated by a copy-neutral interval. Inversion-associated recombination is a proposed formation pathway.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"deﬁned the regions for deletion, intact segment, and for duplication in the ﬁve patients with inv dup del(8p)"

The five mapped cases exemplify this architecture; the statement is not universal across the syndrome.

Invdupdel(8p) without an intervening spacer

Some mapped rearrangements have adjacent deletion and duplication without a copy-neutral spacer, supporting an alternative U-type exchange model.

Show evidence (1 reference)

PMID:35327368 SUPPORT INDIRECT BACKGROUND Human Clinical

"Dicentric chromosome 8 formation can occur by two different mechanisms: U-type exchange and non-allelic homologous recombination mediated by parental paracentric inversion inv(8)(p23.1)"

The authors use endpoint copy-number architecture to distinguish proposed formation routes.

Complex invdupdel(8p) with captured additional chromosomal material

A rearranged 8p end may contain material from another chromosome arm. Buysse characterized an additional 8q gain; that extra imbalance can modify the phenotype and should not be pooled with uncomplicated invdupdel cohorts.

Show evidence (1 reference)

url:https://ricerca.uniba.it/retrieve/dd9e0c64-b05b-1e9c-e053-3a05fe0a45ef/6_sdarticle.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"By high resolution oligo array CGH, we detected the smallest inverted duplication of 8p reported thus far, with additional duplication of 8q24.13/qter on the short arm of the abnormal chromosome 8 (Figs. 1 and 2 A and B)."

The measured complex chromosome contains an additional terminal 8q duplication on 8p. This is evidence for captured material, not direct observation of the proposed replication process.

Discussions and Knowledge Gaps

Which formation steps and gene-dosage mechanisms remain unresolved?

invdupdel8p_mechanism_and_scope

Constitutional FISH, marker and microarray studies establish rearrangement endpoints, while inversion-loop crossover, dicentric breakage and rescue are mechanistic models. GATA4/SOX7 deletion is not a universal explanation for cardiac disease. The 5.1 Mb callosal candidate interval from Vibert combines selected cases, including pure duplications; it does not identify a proven causal gene. Published duplication-size associations are not validated individual prediction rules. Isolated 8p23 deletion network analyses and single-gene animal models cannot be treated as experimental models of the complete invdupdel chromosome. A single severe RSV case proposed defensin deficiency and impaired NK function, but lacked direct DEF copy-number measurement, acute-infection immune assays or rescue; that hypothesis does not justify a universal immunodeficiency pathway.

Show evidence (5 references)

url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf SUPPORT INDIRECT BACKGROUND Human Clinical

"From these ﬁndings, we propose here a model to explain how inv dup del(8p) is formed."

The crossover and rescue sequence is an interpretation of FISH and STR findings, not directly observed meiotic intermediates.

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT INDIRECT BACKGROUND Human Clinical

"we prioritized the candidate genes DLGAP2 and CSMD1 for del(8p) distal and the deleted segment of invdupdel(8p), GATA4 and XKR6 for del(8p)_proximal and dup(8p)_proximal, and RHOBTB2 and CHRNA2 for the duplicated segment of invdupdel(8p) (Supplemental Data)."

Candidate prioritization uses interval content and prior biological knowledge. It does not demonstrate that any one gene accounts for the whole rearrangement phenotype.

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Both GATA4 and SOX7 were copy-number neutral in all individuals with invdupdel(8p) or del(8p)_distal. However, VSD and/or ASD were reported in over one third of individuals with invdupdel(8p) ( n = 15, 38%)"

The recurrent invdupdel subgroup retained both genes despite septal defects in 15/40 assessed individuals. This directly limits a universal GATA4/SOX7-deletion explanation.

+ 2 more references

How should heterogeneous cohorts and proposed care guidance be interpreted?

invdupdel8p_clinical_evidence_scope

The main clinical sources represent selected cohorts: Okur includes 49 recurrent invdupdel cases within 102 individuals with several 8p rearrangements; Vibert includes 33 postnatal cases and three fetuses, with five relatives; Santucci includes 14 invdupdel cases within a 24-person mixed clinic. Their denominators are not pooled. Proposed management recommendations were not evaluated for efficacy. Internal aggregate MRI and cardiac counts in the Santucci table do not reconcile, so those pooled rates are not used. The prenatal 2025 series includes an inherited interstitial-deletion case retaining the terminal 8p segment; its apparently unaffected five-year outcome is not generalized to classic terminal-deletion invdupdel. The eight-case Yurchenko series also reports different seizure and cardiac observations from the larger cohorts, illustrating selection and age effects rather than defining an invariant phenotype.

Show evidence (2 references)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the shared deleted interval in individuals with invdupdel(8p) was the most distal 6.7 Mb and the shared duplicated interval was approximately 11.1 Mb."

CMA-defined shared intervals in the 49-person recurrent subgroup establish simultaneous distal loss and proximal gain; the full duplicated interval varies by individual.

⚙

Pathophysiology

Predisposing 8p23 Repeat and Inversion Architecture

Low-copy repeats at 8p23 and a common inversion polymorphism provide a substrate for a recurrent rearrangement pathway. The inversion alone is not the syndrome. Maternal inversion was measured in five families; other pathways do not require this parental finding.

Downstream

Ectopic Meiotic Recombination In the inversion-associated model, misalignment and crossover generate an abnormal recombinant.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"all ﬁve mothers were heterozygous inv(8)(p23) carriers (inversion heterozygotes)"

Observed in five selected Japanese families. This does not establish that all affected individuals require a maternal inversion.

Ectopic Meiotic Recombination

The inversion-loop model invokes one or two crossovers to explain the observed maternal marker patterns. Historical BAC FISH mapped breakpoint intervals, not nucleotide junctions or the meiosis itself.

DNA recombination GO:0006310

Downstream

Dicentric Chromosome Intermediate The proposed recombination route produces an unstable dicentric intermediate.

Show evidence (2 references)

url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf SUPPORT INDIRECT BACKGROUND Human Clinical

"From these ﬁndings, we propose here a model to explain how inv dup del(8p) is formed."

The crossover and rescue sequence is an interpretation of FISH and STR findings, not directly observed meiotic intermediates.

PMID:35327368 SUPPORT INDIRECT BACKGROUND Human Clinical

"Dicentric chromosome 8 formation can occur by two different mechanisms: U-type exchange and non-allelic homologous recombination mediated by parental paracentric inversion inv(8)(p23.1)"

Formation mechanisms are inferred from constitutional rearrangements and prior molecular studies.

U-type Exchange

An alternative exchange model explains rearrangements lacking the usual spacer. Its assignment is based on endpoint architecture and should not be read as a directly imaged event in every case.

DNA recombination GO:0006310

Downstream

Dicentric Chromosome Intermediate Alternative formation route to a dicentric intermediate.

Show evidence (1 reference)

PMID:35327368 SUPPORT INDIRECT BACKGROUND Human Clinical

"Dicentric chromosome 8 formation can occur by two different mechanisms: U-type exchange and non-allelic homologous recombination mediated by parental paracentric inversion inv(8)(p23.1)"

Formation mechanisms are inferred from constitutional rearrangements and prior molecular studies.

Dicentric Chromosome Intermediate

Two centromeres make the proposed intermediate unstable. Breakage and loss of one centromere can yield the monocentric inverted-duplication/deletion chromosome.

Downstream

Dicentric Resolution Breakage and centromere loss are proposed to resolve the dicentric intermediate.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf SUPPORT INDIRECT BACKGROUND Human Clinical

"rescue by eliminating a part of a duplicated segment and a centromere may result in the inv dup(8) formation."

A proposed rescue explains a stable monocentric endpoint; rescue was not directly observed.

Dicentric Resolution

Breakage with loss of part of the duplicated segment and one centromere is proposed to generate a monocentric chromosome with a broken end. The process is inferred from endpoint marker patterns.

Downstream

Chromosome-End Stabilization The resulting broken end must be stabilized to retain the rearranged chromosome.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf SUPPORT INDIRECT BACKGROUND Human Clinical

"rescue by eliminating a part of a duplicated segment and a centromere may result in the inv dup(8) formation."

A proposed rescue explains a stable monocentric endpoint; rescue was not directly observed.

Chromosome-End Stabilization

After breakage, the chromosome end must be stabilized. Telomere healing and capture are alternative accounts. Complex invdupdel(8p) chromosomes capped by extra 8q material demonstrate capture-associated architecture; a specific break-induced-replication mechanism remains proposed.

telomere maintenance GO:0000723

Downstream

Terminal Deletion with Inverted Proximal Duplication Stabilization leaves the constitutional structural rearrangement.

Show evidence (3 references)

url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf SUPPORT INDIRECT BACKGROUND Human Clinical

"rescue by eliminating a part of a duplicated segment and a centromere may result in the inv dup(8) formation."

A proposed rescue explains a stable monocentric endpoint; rescue was not directly observed.

url:https://ricerca.uniba.it/retrieve/dd9e0c64-b05b-1e9c-e053-3a05fe0a45ef/6_sdarticle.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

The measured complex chromosome contains an additional terminal 8q duplication on 8p. This is evidence for captured material, not direct observation of the proposed replication process.

url:https://ricerca.uniba.it/retrieve/dd9e0c64-b05b-1e9c-e053-3a05fe0a45ef/6_sdarticle.pdf SUPPORT INDIRECT BACKGROUND Human Clinical

"Our data are in favour of break-induced replication (BIR),"

The authors favor BIR after mapping the chromosome; the molecular repair mechanism was not experimentally established.

Terminal Deletion with Inverted Proximal Duplication

The measured endpoint is loss of distal 8p together with inverted gain of a more proximal segment. A spacer is common but not obligatory. Copy-number assays define intervals; cytogenetic or structural studies establish orientation.

Downstream

Reduced Distal 8p Gene Dosage The terminal deletion leaves one copy of genes in the deleted interval.

Increased Proximal 8p Gene Dosage The duplication produces three copies of genes in its interval.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the shared deleted interval in individuals with invdupdel(8p) was the most distal 6.7 Mb and the shared duplicated interval was approximately 11.1 Mb."

CMA-defined shared intervals in the 49-person recurrent subgroup establish simultaneous distal loss and proximal gain; the full duplicated interval varies by individual.

Reduced Distal 8p Gene Dosage

The deleted region contains multiple candidate contributors, including DLGAP2 and CSMD1 in recurrent cases. Gene-specific contributions and interactions with the duplicated segment remain incompletely resolved.

Downstream

Combined Regional Dosage Imbalance Loss acts together with the adjacent gain; the clinical effect cannot generally be assigned to one deleted gene.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT INDIRECT BACKGROUND Human Clinical

Candidate prioritization uses interval content and prior biological knowledge. It does not demonstrate that any one gene accounts for the whole rearrangement phenotype.

Increased Proximal 8p Gene Dosage

Variable duplicated intervals contain neurodevelopmental candidates such as RHOBTB2 and CHRNA2. A gene causing another disorder through a point mutation does not by itself establish triplosensitivity.

Downstream

Combined Regional Dosage Imbalance Increased dosage combines with distal loss and may contribute to variable severity.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT INDIRECT BACKGROUND Human Clinical

Candidate prioritization uses interval content and prior biological knowledge. It does not demonstrate that any one gene accounts for the whole rearrangement phenotype.

Combined Regional Dosage Imbalance

The combined constitutional copy-number lesion underlies the syndrome. Clinical edges summarize associations with this multigene lesion; molecular intermediates for most individual manifestations remain unknown. GATA4 and SOX7 are usually copy-neutral in recurrent spacer-containing cases.

Downstream

Global Developmental Delay Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Intellectual Disability Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Delayed Speech and Language Development Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Motor Delay Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Agenesis of Corpus Callosum Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Hypoplasia of Corpus Callosum Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Seizure Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Hypotonia Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Hypertonia Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Dystonia Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Cerebellar Hypoplasia Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Ventriculomegaly Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Microcephaly Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Macrocephaly Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Stereotypy Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Autistic Behavior Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Sleep Disturbance Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Ventricular Septal Defect Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Atrial Septal Defect Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Patent Foramen Ovale Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Patent Ductus Arteriosus Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Constipation Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Gastroesophageal Reflux Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Feeding Difficulties Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Failure to Thrive Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Short Stature Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Scoliosis Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Joint Hypermobility Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Inguinal Hernia Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Strabismus Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Cerebral Visual Impairment Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Cryptorchidism Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Hypospadias Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Neonatal Respiratory Distress Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Neonatal Hypoglycemia Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Single Umbilical Artery Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Wide Mouth Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Broad Forehead Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Hypertelorism Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Macrotia Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Congenital Heart Malformation Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Polyvalvular Dysplasia Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Congenital Diaphragmatic Hernia Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Brain Atrophy Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Micrognathia Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Thin Upper Lip Vermilion Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.

Show evidence (3 references)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the shared deleted interval in individuals with invdupdel(8p) was the most distal 6.7 Mb and the shared duplicated interval was approximately 11.1 Mb."

CMA-defined shared intervals in the 49-person recurrent subgroup establish simultaneous distal loss and proximal gain; the full duplicated interval varies by individual.

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT INDIRECT BACKGROUND Human Clinical

Candidate prioritization uses interval content and prior biological knowledge. It does not demonstrate that any one gene accounts for the whole rearrangement phenotype.

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

The recurrent invdupdel subgroup retained both genes despite septal defects in 15/40 assessed individuals. This directly limits a universal GATA4/SOX7-deletion explanation.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Cardiovascular 7

Ventricular Septal Defect HP:0001629

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"VSD 30% - 71% 36% ASD 15% - 57% 100% PFO 18% - - - PDA 13% - 29%"

Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.

Atrial Septal Defect HP:0001631

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"ASD 15% - 57% 100% PFO 18% - - - PDA 13% - 29% - PS 3% 25% 71%"

Patent Foramen Ovale HP:0001655

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"PFO 18% - - - PDA 13% - 29% - PS 3% 25% 71% 64% Arrhythmia - - 33%"

Patent Ductus Arteriosus HP:0001643

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"PDA 13% - 29% - PS 3% 25% 71% 64% Arrhythmia - - 33% ( n = 3/9) 8%"

Single Umbilical Artery HP:0001195

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Single umbilical artery 16% - - 17% SGA 14% - 33% 25% Cardiac ﬁnding 10% - - 25% Oligo-/polyhydramnios,"

Congenital Heart Malformation Abnormal heart morphology HP:0001627

Coarse binding: variable spectrum

Show evidence (1 reference)

"Among extra-neurological manifestations, 12/29 patients had congenital heart defects (41%) and 10/34 patients had orthopedic anomalies."

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

Polyvalvular Dysplasia Abnormal heart valve morphology HP:0001654

Coarse binding: no hpo term

Show evidence (1 reference)

PMID:28211984 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the present case had severe polyvalvular dysplasia and the infant deceased at day 12 of life."

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

Digestive 4

Constipation HP:0002019

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Constipation 73% 25% 67% 58% GERD 55% 50% 56% 33% Feeding dif ﬁculty 22% - - 17% Diarrhea 6%"

Gastroesophageal Reflux HP:0002020

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"GERD 55% 50% 56% 33% Feeding dif ﬁculty 22% - - 17% Diarrhea 6% - 11% 8% Musculoskeletal issues"

Feeding Difficulties HP:0011968

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Feeding dif ﬁculty 63% - 22% 42% Poor suck 57% - 33% 42% Overly sleepy 43% 50% 11% 33%"

Inguinal Hernia HP:0000023

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Inguinal hernia 8% 50% - - Visual issues 55% 75% 56% 50% Refractive errors 29% 75% 33% 50% Strabismus"

Ear 2

Recurrent Otitis Media HP:0000403

No specific causal immune pathway is established by the cohort. Recurrent infections are retained as clinical findings without an asserted defensin-to-infection causal edge.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Otitis media 33% 25% 11% 25% Upper respiratory 16% - 11% 17% Urinary tract 14% - 11% 17% Sleep"

Macrotia HP:0000400

Show evidence (1 reference)

"Facial dysmorphisma 28/32 88% Common features: Wide mouth ( n = 9), broad ( n = 6) or prominent (n = 2) forehead or frontal bossing ( n = 2), hypertelorism (n = 5), sunken eyes ( n = 4), plagiocephaly (n = 4), macrotia ( n = 4)"

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

Eye 4

Strabismus HP:0000486

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Strabismus 18% - 33% 17% Cortical visual impairment 12% - 11% - Optic nerve (atrophy/enlarged/cupped) 8% - - -"

Cerebral Visual Impairment HP:0100704

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Cortical visual impairment 12% - 11% - Optic nerve (atrophy/enlarged/cupped) 8% - - - V. Okur et al. 3"

Hypertelorism HP:0000316

Show evidence (1 reference)

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

Abnormal Refraction Abnormality of refraction HP:0000539

Retained as a cohort observation; the source does not establish a specific downstream molecular mechanism.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Refractive errors 29% 75% 33% 50% Strabismus 18% - 33% 17% Cortical visual impairment 12% - 11% - Optic"

Table 1 first column, recurrent invdupdel subgroup n=49; adjacent columns are other rearrangements. The aggregate does not supply lesion-specific frequencies.

Genitourinary 4

Cryptorchidism HP:0000028

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Cryptorchidism 35% ( n = 7/20) 25% ( n = 1/4) - - Hypospadias 10% ( n = 2/20)"

Hypospadias HP:0000047

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Hypospadias 10% ( n = 2/20) - 25% ( n = 1/4) 20% ( n = 1/5) Hydronephrosis, kidney"

Recurrent Urinary Tract Infections HP:0000010

No specific causal immune pathway is established by the cohort. Recurrent infections are retained as clinical findings without an asserted defensin-to-infection causal edge.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Urinary tract 14% - 11% 17% Sleep problems 45% 25% 22% 58% Dental problems 53% 50% 56% 33% Skin"

Renal Abnormalities Abnormality of the kidney HP:0000077

Coarse binding: source unspecified

The cohort groups kidney findings without enough lesion detail to assign a single narrower term or causal pathway.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Hydronephrosis, kidney issues 12% 50% - - Frequent infections 43% 25% 22% 25% Otitis media 33% 25% 11% 25%"

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

Head and Neck 7

Microcephaly HP:0000252

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Microcephaly 4% - 22% 58% Seizures 55% 25% 44% 42% Absence 37% - 11% 25% Febrile 18% - -"

Macrocephaly HP:0000256

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Macrocephaly 10% - - - Microcephaly 4% - 22% 58% Seizures 55% 25% 44% 42% Absence 37% - 11%"

Wide Mouth HP:0000154

Show evidence (1 reference)

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

Broad Forehead HP:0000337

Show evidence (1 reference)

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

Dental Abnormalities Abnormality of the dentition HP:0000164

Coarse binding: source unspecified

Retained as a cohort observation; the source does not establish a specific downstream molecular mechanism.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Dental problems 53% 50% 56% 33% Skin problems 45% 25% 22% 25% ADD attention deﬁcit disorder, ADHD attention deﬁcit–"

Table 1 first column, recurrent invdupdel subgroup n=49; adjacent columns are other rearrangements. The aggregate does not supply lesion-specific frequencies.

Micrognathia HP:0000347

Show evidence (1 reference)

PMID:35327368 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Sloping forehead, hypertelorism, upslanted palpebral fissures, wide nasal base, thin upper lip, micrognathia, malocclusion, large and deformed ears"

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

Thin Upper Lip Vermilion HP:0000219

Show evidence (1 reference)

PMID:35327368 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Sloping forehead, hypertelorism, upslanted palpebral fissures, wide nasal base, thin upper lip, micrognathia, malocclusion, large and deformed ears"

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

Immune 1

Recurrent Respiratory Infections HP:0002205

No specific causal immune pathway is established by the cohort. Recurrent infections are retained as clinical findings without an asserted defensin-to-infection causal edge.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Upper respiratory 16% - 11% 17% Urinary tract 14% - 11% 17% Sleep problems 45% 25% 22% 58% Dental"

Integument 1

Skin Abnormalities Abnormality of the skin HP:0000951

Coarse binding: source unspecified

Retained as a cohort observation; the source does not establish a specific downstream molecular mechanism.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Skin problems 45% 25% 22% 25% ADD attention deﬁcit disorder, ADHD attention deﬁcit– hyperactivity disorder, ASD atrial septal defect,"

Table 1 first column, recurrent invdupdel subgroup n=49; adjacent columns are other rearrangements. The aggregate does not supply lesion-specific frequencies.

Metabolism 1

Neonatal Hypoglycemia HP:0001998

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Hypoglycemia 18% 25% 22% 8% Anthropometric measurements Birth weight Z-scores Mean −0.2 0.08 −1.0 −1.45 Median −0.13 0.3 −0.8"

Musculoskeletal 5

Hypotonia HP:0001252

Show evidence (2 references)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Hypotonia 88% 50% 56% 42% Hypertonia 39% 25% 56% 25% Difﬁculty walking/clumsiness 29% - 67% 33% Macrocephaly 10% -"

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

PMID:35327368 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All patients were characterized by a delay in early psychomotor and language development of varying degrees, craniofacial dysmorphisms, and hypotonia."

All eight unrelated children aged two to nine years had these findings. This small series is not pooled with the other cohorts.

Hypertonia HP:0001276

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Hypotonia was accompanied by hypertonia, prominently in the lower extremities, later in life."

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

Scoliosis HP:0002650

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Scoliosis 22% 25% - 25% Vertebral abnormalities 8% 25% - - Hypermobile joints 8% - 11% 8% Coxa valga/hip"

Joint Hypermobility HP:0001382

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Hypermobile joints 8% - 11% 8% Coxa valga/hip anomalies 8% - - 17% Rib anomalies 6% - - -"

Congenital Diaphragmatic Hernia HP:0000776

Show evidence (1 reference)

"Two patients were deceased, patient 5 at 4 years old (cause of death undetailed) and patient 33 at 4 months in a context of diaphragmatic hernia."

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

Nervous System 15

Global Developmental Delay HP:0001263

Show evidence (2 references)

"Global developmental delay 32/33 97% 27"

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

PMID:35327368 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All patients were characterized by a delay in early psychomotor and language development of varying degrees, craniofacial dysmorphisms, and hypotonia."

All eight unrelated children aged two to nine years had these findings. This small series is not pooled with the other cohorts.

Intellectual Disability HP:0001249

Show evidence (1 reference)

"Intellectual disability (patients ≥5 years old) 19/19 100% 38"

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

Delayed Speech and Language Development HP:0000750

Show evidence (2 references)

"Ninety-six percentage (27/28) of patients had speech delay and 37.5% (9/24) of patients older than 3 years (3 – 13.8 years) had not acquired language at last evaluation."

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

PMID:35327368 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All patients were characterized by a delay in early psychomotor and language development of varying degrees, craniofacial dysmorphisms, and hypotonia."

All eight unrelated children aged two to nine years had these findings. This small series is not pooled with the other cohorts.

Motor Delay HP:0001270

Show evidence (1 reference)

"developed global development delay including motor delay in 93% (27/29) of patients."

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

Agenesis of Corpus Callosum HP:0001274

Show evidence (1 reference)

"Sixty-three percent of patients presented AnCC ( n = 17/27). ACC was complete in 35% ( n = 6/17) of cases and partial in 29% (n = 5/17)."

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

Hypoplasia of Corpus Callosum Hypoplasia of the corpus callosum HP:0002079

Show evidence (1 reference)

"Twenty-four percentage of patients ( n = 4/17) had a short and thin CC and 12% ( n = 2/17) had CC hypoplasia."

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

Seizure HP:0001250

Show evidence (1 reference)

"Thirty-four percent ( n = 11/32) of patients had epilepsy starting between 2 months and 9 years, characterized by absences ( n = 5), generalized tonic –clonic ( n = 3), myoclonic ( n = 2), and focal motor (n = 2) seizures."

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

Dystonia HP:0001332

Show evidence (1 reference)

"Other neurological symptoms included spasticity (n = 6) and dystonia ( n = 2)."

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

Cerebellar Hypoplasia HP:0001321

Show evidence (1 reference)

"Other described major cerebral anomalies were cerebellar hypoplasia ( n = 2), Dandy – Walker complex ( n = 1), and simplified frontal gyration with a lipoma of the pituitary stalk ( n = 1)."

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

Ventriculomegaly HP:0002119

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Hydrocephalus/ventriculomegaly 27% - - 20% Cerebral/cerebellar atrophy 16% - - - Dandy– Walker 9% - - Intracranial cyst 9%"

Stereotypy Motor stereotypy HP:0000733

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Stereotype 22% 25% 13% 25% Aggressivity/tantrums/impulsivity 14% - 50% 33% Sensory issues 8% 25% - 25% Autism 6% 50%"

Autistic Behavior HP:0000729

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Autism 6% 50% 25% 17% ADD/ADHD/hyperactivity 4% 50% 38% 58% Echolalia 2% - 11% 17% Anxiety 2% 25% 13%"

Sleep Disturbance HP:0002360

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Sleep problems 45% 25% 22% 58% Dental problems 53% 50% 56% 33% Skin problems 45% 25% 22% 25% ADD"

Aggressive Behavior HP:0000718

Retained as a cohort observation; the source does not establish a specific downstream molecular mechanism.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Aggressivity/tantrums/impulsivity 14% - 50% 33% Sensory issues 8% 25% - 25% Autism 6% 50% 25% 17% ADD/ADHD/hyperactivity 4% 50%"

Table 1 first column, recurrent invdupdel subgroup n=49; adjacent columns are other rearrangements. The aggregate does not supply lesion-specific frequencies.

Brain Atrophy HP:0012444

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Cerebral/cerebellar atrophy 16% - - - Dandy– Walker 9% - - Intracranial cyst 9% - - - Other 22%"

The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.

Respiratory 1

Neonatal Respiratory Distress HP:0002643

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Respiratory distress 18% - 22% 17% Hypoglycemia 18% 25% 22% 8% Anthropometric measurements Birth weight Z-scores Mean −0.2 0.08"

Growth 2

Failure to Thrive HP:0001508

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"FTT/poor weight gain 37% - 11% 17% Obesity/overweight - 50% 67% 30% V. Okur et al. 2 Genetics in"

Short Stature HP:0004322

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Short stature was reported in 10–20% of individuals across all rearrangements (Table 1)."

🧬

Genetic Associations

GATA4

Gene: GATA4 hgnc:4173

Show evidence (2 references)

PMID:27343326 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"aCGH detected an 11.35 Mb deletion in 8p23.3-p23.1 encompassing SOX7 and GATA4, and a 31.99 Mb duplication in 8p23.1-p11.1 in the fetus."

A molecularly characterized atypical fetus with hypoplastic left heart demonstrates conditional deletion of both genes, not universal involvement.

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

The recurrent invdupdel subgroup retained both genes despite septal defects in 15/40 assessed individuals. This directly limits a universal GATA4/SOX7-deletion explanation.

SOX7

Gene: SOX7 hgnc:18196

Show evidence (2 references)

PMID:27343326 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"aCGH detected an 11.35 Mb deletion in 8p23.3-p23.1 encompassing SOX7 and GATA4, and a 31.99 Mb duplication in 8p23.1-p11.1 in the fetus."

A molecularly characterized atypical fetus with hypoplastic left heart demonstrates conditional deletion of both genes, not universal involvement.

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

The recurrent invdupdel subgroup retained both genes despite septal defects in 15/40 assessed individuals. This directly limits a universal GATA4/SOX7-deletion explanation.

RHOBTB2

Gene: RHOBTB2 hgnc:18756

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT INDIRECT BACKGROUND Human Clinical

Candidate prioritization uses interval content and prior biological knowledge. It does not demonstrate that any one gene accounts for the whole rearrangement phenotype.

CHRNA2

Gene: CHRNA2 hgnc:1956

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT INDIRECT BACKGROUND Human Clinical

Candidate prioritization uses interval content and prior biological knowledge. It does not demonstrate that any one gene accounts for the whole rearrangement phenotype.

💊

Medical Actions

Antiseizure Medication

Action: Pharmacotherapy NCIT:C15986

Individualize antiseizure treatment to seizure type and clinical response. Cohort patients received levetiracetam, valproate, oxcarbazepine and other agents; this observational experience does not establish a preferred syndrome-specific drug.

Mechanism Target:

INHIBITS Seizure — Symptomatic management of this manifestation; the underlying chromosome rearrangement is unchanged.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Many individuals with invdupdel(8p) had medically manageable seizures. Levetiracetam, sodium valproate, oxcarbazepine, pheno- barbital, topiramate, and phenytoin were used as monotherapy or in combinations."

Direct clinical treatment experience in invdupdel(8p); no randomized comparison or universal response is implied.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

Direct clinical treatment experience in invdupdel(8p); no randomized comparison or universal response is implied.

Developmental Rehabilitation

Action: Rehabilitation NCIT:C15315

Occupational and physical therapy support motor function, daily activities and independence. Intensity is individualized over development; the proposed guidance recommends ongoing oversight rather than automatic lifelong continuous therapy. This functional support is not evidence that therapy reverses the underlying hypotonia.

Mechanism Target:

INHIBITS Motor Delay — Symptomatic management of this manifestation; the underlying chromosome rearrangement is unchanged.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"Occupational, physical, and speech therapy play an important role for individuals with 8p, due to the helpful impact on func - tional mobility, activities of daily living, and communication."

Expert care recommendations informed by a mixed 8p clinic cohort, not a treatment efficacy trial.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"Occupational, physical, and speech therapy play an important role for individuals with 8p, due to the helpful impact on func - tional mobility, activities of daily living, and communication."

Expert care recommendations informed by a mixed 8p clinic cohort, not a treatment efficacy trial.

Speech Therapy and Augmentative Communication

Action: Speech Language Therapy NCIT:C159273

Use speech-language therapy and augmentative or alternative communication suited to abilities. In the clinic series all 14 invdupdel participants used or were recommended augmentative communication; this is a care observation, not proof of a particular device benefit.

Mechanism Target:

INHIBITS Delayed Speech and Language Development — Symptomatic management of this manifestation; the underlying chromosome rearrangement is unchanged.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"speech therapy is recommended to increase communication for individuals with difficulty speaking, understanding, learning, and communicating."

Proposed care supports communication-focused therapy.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"speech therapy is recommended to increase communication for individuals with difficulty speaking, understanding, learning, and communicating."

Proposed care supports communication-focused therapy.

Feeding and Nutritional Support

Action: Nutritional Support NCIT:C15433

Assess swallowing safety and nutritional adequacy; modify feeds and consider nasogastric or gastrostomy support when required.

Mechanism Target:

INHIBITS Feeding Difficulties — Symptomatic management of this manifestation; the underlying chromosome rearrangement is unchanged.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"Assess nutritional adequacy, consider nasogastric or gastrostomy tube placement if needed."

Expert care recommendation; tube feeding is based on individual need.

INHIBITS Failure to Thrive — Symptomatic management of this manifestation; the underlying chromosome rearrangement is unchanged.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"Assess nutritional adequacy, consider nasogastric or gastrostomy tube placement if needed."

Expert care recommendation; tube feeding is based on individual need.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"Assess nutritional adequacy, consider nasogastric or gastrostomy tube placement if needed."

Expert care recommendation; tube feeding is based on individual need.

Indicated Cardiac Surgical Intervention

Action: Cardiovascular Surgical Procedure NCIT:C49803

Platform: Surgery

Correct congenital cardiac lesions when standard cardiology and cardiac-surgery evaluation indicates an intervention. In the mixed 8p clinic cohort, most cardiac findings did not require surgery, while four children had pacemaker placement, PDA coiling, ASD repair or Tetralogy of Fallot-associated surgery; this supports anomaly-specific management rather than routine syndrome-wide repair.

Mechanism Target:

INHIBITS Congenital Heart Malformation — Symptomatic, lesion-specific management of structural heart disease; the underlying chromosome rearrangement is unchanged.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"Cardiac findings largely did not require surgical interventions; 4 children that did require sur - gical interventions included a pacemaker for supraventricular tachycardia, a child requiring coiling for a patent ductus arteri - osus (PDA), repair for atrial septal defect (ASD), and one child..."

Mixed 8p clinic data document that a minority of cardiac findings required procedural intervention; the passage does not establish a fixed operation or frequency for invdupdel(8p).

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

Mixed 8p clinic data document that a minority of cardiac findings required procedural intervention; the passage does not establish a fixed operation or frequency for invdupdel(8p).

Constipation Management

Action: Supportive Care NCIT:C15747

Treat constipation according to clinical need as part of multidisciplinary supportive care. The syndrome literature does not establish a preferred drug regimen.

Mechanism Target:

INHIBITS Constipation — Symptomatic management of this manifestation; the underlying chromosome rearrangement is unchanged.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"Assess for and manage constipation [2]."

The care table explicitly includes constipation management; a specific agent is not prescribed.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"Assess for and manage constipation [2]."

The care table explicitly includes constipation management; a specific agent is not prescribed.

Genetic Counseling

Category: Counseling / Informational Action: Genetic Counseling NCIT:C15240

Discuss the measured rearrangement, variable phenotype, parental testing and possible transmission. A common inversion polymorphism alone does not determine an individual recurrence probability.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"Consultation with a clinical geneticist and/or genetic counselor helps the family to understand the diagnosis and consider implications for family planning."

Guidance supports counseling; the familial cohort prevents a universal no-recurrence claim.

🔬

Diagnosis

Chromosomal microarray and structural characterization

CMA identifies the terminal deletion, duplicated interval, spacer if present, and additional pathogenic copy-number changes. Karyotyping and targeted FISH can establish the orientation and chromosomal context. Array intervals are platform-dependent and are not nucleotide-resolved junctions.

Show evidence (2 references)

PMID:27343326 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Metaphase FISH confirmed inv dup del(8p)."

CMA established copy-number intervals and metaphase FISH confirmed the structural rearrangement.

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the shared deleted interval in individuals with invdupdel(8p) was the most distal 6.7 Mb and the shared duplicated interval was approximately 11.1 Mb."

CMA-defined shared intervals in the 49-person recurrent subgroup establish simultaneous distal loss and proximal gain; the full duplicated interval varies by individual.

Parental studies and individualized recurrence assessment

Study both parents according to the proband architecture. Routine karyotyping can miss a cryptic inversion; targeted structural testing may be needed. Distinguish a benign inversion carrier from a parent carrying the unbalanced rearrangement. Do not give a universal zero-recurrence assurance.

Show evidence (2 references)

url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"all ﬁve mothers were heterozygous inv(8)(p23) carriers (inversion heterozygotes)"

Observed in five selected Japanese families. This does not establish that all affected individuals require a maternal inversion.

Neurologic evaluation and indicated EEG or MRI

The proposed 8p care guidance recommends EEG when seizures are suspected. Brain MRI is considered before age three for seizures, abnormal head growth or focal findings; screening MRI after age three is proposed in the absence of focal findings. This is expert guidance from a small mixed-8p clinic, not a tested screening trial.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"Neurological • Electroencephalogram (EEG) if seizures are suspected. • MRI brain (without contrast) to evaluate for brain malformations if seizures are present, if head circumference is not progressing steadily, or if there are focal abnormalities on the neurologic exam prior to age 3. •..."

Table 4 recommendations; clinical indications and age are preserved.

Cardiac evaluation

Cardiology evaluation with consideration of echocardiography assesses congenital heart disease; ECG can be considered for arrhythmia assessment. The spectrum is not explained solely by GATA4 dosage.

Show evidence (1 reference)

url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"Cardiovascular • Cardiology referral for consideration of echocardiogram (ECHO) to assess congenital heart disease and electrocardiogram (ECG) for arrhythmia assessment."

Proposed care guidance across chromosome 8p disorders; not evidence of screening efficacy.

Growth, vision, hearing and complication surveillance

Track growth and feeding, assess scoliosis clinically, and examine for undescended testes or hypospadias. The proposed guidance includes annual comprehensive ophthalmology with cerebral visual impairment assessment and audiology for speech delay or hearing concerns. It does not establish an elevated population frequency of hearing loss.

Show evidence (2 references)

url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"Eyes • Ophthalmologic evaluation annually with an ophthalmologist, specifically requesting a comprehensive examination that includes testing for cortical vision impairment."

Annual ophthalmology is proposed with explicit assessment of cortical/cerebral visual impairment.

url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf SUPPORT DIRECT REVIEW SYNTHESIS Other

"Hearing • Audiologic evaluation with an Audiologist is recommended if speech delay or clinical concerns, rates of hearing loss are not reported as elevated in this population."

Audiology is indicated for concerns or speech delay; the source does not claim a high hearing-loss rate.

📈

Progression

Infancy and early childhood

Congenital abnormalities and neonatal hypotonia or feeding difficulties may precede developmental and speech delay. Seizure onset is variable, and selected cohorts cannot provide an individual prognosis.

Show evidence (1 reference)

"Neonatal hypotonia was described in 12/28 patients (data not avail- able for five patients; Table 1). Then, 97% of patients ( n = 32/33) developed global development delay including motor delay in 93% (27/29) of patients."

Describes the temporal clinical pattern in the cohort.

Later childhood and adulthood

Some patients acquire independent walking while speech and adaptive support needs persist. Hypertonia and orthopedic complications can emerge later. Familial adult cases show that survival to reproductive age and transmission are possible; rare severe congenital presentations should not define the whole syndrome.

Show evidence (2 references)

url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Hypotonia was accompanied by hypertonia, prominently in the lower extremities, later in life."

Later lower-limb hypertonia can coexist with earlier hypotonia.

📊

Prevalence

Published invdupdel(8p) reports

Unknown Rare

The literature describes a rare rearrangement. Clinic cohorts and prenatal diagnostic samples do not supply a population denominator; background birth-frequency estimates are not treated as newly measured epidemiology.

Show evidence (1 reference)

PMID:28211984 SUPPORT DIRECT BACKGROUND Human Clinical

"is a well-described and uncommon chromosomal rearrangement."

Qualitative rarity only; no numerical population rate is inferred.

{ }

Source YAML

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name: 8p Inverted Duplication Deletion Syndrome
category: Chromosomal
creation_date: '2026-09-03T19:00:00Z'
synonyms:
- invdupdel(8p)
- inv dup del(8p)
- inverted 8p duplication/deletion syndrome
- inverted duplication deletion 8p
disease_term:
  preferred_term: 8p inverted duplication/deletion syndrome
  term:
    id: MONDO:0019876
    label: 8p inverted duplication/deletion syndrome
parents:
- Chromosomal Disorder
description: 8p inverted duplication/deletion syndrome combines a terminal loss of 8p with an inverted duplication of a more proximal segment on the same chromosome. Many recurrent rearrangements retain a copy-neutral spacer, whereas some nonrecurrent forms lack it or acquire additional chromosomal material during stabilization. The phenotype includes developmental and speech delay, intellectual disability, hypotonia, callosal anomalies, seizures and variable congenital malformations. Gene content and clinical severity vary. Common spacer-containing rearrangements preserve GATA4 and SOX7; their deletion is relevant only to particular larger deletions. Most studied cases are sporadic, but transmission of the unbalanced rearrangement across generations has been documented.
inheritance:
- name: Usually sporadic structural rearrangement
  inheritance_term:
    preferred_term: Sporadic
    term:
      id: HP:0003745
      label: Sporadic
  description: The common inversion-associated pathway was characterized in sporadic cases with maternal origin. Alternative architectures and familial unbalanced transmission prevent a universal de novo or exclusively maternal rule.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: all ﬁve mothers were heterozygous inv(8)(p23) carriers (inversion heterozygotes)
    explanation: Observed in five selected Japanese families. This does not establish that all affected individuals require a maternal inversion.
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: all deletions in the ﬁve patients had arisen in the maternally derived chromosomes 8
    explanation: STRP analysis establishes parent of origin independently of the maternal inversion FISH result. The observation is confined to the five studied families.
- name: Familial transmission of the unbalanced chromosome
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: Autosomal transmission was documented in a two-generation family with variable intellectual disability. Reproductive counseling depends on the actual rearrangement and parental studies; the small family cannot establish a numerical recurrence risk.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Patients 16, 17, 18, 19, and 20 were from the same family and included two sibs and their children (Figure 1). All five individuals pres- ented with mild to moderate ID without any major associated malforma- tion.
    explanation: Five affected relatives in two generations carried the rearrangement; all had mild to moderate intellectual disability. This is direct transmission of the unbalanced chromosome, not just inheritance of a benign inversion.
has_subtypes:
- name: Spacer-containing invdupdel(8p)
  description: Terminal deletion and inverted duplication are separated by a copy-neutral interval. Inversion-associated recombination is a proposed formation pathway.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: deﬁned the regions for deletion, intact segment, and for duplication in the ﬁve patients with inv dup del(8p)
    explanation: The five mapped cases exemplify this architecture; the statement is not universal across the syndrome.
- name: Invdupdel(8p) without an intervening spacer
  description: Some mapped rearrangements have adjacent deletion and duplication without a copy-neutral spacer, supporting an alternative U-type exchange model.
  evidence:
  - reference: PMID:35327368
    reference_title: Clinical Manifestations of Various Molecular Cytogenetic Variants of Eight Cases of "8p Inverted Duplication/Deletion Syndrome".
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: 'Dicentric chromosome 8 formation can occur by two different mechanisms: U-type exchange and non-allelic homologous recombination mediated by parental paracentric inversion inv(8)(p23.1)'
    explanation: The authors use endpoint copy-number architecture to distinguish proposed formation routes.
- name: Complex invdupdel(8p) with captured additional chromosomal material
  description: A rearranged 8p end may contain material from another chromosome arm. Buysse characterized an additional 8q gain; that extra imbalance can modify the phenotype and should not be pooled with uncomplicated invdupdel cohorts.
  evidence:
  - reference: url:https://ricerca.uniba.it/retrieve/dd9e0c64-b05b-1e9c-e053-3a05fe0a45ef/6_sdarticle.pdf
    reference_title: https://ricerca.uniba.it/retrieve/dd9e0c64-b05b-1e9c-e053-3a05fe0a45ef/6_sdarticle.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: By high resolution oligo array CGH, we detected the smallest inverted duplication of 8p reported thus far, with additional duplication of 8q24.13/qter on the short arm of the abnormal chromosome 8 (Figs. 1 and 2 A and B).
    explanation: The measured complex chromosome contains an additional terminal 8q duplication on 8p. This is evidence for captured material, not direct observation of the proposed replication process.
prevalence:
- population: Published invdupdel(8p) reports
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: The literature describes a rare rearrangement. Clinic cohorts and prenatal diagnostic samples do not supply a population denominator; background birth-frequency estimates are not treated as newly measured epidemiology.
  evidence:
  - reference: PMID:28211984
    reference_title: Prenatal diagnosis of inverted duplication deletion 8p syndrome mimicking trisomy 18.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: is a well-described and uncommon chromosomal rearrangement.
    explanation: Qualitative rarity only; no numerical population rate is inferred.
pathophysiology:
- name: Predisposing 8p23 Repeat and Inversion Architecture
  biological_scale: MOLECULAR
  description: Low-copy repeats at 8p23 and a common inversion polymorphism provide a substrate for a recurrent rearrangement pathway. The inversion alone is not the syndrome. Maternal inversion was measured in five families; other pathways do not require this parental finding.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: all ﬁve mothers were heterozygous inv(8)(p23) carriers (inversion heterozygotes)
    explanation: Observed in five selected Japanese families. This does not establish that all affected individuals require a maternal inversion.
  downstream:
  - target: Ectopic Meiotic Recombination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: In the inversion-associated model, misalignment and crossover generate an abnormal recombinant.
    evidence:
    - reference: url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
      reference_title: https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      directness: INDIRECT
      snippet: From these ﬁndings, we propose here a model to explain how inv dup del(8p) is formed.
      explanation: The crossover and rescue sequence is an interpretation of FISH and STR findings, not directly observed meiotic intermediates.
- name: Ectopic Meiotic Recombination
  biological_scale: MOLECULAR
  description: The inversion-loop model invokes one or two crossovers to explain the observed maternal marker patterns. Historical BAC FISH mapped breakpoint intervals, not nucleotide junctions or the meiosis itself.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: From these ﬁndings, we propose here a model to explain how inv dup del(8p) is formed.
    explanation: The crossover and rescue sequence is an interpretation of FISH and STR findings, not directly observed meiotic intermediates.
  - reference: PMID:35327368
    reference_title: Clinical Manifestations of Various Molecular Cytogenetic Variants of Eight Cases of "8p Inverted Duplication/Deletion Syndrome".
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: 'Dicentric chromosome 8 formation can occur by two different mechanisms: U-type exchange and non-allelic homologous recombination mediated by parental paracentric inversion inv(8)(p23.1)'
    explanation: Formation mechanisms are inferred from constitutional rearrangements and prior molecular studies.
  downstream:
  - target: Dicentric Chromosome Intermediate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The proposed recombination route produces an unstable dicentric intermediate.
    evidence:
    - reference: PMID:35327368
      reference_title: Clinical Manifestations of Various Molecular Cytogenetic Variants of Eight Cases of "8p Inverted Duplication/Deletion Syndrome".
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      directness: INDIRECT
      snippet: 'Dicentric chromosome 8 formation can occur by two different mechanisms: U-type exchange and non-allelic homologous recombination mediated by parental paracentric inversion inv(8)(p23.1)'
      explanation: Formation mechanisms are inferred from constitutional rearrangements and prior molecular studies.
  biological_processes:
  - preferred_term: DNA recombination
    term:
      id: GO:0006310
      label: DNA recombination
- name: U-type Exchange
  biological_scale: MOLECULAR
  description: An alternative exchange model explains rearrangements lacking the usual spacer. Its assignment is based on endpoint architecture and should not be read as a directly imaged event in every case.
  evidence:
  - reference: PMID:35327368
    reference_title: Clinical Manifestations of Various Molecular Cytogenetic Variants of Eight Cases of "8p Inverted Duplication/Deletion Syndrome".
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: 'Dicentric chromosome 8 formation can occur by two different mechanisms: U-type exchange and non-allelic homologous recombination mediated by parental paracentric inversion inv(8)(p23.1)'
    explanation: Formation mechanisms are inferred from constitutional rearrangements and prior molecular studies.
  downstream:
  - target: Dicentric Chromosome Intermediate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Alternative formation route to a dicentric intermediate.
    evidence:
    - reference: PMID:35327368
      reference_title: Clinical Manifestations of Various Molecular Cytogenetic Variants of Eight Cases of "8p Inverted Duplication/Deletion Syndrome".
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      directness: INDIRECT
      snippet: 'Dicentric chromosome 8 formation can occur by two different mechanisms: U-type exchange and non-allelic homologous recombination mediated by parental paracentric inversion inv(8)(p23.1)'
      explanation: Formation mechanisms are inferred from constitutional rearrangements and prior molecular studies.
  biological_processes:
  - preferred_term: DNA recombination
    term:
      id: GO:0006310
      label: DNA recombination
- name: Dicentric Chromosome Intermediate
  biological_scale: MOLECULAR
  description: Two centromeres make the proposed intermediate unstable. Breakage and loss of one centromere can yield the monocentric inverted-duplication/deletion chromosome.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: rescue by eliminating a part of a duplicated segment and a centromere may result in the inv dup(8) formation.
    explanation: A proposed rescue explains a stable monocentric endpoint; rescue was not directly observed.
  downstream:
  - target: Dicentric Resolution
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Breakage and centromere loss are proposed to resolve the dicentric intermediate.
    evidence:
    - reference: url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
      reference_title: https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      directness: INDIRECT
      snippet: rescue by eliminating a part of a duplicated segment and a centromere may result in the inv dup(8) formation.
      explanation: A proposed rescue explains a stable monocentric endpoint; rescue was not directly observed.
- name: Dicentric Resolution
  biological_scale: MOLECULAR
  description: Breakage with loss of part of the duplicated segment and one centromere is proposed to generate a monocentric chromosome with a broken end. The process is inferred from endpoint marker patterns.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: rescue by eliminating a part of a duplicated segment and a centromere may result in the inv dup(8) formation.
    explanation: A proposed rescue explains a stable monocentric endpoint; rescue was not directly observed.
  downstream:
  - target: Chromosome-End Stabilization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The resulting broken end must be stabilized to retain the rearranged chromosome.
    evidence:
    - reference: url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
      reference_title: https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      directness: INDIRECT
      snippet: rescue by eliminating a part of a duplicated segment and a centromere may result in the inv dup(8) formation.
      explanation: A proposed rescue explains a stable monocentric endpoint; rescue was not directly observed.
- name: Chromosome-End Stabilization
  biological_scale: MOLECULAR
  description: After breakage, the chromosome end must be stabilized. Telomere healing and capture are alternative accounts. Complex invdupdel(8p) chromosomes capped by extra 8q material demonstrate capture-associated architecture; a specific break-induced-replication mechanism remains proposed.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: rescue by eliminating a part of a duplicated segment and a centromere may result in the inv dup(8) formation.
    explanation: A proposed rescue explains a stable monocentric endpoint; rescue was not directly observed.
  - reference: url:https://ricerca.uniba.it/retrieve/dd9e0c64-b05b-1e9c-e053-3a05fe0a45ef/6_sdarticle.pdf
    reference_title: https://ricerca.uniba.it/retrieve/dd9e0c64-b05b-1e9c-e053-3a05fe0a45ef/6_sdarticle.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: By high resolution oligo array CGH, we detected the smallest inverted duplication of 8p reported thus far, with additional duplication of 8q24.13/qter on the short arm of the abnormal chromosome 8 (Figs. 1 and 2 A and B).
    explanation: The measured complex chromosome contains an additional terminal 8q duplication on 8p. This is evidence for captured material, not direct observation of the proposed replication process.
  - reference: url:https://ricerca.uniba.it/retrieve/dd9e0c64-b05b-1e9c-e053-3a05fe0a45ef/6_sdarticle.pdf
    reference_title: https://ricerca.uniba.it/retrieve/dd9e0c64-b05b-1e9c-e053-3a05fe0a45ef/6_sdarticle.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: Our data are in favour of break-induced replication (BIR),
    explanation: The authors favor BIR after mapping the chromosome; the molecular repair mechanism was not experimentally established.
  downstream:
  - target: Terminal Deletion with Inverted Proximal Duplication
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Stabilization leaves the constitutional structural rearrangement.
    evidence:
    - reference: url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
      reference_title: https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      directness: INDIRECT
      snippet: rescue by eliminating a part of a duplicated segment and a centromere may result in the inv dup(8) formation.
      explanation: A proposed rescue explains a stable monocentric endpoint; rescue was not directly observed.
  biological_processes:
  - preferred_term: telomere maintenance
    term:
      id: GO:0000723
      label: telomere maintenance
- name: Terminal Deletion with Inverted Proximal Duplication
  biological_scale: MOLECULAR
  description: The measured endpoint is loss of distal 8p together with inverted gain of a more proximal segment. A spacer is common but not obligatory. Copy-number assays define intervals; cytogenetic or structural studies establish orientation.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the shared deleted interval in individuals with invdupdel(8p) was the most distal 6.7 Mb and the shared duplicated interval was approximately 11.1 Mb.
    explanation: CMA-defined shared intervals in the 49-person recurrent subgroup establish simultaneous distal loss and proximal gain; the full duplicated interval varies by individual.
  downstream:
  - target: Reduced Distal 8p Gene Dosage
    causal_link_type: DIRECT
    description: The terminal deletion leaves one copy of genes in the deleted interval.
    evidence:
    - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
      reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: the shared deleted interval in individuals with invdupdel(8p) was the most distal 6.7 Mb and the shared duplicated interval was approximately 11.1 Mb.
      explanation: CMA-defined shared intervals in the 49-person recurrent subgroup establish simultaneous distal loss and proximal gain; the full duplicated interval varies by individual.
  - target: Increased Proximal 8p Gene Dosage
    causal_link_type: DIRECT
    description: The duplication produces three copies of genes in its interval.
    evidence:
    - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
      reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: the shared deleted interval in individuals with invdupdel(8p) was the most distal 6.7 Mb and the shared duplicated interval was approximately 11.1 Mb.
      explanation: CMA-defined shared intervals in the 49-person recurrent subgroup establish simultaneous distal loss and proximal gain; the full duplicated interval varies by individual.
- name: Reduced Distal 8p Gene Dosage
  biological_scale: MOLECULAR
  description: The deleted region contains multiple candidate contributors, including DLGAP2 and CSMD1 in recurrent cases. Gene-specific contributions and interactions with the duplicated segment remain incompletely resolved.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: we prioritized the candidate genes DLGAP2 and CSMD1 for del(8p) distal and the deleted segment of invdupdel(8p), GATA4 and XKR6 for del(8p)_proximal and dup(8p)_proximal, and RHOBTB2 and CHRNA2 for the duplicated segment of invdupdel(8p) (Supplemental Data).
    explanation: Candidate prioritization uses interval content and prior biological knowledge. It does not demonstrate that any one gene accounts for the whole rearrangement phenotype.
  downstream:
  - target: Combined Regional Dosage Imbalance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss acts together with the adjacent gain; the clinical effect cannot generally be assigned to one deleted gene.
    evidence:
    - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
      reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      directness: INDIRECT
      snippet: we prioritized the candidate genes DLGAP2 and CSMD1 for del(8p) distal and the deleted segment of invdupdel(8p), GATA4 and XKR6 for del(8p)_proximal and dup(8p)_proximal, and RHOBTB2 and CHRNA2 for the duplicated segment of invdupdel(8p) (Supplemental Data).
      explanation: Candidate prioritization uses interval content and prior biological knowledge. It does not demonstrate that any one gene accounts for the whole rearrangement phenotype.
- name: Increased Proximal 8p Gene Dosage
  biological_scale: MOLECULAR
  description: Variable duplicated intervals contain neurodevelopmental candidates such as RHOBTB2 and CHRNA2. A gene causing another disorder through a point mutation does not by itself establish triplosensitivity.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: we prioritized the candidate genes DLGAP2 and CSMD1 for del(8p) distal and the deleted segment of invdupdel(8p), GATA4 and XKR6 for del(8p)_proximal and dup(8p)_proximal, and RHOBTB2 and CHRNA2 for the duplicated segment of invdupdel(8p) (Supplemental Data).
    explanation: Candidate prioritization uses interval content and prior biological knowledge. It does not demonstrate that any one gene accounts for the whole rearrangement phenotype.
  downstream:
  - target: Combined Regional Dosage Imbalance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Increased dosage combines with distal loss and may contribute to variable severity.
    evidence:
    - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
      reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      directness: INDIRECT
      snippet: we prioritized the candidate genes DLGAP2 and CSMD1 for del(8p) distal and the deleted segment of invdupdel(8p), GATA4 and XKR6 for del(8p)_proximal and dup(8p)_proximal, and RHOBTB2 and CHRNA2 for the duplicated segment of invdupdel(8p) (Supplemental Data).
      explanation: Candidate prioritization uses interval content and prior biological knowledge. It does not demonstrate that any one gene accounts for the whole rearrangement phenotype.
- name: Combined Regional Dosage Imbalance
  biological_scale: MOLECULAR
  description: The combined constitutional copy-number lesion underlies the syndrome. Clinical edges summarize associations with this multigene lesion; molecular intermediates for most individual manifestations remain unknown. GATA4 and SOX7 are usually copy-neutral in recurrent spacer-containing cases.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the shared deleted interval in individuals with invdupdel(8p) was the most distal 6.7 Mb and the shared duplicated interval was approximately 11.1 Mb.
    explanation: CMA-defined shared intervals in the 49-person recurrent subgroup establish simultaneous distal loss and proximal gain; the full duplicated interval varies by individual.
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: we prioritized the candidate genes DLGAP2 and CSMD1 for del(8p) distal and the deleted segment of invdupdel(8p), GATA4 and XKR6 for del(8p)_proximal and dup(8p)_proximal, and RHOBTB2 and CHRNA2 for the duplicated segment of invdupdel(8p) (Supplemental Data).
    explanation: Candidate prioritization uses interval content and prior biological knowledge. It does not demonstrate that any one gene accounts for the whole rearrangement phenotype.
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Both GATA4 and SOX7 were copy-number neutral in all individuals with invdupdel(8p) or del(8p)_distal. However, VSD and/or ASD were reported in over one third of individuals with invdupdel(8p) ( n = 15, 38%)
    explanation: The recurrent invdupdel subgroup retained both genes despite septal defects in 15/40 assessed individuals. This directly limits a universal GATA4/SOX7-deletion explanation.
  downstream:
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Delayed Speech and Language Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Motor Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Agenesis of Corpus Callosum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Hypoplasia of Corpus Callosum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Hypertonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Dystonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Cerebellar Hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Ventriculomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Macrocephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Stereotypy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Autistic Behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Sleep Disturbance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Ventricular Septal Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Atrial Septal Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Patent Foramen Ovale
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Patent Ductus Arteriosus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Constipation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Gastroesophageal Reflux
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Feeding Difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Failure to Thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Short Stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Scoliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Joint Hypermobility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Inguinal Hernia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Strabismus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Cerebral Visual Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Cryptorchidism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Hypospadias
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Neonatal Respiratory Distress
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Neonatal Hypoglycemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Single Umbilical Artery
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Wide Mouth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Broad Forehead
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Hypertelorism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Macrotia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Congenital Heart Malformation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Polyvalvular Dysplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Congenital Diaphragmatic Hernia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Brain Atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Micrognathia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
  - target: Thin Upper Lip Vermilion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Associated with the constitutional multigene lesion; the intervening gene-to-organ mechanism is unresolved.
phenotypes:
- name: Global Developmental Delay
  category: Neurologic
  phenotype_term:
    preferred_term: Global Developmental Delay
    term:
      id: HP:0001263
      label: Global developmental delay
  description: Reported in 32/33 postnatal patients in the Vibert cohort; age and ascertainment limit generalization.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Global developmental delay 32/33 97% 27
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
  - reference: PMID:35327368
    reference_title: Clinical Manifestations of Various Molecular Cytogenetic Variants of Eight Cases of "8p Inverted Duplication/Deletion Syndrome".
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: All patients were characterized by a delay in early psychomotor and language development of varying degrees, craniofacial dysmorphisms, and hypotonia.
    explanation: All eight unrelated children aged two to nine years had these findings. This small series is not pooled with the other cohorts.
- name: Intellectual Disability
  category: Neurologic
  phenotype_term:
    preferred_term: Intellectual Disability
    term:
      id: HP:0001249
      label: Intellectual disability
  description: All 19 evaluated patients aged at least five years in the Vibert cohort had mild, moderate or severe intellectual disability. This age-restricted denominator is distinct from global developmental delay.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Intellectual disability (patients ≥5 years old) 19/19 100% 38
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
- name: Delayed Speech and Language Development
  category: Neurologic
  phenotype_term:
    preferred_term: Delayed Speech and Language Development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  description: Speech delay affected 27/28 assessed patients; 9/24 older than three years had not acquired language at last assessment.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Ninety-six percentage (27/28) of patients had speech delay and 37.5% (9/24) of patients older than 3 years (3 – 13.8 years) had not acquired language at last evaluation.
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
  - reference: PMID:35327368
    reference_title: Clinical Manifestations of Various Molecular Cytogenetic Variants of Eight Cases of "8p Inverted Duplication/Deletion Syndrome".
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: All patients were characterized by a delay in early psychomotor and language development of varying degrees, craniofacial dysmorphisms, and hypotonia.
    explanation: All eight unrelated children aged two to nine years had these findings. This small series is not pooled with the other cohorts.
- name: Motor Delay
  category: Neurologic
  phenotype_term:
    preferred_term: Motor Delay
    term:
      id: HP:0001270
      label: Motor delay
  description: Motor delay was reported in 27/29 assessed patients. Independent walking was attained by 14/15 patients older than six in this selected cohort.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: developed global development delay including motor delay in 93% (27/29) of patients.
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
- name: Agenesis of Corpus Callosum
  category: Neurologic
  phenotype_term:
    preferred_term: Agenesis of Corpus Callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  description: 'Callosal abnormalities occurred in 17/27 patients assessed by MRI or fetal neuropathology: six complete and five partial agenesis cases. These are not denominators for all affected people.'
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Sixty-three percent of patients presented AnCC ( n = 17/27). ACC was complete in 35% ( n = 6/17) of cases and partial in 29% (n = 5/17).
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
- name: Hypoplasia of Corpus Callosum
  category: Neurologic
  phenotype_term:
    preferred_term: Hypoplasia of Corpus Callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  description: The same series distinguished four short/thin callosa from two called hypoplastic; callosal agenesis is recorded separately.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Twenty-four percentage of patients ( n = 4/17) had a short and thin CC and 12% ( n = 2/17) had CC hypoplasia.
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
- name: Seizure
  category: Neurologic
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  description: Epilepsy occurred in 11/32 assessed Vibert patients, with onset from two months to nine years. Okur reported any seizure in 27/49, including febrile events, which is a different outcome and cannot be equated with epilepsy penetrance.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Thirty-four percent ( n = 11/32) of patients had epilepsy starting between 2 months and 9 years, characterized by absences ( n = 5), generalized tonic –clonic ( n = 3), myoclonic ( n = 2), and focal motor (n = 2) seizures.
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
- name: Hypotonia
  category: Neurologic
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  description: Generalized or truncal hypotonia was reported in 88% of the 49-person recurrent invdupdel subgroup.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Hypotonia 88% 50% 56% 42% Hypertonia 39% 25% 56% 25% Difﬁculty walking/clumsiness 29% - 67% 33% Macrocephaly 10% -
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
  - reference: PMID:35327368
    reference_title: Clinical Manifestations of Various Molecular Cytogenetic Variants of Eight Cases of "8p Inverted Duplication/Deletion Syndrome".
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: All patients were characterized by a delay in early psychomotor and language development of varying degrees, craniofacial dysmorphisms, and hypotonia.
    explanation: All eight unrelated children aged two to nine years had these findings. This small series is not pooled with the other cohorts.
- name: Hypertonia
  category: Neurologic
  phenotype_term:
    preferred_term: Hypertonia
    term:
      id: HP:0001276
      label: Hypertonia
  description: Hypertonia can develop later, particularly in the lower limbs, despite earlier hypotonia.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Hypotonia was accompanied by hypertonia, prominently in the lower extremities, later in life.
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
- name: Dystonia
  category: Neurologic
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  description: Dystonia was reported in two patients in the Vibert cohort; no disease-wide frequency band is assigned.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Other neurological symptoms included spasticity (n = 6) and dystonia ( n = 2).
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
- name: Cerebellar Hypoplasia
  category: Neurologic
  phenotype_term:
    preferred_term: Cerebellar Hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
  description: Two patients in the Vibert cohort had cerebellar hypoplasia; other structural brain findings varied.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Other described major cerebral anomalies were cerebellar hypoplasia ( n = 2), Dandy – Walker complex ( n = 1), and simplified frontal gyration with a lipoma of the pituitary stalk ( n = 1).
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
- name: Ventriculomegaly
  category: Neurologic
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  description: Hydrocephalus or ventriculomegaly was reported jointly in 27% of imaged recurrent invdupdel cases. The table does not give separate rates for each component.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Hydrocephalus/ventriculomegaly 27% - - 20% Cerebral/cerebellar atrophy 16% - - - Dandy– Walker 9% - - Intracranial cyst 9%
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Microcephaly
  category: Neurologic
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  description: Two of 49 recurrent invdupdel patients had microcephaly; it was more prominent in other deletion subgroups.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Microcephaly 4% - 22% 58% Seizures 55% 25% 44% 42% Absence 37% - 11% 25% Febrile 18% - -
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Macrocephaly
  category: Neurologic
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  description: Five recurrent invdupdel patients had macrocephaly; three also had hydrocephalus or ventriculomegaly.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Macrocephaly 10% - - - Microcephaly 4% - 22% 58% Seizures 55% 25% 44% 42% Absence 37% - 11%
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Stereotypy
  category: Behavioral
  phenotype_term:
    preferred_term: Stereotypy
    term:
      id: HP:0000733
      label: Motor stereotypy
  description: Stereotyped behavior was recorded in 22% of the recurrent invdupdel subgroup.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Stereotype 22% 25% 13% 25% Aggressivity/tantrums/impulsivity 14% - 50% 33% Sensory issues 8% 25% - 25% Autism 6% 50%
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Autistic Behavior
  category: Behavioral
  phenotype_term:
    preferred_term: Autistic Behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  description: Autism was reported in 6% of the recurrent invdupdel subgroup. Warning signs alone in other cohorts are not counted as confirmed autism.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Autism 6% 50% 25% 17% ADD/ADHD/hyperactivity 4% 50% 38% 58% Echolalia 2% - 11% 17% Anxiety 2% 25% 13%
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Sleep Disturbance
  category: Neurologic
  phenotype_term:
    preferred_term: Sleep Disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  description: Sleep problems were reported in 45% of the recurrent invdupdel subgroup; this does not establish sleep apnea.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Sleep problems 45% 25% 22% 58% Dental problems 53% 50% 56% 33% Skin problems 45% 25% 22% 25% ADD
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Ventricular Septal Defect
  category: Cardiovascular
  phenotype_term:
    preferred_term: Ventricular Septal Defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  description: Ventricular septal defects were reported in 30% of the 40 assessed recurrent invdupdel patients.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: VSD 30% - 71% 36% ASD 15% - 57% 100% PFO 18% - - - PDA 13% - 29%
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Atrial Septal Defect
  category: Cardiovascular
  phenotype_term:
    preferred_term: Atrial Septal Defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  description: Atrial septal defects were reported in 15% of the 40 assessed recurrent invdupdel patients.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: ASD 15% - 57% 100% PFO 18% - - - PDA 13% - 29% - PS 3% 25% 71%
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Patent Foramen Ovale
  category: Cardiovascular
  phenotype_term:
    preferred_term: Patent Foramen Ovale
    term:
      id: HP:0001655
      label: Patent foramen ovale
  description: Patent foramen ovale was reported in the cardiac table; minor lesions and spontaneous closure contributed to the aggregate cardiac findings.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: PFO 18% - - - PDA 13% - 29% - PS 3% 25% 71% 64% Arrhythmia - - 33%
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Patent Ductus Arteriosus
  category: Cardiovascular
  phenotype_term:
    preferred_term: Patent Ductus Arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  description: Patent ductus arteriosus was reported in 13% of the 40 assessed recurrent invdupdel patients.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: PDA 13% - 29% - PS 3% 25% 71% 64% Arrhythmia - - 33% ( n = 3/9) 8%
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Constipation
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  description: Constipation was reported in 73% of the recurrent invdupdel subgroup.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Constipation 73% 25% 67% 58% GERD 55% 50% 56% 33% Feeding dif ﬁculty 22% - - 17% Diarrhea 6%
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Gastroesophageal Reflux
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Gastroesophageal Reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  description: Gastroesophageal reflux was reported in 55% of the recurrent invdupdel subgroup.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: GERD 55% 50% 56% 33% Feeding dif ﬁculty 22% - - 17% Diarrhea 6% - 11% 8% Musculoskeletal issues
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Feeding Difficulties
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Feeding Difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  description: Feeding difficulty was reported neonatally in 63%, and later in 22%, of the recurrent invdupdel subgroup. Feeding safety and nutritional adequacy require individual assessment.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Feeding dif ﬁculty 63% - 22% 42% Poor suck 57% - 33% 42% Overly sleepy 43% 50% 11% 33%
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Failure to Thrive
  category: Growth
  phenotype_term:
    preferred_term: Failure to Thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  description: Failure to thrive or poor weight gain was reported in 37% of the recurrent invdupdel subgroup.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: FTT/poor weight gain 37% - 11% 17% Obesity/overweight - 50% 67% 30% V. Okur et al. 2 Genetics in
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Short Stature
  category: Growth
  phenotype_term:
    preferred_term: Short Stature
    term:
      id: HP:0004322
      label: Short stature
  description: Short stature was reported in 12% of the recurrent invdupdel subgroup; birth size and feeding histories varied.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Short stature was reported in 10–20% of individuals across all rearrangements (Table 1).
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Scoliosis
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  description: Scoliosis was reported in 22% of the recurrent invdupdel subgroup.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Scoliosis 22% 25% - 25% Vertebral abnormalities 8% 25% - - Hypermobile joints 8% - 11% 8% Coxa valga/hip
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Joint Hypermobility
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Joint Hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  description: Joint hypermobility was reported in the recurrent invdupdel subgroup.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Hypermobile joints 8% - 11% 8% Coxa valga/hip anomalies 8% - - 17% Rib anomalies 6% - - -
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Inguinal Hernia
  category: Abdominal
  phenotype_term:
    preferred_term: Inguinal Hernia
    term:
      id: HP:0000023
      label: Inguinal hernia
  description: Inguinal hernia was reported in the recurrent invdupdel subgroup.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Inguinal hernia 8% 50% - - Visual issues 55% 75% 56% 50% Refractive errors 29% 75% 33% 50% Strabismus
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Strabismus
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  description: Strabismus was reported in 18% of the recurrent invdupdel subgroup.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Strabismus 18% - 33% 17% Cortical visual impairment 12% - 11% - Optic nerve (atrophy/enlarged/cupped) 8% - - -
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Cerebral Visual Impairment
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Cerebral Visual Impairment
    term:
      id: HP:0100704
      label: Cerebral visual impairment
  description: The cohort used the term cortical visual impairment and reported it in 12% of the recurrent invdupdel subgroup.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Cortical visual impairment 12% - 11% - Optic nerve (atrophy/enlarged/cupped) 8% - - - V. Okur et al. 3
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Cryptorchidism
  category: Genitourinary
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  description: Cryptorchidism occurred in 7/20 males in the recurrent invdupdel subgroup.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Cryptorchidism 35% ( n = 7/20) 25% ( n = 1/4) - - Hypospadias 10% ( n = 2/20)
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Hypospadias
  category: Genitourinary
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  description: Hypospadias occurred in 2/20 males in the recurrent invdupdel subgroup.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Hypospadias 10% ( n = 2/20) - 25% ( n = 1/4) 20% ( n = 1/5) Hydronephrosis, kidney
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Recurrent Otitis Media
  category: Otologic
  phenotype_term:
    preferred_term: Recurrent Otitis Media
    term:
      id: HP:0000403
      label: Recurrent otitis media
  description: Otitis media was listed among frequent infections in 33% of the recurrent invdupdel subgroup.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Otitis media 33% 25% 11% 25% Upper respiratory 16% - 11% 17% Urinary tract 14% - 11% 17% Sleep
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
  notes: No specific causal immune pathway is established by the cohort. Recurrent infections are retained as clinical findings without an asserted defensin-to-infection causal edge.
- name: Recurrent Respiratory Infections
  category: Respiratory
  phenotype_term:
    preferred_term: Recurrent Respiratory Infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  description: Upper respiratory infections were listed among frequent infections in 16% of the recurrent invdupdel subgroup. This cohort evidence does not establish a specific immune defect.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Upper respiratory 16% - 11% 17% Urinary tract 14% - 11% 17% Sleep problems 45% 25% 22% 58% Dental
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
  notes: No specific causal immune pathway is established by the cohort. Recurrent infections are retained as clinical findings without an asserted defensin-to-infection causal edge.
- name: Recurrent Urinary Tract Infections
  category: Genitourinary
  phenotype_term:
    preferred_term: Recurrent Urinary Tract Infections
    term:
      id: HP:0000010
      label: Recurrent urinary tract infections
  description: Urinary tract infections were listed among frequent infections in 14% of the recurrent invdupdel subgroup.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Urinary tract 14% - 11% 17% Sleep problems 45% 25% 22% 58% Dental problems 53% 50% 56% 33% Skin
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
  notes: No specific causal immune pathway is established by the cohort. Recurrent infections are retained as clinical findings without an asserted defensin-to-infection causal edge.
- name: Neonatal Respiratory Distress
  category: Respiratory
  phenotype_term:
    preferred_term: Neonatal Respiratory Distress
    term:
      id: HP:0002643
      label: Neonatal respiratory distress
  description: Neonatal respiratory distress was reported in 18% of the recurrent invdupdel subgroup.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Respiratory distress 18% - 22% 17% Hypoglycemia 18% 25% 22% 8% Anthropometric measurements Birth weight Z-scores Mean −0.2 0.08
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Neonatal Hypoglycemia
  category: Metabolic
  phenotype_term:
    preferred_term: Neonatal Hypoglycemia
    term:
      id: HP:0001998
      label: Neonatal hypoglycemia
  description: Transient neonatal hypoglycemia was reported in 18% of the recurrent invdupdel subgroup.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Hypoglycemia 18% 25% 22% 8% Anthropometric measurements Birth weight Z-scores Mean −0.2 0.08 −1.0 −1.45 Median −0.13 0.3 −0.8
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Single Umbilical Artery
  category: Prenatal
  phenotype_term:
    preferred_term: Single Umbilical Artery
    term:
      id: HP:0001195
      label: Single umbilical artery
  description: Single umbilical artery was reported prenatally in 16% of the recurrent invdupdel subgroup.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Single umbilical artery 16% - - 17% SGA 14% - 33% 25% Cardiac ﬁnding 10% - - 25% Oligo-/polyhydramnios,
    explanation: 'Okur Table 1: use only the first data column, recurrent invdupdel(8p), n=49. Cardiac findings use n=40 and imaging findings n=45; adjacent snippet columns describe other rearrangements. These selected-cohort observations are not population penetrance.'
- name: Wide Mouth
  category: Craniofacial
  phenotype_term:
    preferred_term: Wide Mouth
    term:
      id: HP:0000154
      label: Wide mouth
  description: One of the component facial findings reported in the Vibert cohort. Facial appearance is variable; no frequency band is inferred from a selected case series.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: "Facial dysmorphisma 28/32 88% Common features: \x81 Wide mouth ( n = 9), broad ( n = 6) or prominent (n = 2) forehead or frontal bossing ( n = 2), hypertelorism (n = 5), sunken eyes ( n = 4), plagiocephaly (n = 4), macrotia ( n = 4)"
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
- name: Broad Forehead
  category: Craniofacial
  phenotype_term:
    preferred_term: Broad Forehead
    term:
      id: HP:0000337
      label: Broad forehead
  description: One of the component facial findings reported in the Vibert cohort. Facial appearance is variable; no frequency band is inferred from a selected case series.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: "Facial dysmorphisma 28/32 88% Common features: \x81 Wide mouth ( n = 9), broad ( n = 6) or prominent (n = 2) forehead or frontal bossing ( n = 2), hypertelorism (n = 5), sunken eyes ( n = 4), plagiocephaly (n = 4), macrotia ( n = 4)"
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
- name: Hypertelorism
  category: Craniofacial
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  description: One of the component facial findings reported in the Vibert cohort. Facial appearance is variable; no frequency band is inferred from a selected case series.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: "Facial dysmorphisma 28/32 88% Common features: \x81 Wide mouth ( n = 9), broad ( n = 6) or prominent (n = 2) forehead or frontal bossing ( n = 2), hypertelorism (n = 5), sunken eyes ( n = 4), plagiocephaly (n = 4), macrotia ( n = 4)"
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
- name: Macrotia
  category: Craniofacial
  phenotype_term:
    preferred_term: Macrotia
    term:
      id: HP:0000400
      label: Macrotia
  description: One of the component facial findings reported in the Vibert cohort. Facial appearance is variable; no frequency band is inferred from a selected case series.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: "Facial dysmorphisma 28/32 88% Common features: \x81 Wide mouth ( n = 9), broad ( n = 6) or prominent (n = 2) forehead or frontal bossing ( n = 2), hypertelorism (n = 5), sunken eyes ( n = 4), plagiocephaly (n = 4), macrotia ( n = 4)"
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
- name: Congenital Heart Malformation
  category: Cardiovascular
  phenotype_term:
    preferred_term: Congenital Heart Malformation
    term:
      id: HP:0001627
      label: Abnormal heart morphology
    coarse_binding_basis: VARIABLE_SPECTRUM
  description: The cardiac spectrum includes septal defects, tetralogy of Fallot and valvar lesions. Vibert reported 12/29; Okur reported cardiac findings in 26/40, often minor. Ascertainment and lesion definitions differ.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Among extra-neurological manifestations, 12/29 patients had congenital heart defects (41%) and 10/34 patients had orthopedic anomalies.
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
- name: Polyvalvular Dysplasia
  category: Cardiovascular
  phenotype_term:
    preferred_term: Polyvalvular Dysplasia
    term:
      id: HP:0001654
      label: Abnormal heart valve morphology
    coarse_binding_basis: NO_HPO_TERM
  description: A prenatal case had severe polyvalvular dysplasia and a fatal neonatal course. Full text also describes necrotizing enterocolitis and worsening perfusion before withdrawal of care; mortality cannot be attributed solely to the valves. A single case does not establish a numerical frequency.
  evidence:
  - reference: PMID:28211984
    reference_title: Prenatal diagnosis of inverted duplication deletion 8p syndrome mimicking trisomy 18.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the present case had severe polyvalvular dysplasia and the infant deceased at day 12 of life.
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
- name: Congenital Diaphragmatic Hernia
  category: Respiratory
  phenotype_term:
    preferred_term: Congenital Diaphragmatic Hernia
    term:
      id: HP:0000776
      label: Congenital diaphragmatic hernia
  description: The Vibert cohort included an infant who died at four months in the setting of diaphragmatic hernia. This establishes occurrence, not a general lethal prognosis.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Two patients were deceased, patient 5 at 4 years old (cause of death undetailed) and patient 33 at 4 months in a context of diaphragmatic hernia.
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
- name: Abnormal Refraction
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Abnormal Refraction
    term:
      id: HP:0000539
      label: Abnormality of refraction
  description: Refractive errors were reported in 29% of the recurrent invdupdel subgroup; the table does not separate types.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Refractive errors 29% 75% 33% 50% Strabismus 18% - 33% 17% Cortical visual impairment 12% - 11% - Optic
    explanation: Table 1 first column, recurrent invdupdel subgroup n=49; adjacent columns are other rearrangements. The aggregate does not supply lesion-specific frequencies.
  notes: Retained as a cohort observation; the source does not establish a specific downstream molecular mechanism.
- name: Aggressive Behavior
  category: Behavioral
  phenotype_term:
    preferred_term: Aggressive Behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  description: Aggressivity, tantrums and impulsivity were pooled in 14% of the recurrent invdupdel subgroup; no separate aggressive-behavior rate is implied.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Aggressivity/tantrums/impulsivity 14% - 50% 33% Sensory issues 8% 25% - 25% Autism 6% 50% 25% 17% ADD/ADHD/hyperactivity 4% 50%
    explanation: Table 1 first column, recurrent invdupdel subgroup n=49; adjacent columns are other rearrangements. The aggregate does not supply lesion-specific frequencies.
  notes: Retained as a cohort observation; the source does not establish a specific downstream molecular mechanism.
- name: Dental Abnormalities
  category: Dental
  phenotype_term:
    preferred_term: Dental Abnormalities
    term:
      id: HP:0000164
      label: Abnormality of the dentition
    coarse_binding_basis: SOURCE_UNSPECIFIED
  description: The recurrent invdupdel table reports dental problems in 53% without identifying the lesions in that aggregate. More specific findings cannot be assigned from this row.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Dental problems 53% 50% 56% 33% Skin problems 45% 25% 22% 25% ADD attention deﬁcit disorder, ADHD attention deﬁcit–
    explanation: Table 1 first column, recurrent invdupdel subgroup n=49; adjacent columns are other rearrangements. The aggregate does not supply lesion-specific frequencies.
  notes: Retained as a cohort observation; the source does not establish a specific downstream molecular mechanism.
- name: Skin Abnormalities
  category: Dermatologic
  phenotype_term:
    preferred_term: Skin Abnormalities
    term:
      id: HP:0000951
      label: Abnormality of the skin
    coarse_binding_basis: SOURCE_UNSPECIFIED
  description: Skin problems were reported in 45% of the recurrent invdupdel subgroup, without lesion-level detail in the aggregate table.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Skin problems 45% 25% 22% 25% ADD attention deﬁcit disorder, ADHD attention deﬁcit– hyperactivity disorder, ASD atrial septal defect,
    explanation: Table 1 first column, recurrent invdupdel subgroup n=49; adjacent columns are other rearrangements. The aggregate does not supply lesion-specific frequencies.
  notes: Retained as a cohort observation; the source does not establish a specific downstream molecular mechanism.
- name: Brain Atrophy
  category: Neurologic
  phenotype_term:
    preferred_term: Brain Atrophy
    term:
      id: HP:0012444
      label: Brain atrophy
  description: Cerebral or cerebellar atrophy was reported jointly in 16% of imaged recurrent invdupdel cases. The table does not provide separate regional rates.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Cerebral/cerebellar atrophy 16% - - - Dandy– Walker 9% - - Intracranial cyst 9% - - - Other 22%
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
- name: Renal Abnormalities
  category: Genitourinary
  phenotype_term:
    preferred_term: Renal Abnormalities
    term:
      id: HP:0000077
      label: Abnormality of the kidney
    coarse_binding_basis: SOURCE_UNSPECIFIED
  description: Hydronephrosis and other kidney issues were combined in 12% of the recurrent invdupdel subgroup; no separate hydronephrosis frequency is inferred.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Hydronephrosis, kidney issues 12% 50% - - Frequent infections 43% 25% 22% 25% Otitis media 33% 25% 11% 25%
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
  notes: The cohort groups kidney findings without enough lesion detail to assign a single narrower term or causal pathway.
- name: Micrognathia
  category: Craniofacial
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  description: A component facial finding directly described in the patient-level table of the eight-case Yurchenko series. No disease-wide frequency is inferred.
  evidence:
  - reference: PMID:35327368
    reference_title: Clinical Manifestations of Various Molecular Cytogenetic Variants of Eight Cases of "8p Inverted Duplication/Deletion Syndrome".
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Sloping forehead, hypertelorism, upslanted palpebral fissures, wide nasal base, thin upper lip, micrognathia, malocclusion, large and deformed ears
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
- name: Thin Upper Lip Vermilion
  category: Craniofacial
  phenotype_term:
    preferred_term: Thin Upper Lip Vermilion
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  description: A component facial finding directly described in the patient-level table of the eight-case Yurchenko series. No disease-wide frequency is inferred.
  evidence:
  - reference: PMID:35327368
    reference_title: Clinical Manifestations of Various Molecular Cytogenetic Variants of Eight Cases of "8p Inverted Duplication/Deletion Syndrome".
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Sloping forehead, hypertelorism, upslanted palpebral fissures, wide nasal base, thin upper lip, micrognathia, malocclusion, large and deformed ears
    explanation: The source documents this manifestation in invdupdel(8p). Cohort observations are descriptive and do not establish population penetrance.
genetic:
- name: GATA4
  gene_term:
    preferred_term: GATA4
    term:
      id: hgnc:4173
      label: GATA4
  notes: Usually copy-neutral in the recurrent spacer-containing rearrangement. A larger atypical deletion can encompass this gene; candidate contribution to heart or diaphragm development must be conditioned on measured copy number. Presence of heart disease alone does not imply its deletion.
  evidence:
  - reference: PMID:27343326
    reference_title: Molecular cytogenetic characterization of inv dup del(8p) in a fetus associated with ventriculomegaly, hypoplastic left heart, polyhydramnios and intestinal obstruction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: aCGH detected an 11.35 Mb deletion in 8p23.3-p23.1 encompassing SOX7 and GATA4, and a 31.99 Mb duplication in 8p23.1-p11.1 in the fetus.
    explanation: A molecularly characterized atypical fetus with hypoplastic left heart demonstrates conditional deletion of both genes, not universal involvement.
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Both GATA4 and SOX7 were copy-number neutral in all individuals with invdupdel(8p) or del(8p)_distal. However, VSD and/or ASD were reported in over one third of individuals with invdupdel(8p) ( n = 15, 38%)
    explanation: The recurrent invdupdel subgroup retained both genes despite septal defects in 15/40 assessed individuals. This directly limits a universal GATA4/SOX7-deletion explanation.
- name: SOX7
  gene_term:
    preferred_term: SOX7
    term:
      id: hgnc:18196
      label: SOX7
  notes: Usually copy-neutral in the recurrent spacer-containing rearrangement. A larger atypical deletion can encompass this gene; candidate contribution to heart or diaphragm development must be conditioned on measured copy number. Presence of heart disease alone does not imply its deletion.
  evidence:
  - reference: PMID:27343326
    reference_title: Molecular cytogenetic characterization of inv dup del(8p) in a fetus associated with ventriculomegaly, hypoplastic left heart, polyhydramnios and intestinal obstruction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: aCGH detected an 11.35 Mb deletion in 8p23.3-p23.1 encompassing SOX7 and GATA4, and a 31.99 Mb duplication in 8p23.1-p11.1 in the fetus.
    explanation: A molecularly characterized atypical fetus with hypoplastic left heart demonstrates conditional deletion of both genes, not universal involvement.
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Both GATA4 and SOX7 were copy-number neutral in all individuals with invdupdel(8p) or del(8p)_distal. However, VSD and/or ASD were reported in over one third of individuals with invdupdel(8p) ( n = 15, 38%)
    explanation: The recurrent invdupdel subgroup retained both genes despite septal defects in 15/40 assessed individuals. This directly limits a universal GATA4/SOX7-deletion explanation.
- name: RHOBTB2
  gene_term:
    preferred_term: RHOBTB2
    term:
      id: hgnc:18756
      label: RHOBTB2
  notes: Prioritized candidate within the duplicated segment. Known sequence-variant disorders and gene function motivate study, but do not establish a validated duplication mechanism or sole responsibility for invdupdel phenotypes.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: we prioritized the candidate genes DLGAP2 and CSMD1 for del(8p) distal and the deleted segment of invdupdel(8p), GATA4 and XKR6 for del(8p)_proximal and dup(8p)_proximal, and RHOBTB2 and CHRNA2 for the duplicated segment of invdupdel(8p) (Supplemental Data).
    explanation: Candidate prioritization uses interval content and prior biological knowledge. It does not demonstrate that any one gene accounts for the whole rearrangement phenotype.
- name: CHRNA2
  gene_term:
    preferred_term: CHRNA2
    term:
      id: hgnc:1956
      label: CHRNA2
  notes: Prioritized candidate within the duplicated segment. Known sequence-variant disorders and gene function motivate study, but do not establish a validated duplication mechanism or sole responsibility for invdupdel phenotypes.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: we prioritized the candidate genes DLGAP2 and CSMD1 for del(8p) distal and the deleted segment of invdupdel(8p), GATA4 and XKR6 for del(8p)_proximal and dup(8p)_proximal, and RHOBTB2 and CHRNA2 for the duplicated segment of invdupdel(8p) (Supplemental Data).
    explanation: Candidate prioritization uses interval content and prior biological knowledge. It does not demonstrate that any one gene accounts for the whole rearrangement phenotype.
diagnosis:
- name: Chromosomal microarray and structural characterization
  description: CMA identifies the terminal deletion, duplicated interval, spacer if present, and additional pathogenic copy-number changes. Karyotyping and targeted FISH can establish the orientation and chromosomal context. Array intervals are platform-dependent and are not nucleotide-resolved junctions.
  evidence:
  - reference: PMID:27343326
    reference_title: Molecular cytogenetic characterization of inv dup del(8p) in a fetus associated with ventriculomegaly, hypoplastic left heart, polyhydramnios and intestinal obstruction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Metaphase FISH confirmed inv dup del(8p).
    explanation: CMA established copy-number intervals and metaphase FISH confirmed the structural rearrangement.
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the shared deleted interval in individuals with invdupdel(8p) was the most distal 6.7 Mb and the shared duplicated interval was approximately 11.1 Mb.
    explanation: CMA-defined shared intervals in the 49-person recurrent subgroup establish simultaneous distal loss and proximal gain; the full duplicated interval varies by individual.
- name: Parental studies and individualized recurrence assessment
  description: Study both parents according to the proband architecture. Routine karyotyping can miss a cryptic inversion; targeted structural testing may be needed. Distinguish a benign inversion carrier from a parent carrying the unbalanced rearrangement. Do not give a universal zero-recurrence assurance.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: all ﬁve mothers were heterozygous inv(8)(p23) carriers (inversion heterozygotes)
    explanation: Observed in five selected Japanese families. This does not establish that all affected individuals require a maternal inversion.
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Patients 16, 17, 18, 19, and 20 were from the same family and included two sibs and their children (Figure 1). All five individuals pres- ented with mild to moderate ID without any major associated malforma- tion.
    explanation: Five affected relatives in two generations carried the rearrangement; all had mild to moderate intellectual disability. This is direct transmission of the unbalanced chromosome, not just inheritance of a benign inversion.
- name: Neurologic evaluation and indicated EEG or MRI
  description: The proposed 8p care guidance recommends EEG when seizures are suspected. Brain MRI is considered before age three for seizures, abnormal head growth or focal findings; screening MRI after age three is proposed in the absence of focal findings. This is expert guidance from a small mixed-8p clinic, not a tested screening trial.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
    reference_title: https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Neurological • Electroencephalogram (EEG) if seizures are suspected. • MRI brain (without contrast) to evaluate for brain malformations if seizures are present, if head circumference is not progressing steadily, or if there are focal abnormalities on the neurologic exam prior to age 3. • Screening MRI brain after age 3 in the absence of focal findings.
    explanation: Table 4 recommendations; clinical indications and age are preserved.
- name: Cardiac evaluation
  description: Cardiology evaluation with consideration of echocardiography assesses congenital heart disease; ECG can be considered for arrhythmia assessment. The spectrum is not explained solely by GATA4 dosage.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
    reference_title: https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Cardiovascular • Cardiology referral for consideration of echocardiogram (ECHO) to assess congenital heart disease and electrocardiogram (ECG) for arrhythmia assessment.
    explanation: Proposed care guidance across chromosome 8p disorders; not evidence of screening efficacy.
- name: Growth, vision, hearing and complication surveillance
  description: Track growth and feeding, assess scoliosis clinically, and examine for undescended testes or hypospadias. The proposed guidance includes annual comprehensive ophthalmology with cerebral visual impairment assessment and audiology for speech delay or hearing concerns. It does not establish an elevated population frequency of hearing loss.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
    reference_title: https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Eyes • Ophthalmologic evaluation annually with an ophthalmologist, specifically requesting a comprehensive examination that includes testing for cortical vision impairment.
    explanation: Annual ophthalmology is proposed with explicit assessment of cortical/cerebral visual impairment.
  - reference: url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
    reference_title: https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Hearing • Audiologic evaluation with an Audiologist is recommended if speech delay or clinical concerns, rates of hearing loss are not reported as elevated in this population.
    explanation: Audiology is indicated for concerns or speech delay; the source does not claim a high hearing-loss rate.
treatments:
- name: Antiseizure Medication
  description: Individualize antiseizure treatment to seizure type and clinical response. Cohort patients received levetiracetam, valproate, oxcarbazepine and other agents; this observational experience does not establish a preferred syndrome-specific drug.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Many individuals with invdupdel(8p) had medically manageable seizures. Levetiracetam, sodium valproate, oxcarbazepine, pheno- barbital, topiramate, and phenytoin were used as monotherapy or in combinations.
    explanation: Direct clinical treatment experience in invdupdel(8p); no randomized comparison or universal response is implied.
  target_mechanisms:
  - target: Seizure
    treatment_effect: INHIBITS
    description: Symptomatic management of this manifestation; the underlying chromosome rearrangement is unchanged.
    evidence:
    - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
      reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Many individuals with invdupdel(8p) had medically manageable seizures. Levetiracetam, sodium valproate, oxcarbazepine, pheno- barbital, topiramate, and phenytoin were used as monotherapy or in combinations.
      explanation: Direct clinical treatment experience in invdupdel(8p); no randomized comparison or universal response is implied.
- name: Developmental Rehabilitation
  description: Occupational and physical therapy support motor function, daily activities and independence. Intensity is individualized over development; the proposed guidance recommends ongoing oversight rather than automatic lifelong continuous therapy. This functional support is not evidence that therapy reverses the underlying hypotonia.
  treatment_term:
    preferred_term: Rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
    reference_title: https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Occupational, physical, and speech therapy play an important role for individuals with 8p, due to the helpful impact on func - tional mobility, activities of daily living, and communication.
    explanation: Expert care recommendations informed by a mixed 8p clinic cohort, not a treatment efficacy trial.
  target_mechanisms:
  - target: Motor Delay
    treatment_effect: INHIBITS
    description: Symptomatic management of this manifestation; the underlying chromosome rearrangement is unchanged.
    evidence:
    - reference: url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
      reference_title: https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Occupational, physical, and speech therapy play an important role for individuals with 8p, due to the helpful impact on func - tional mobility, activities of daily living, and communication.
      explanation: Expert care recommendations informed by a mixed 8p clinic cohort, not a treatment efficacy trial.
- name: Speech Therapy and Augmentative Communication
  description: Use speech-language therapy and augmentative or alternative communication suited to abilities. In the clinic series all 14 invdupdel participants used or were recommended augmentative communication; this is a care observation, not proof of a particular device benefit.
  treatment_term:
    preferred_term: Speech Language Therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
    reference_title: https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: speech therapy is recommended to increase communication for individuals with difficulty speaking, understanding, learning, and communicating.
    explanation: Proposed care supports communication-focused therapy.
  target_mechanisms:
  - target: Delayed Speech and Language Development
    treatment_effect: INHIBITS
    description: Symptomatic management of this manifestation; the underlying chromosome rearrangement is unchanged.
    evidence:
    - reference: url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
      reference_title: https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: speech therapy is recommended to increase communication for individuals with difficulty speaking, understanding, learning, and communicating.
      explanation: Proposed care supports communication-focused therapy.
- name: Feeding and Nutritional Support
  description: Assess swallowing safety and nutritional adequacy; modify feeds and consider nasogastric or gastrostomy support when required.
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
    reference_title: https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Assess nutritional adequacy, consider nasogastric or gastrostomy tube placement if needed.
    explanation: Expert care recommendation; tube feeding is based on individual need.
  target_mechanisms:
  - target: Feeding Difficulties
    treatment_effect: INHIBITS
    description: Symptomatic management of this manifestation; the underlying chromosome rearrangement is unchanged.
    evidence:
    - reference: url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
      reference_title: https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Assess nutritional adequacy, consider nasogastric or gastrostomy tube placement if needed.
      explanation: Expert care recommendation; tube feeding is based on individual need.
  - target: Failure to Thrive
    treatment_effect: INHIBITS
    description: Symptomatic management of this manifestation; the underlying chromosome rearrangement is unchanged.
    evidence:
    - reference: url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
      reference_title: https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Assess nutritional adequacy, consider nasogastric or gastrostomy tube placement if needed.
      explanation: Expert care recommendation; tube feeding is based on individual need.
- name: Indicated Cardiac Surgical Intervention
  description: Correct congenital cardiac lesions when standard cardiology and cardiac-surgery evaluation indicates an intervention. In the mixed 8p clinic cohort, most cardiac findings did not require surgery, while four children had pacemaker placement, PDA coiling, ASD repair or Tetralogy of Fallot-associated surgery; this supports anomaly-specific management rather than routine syndrome-wide repair.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Cardiovascular Surgical Procedure
    term:
      id: NCIT:C49803
      label: Cardiovascular Surgical Procedure
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
    reference_title: https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Cardiac findings largely did not require surgical interventions; 4 children that did require sur - gical interventions included a pacemaker for supraventricular tachycardia, a child requiring coiling for a patent ductus arteri - osus (PDA), repair for atrial septal defect (ASD), and one child had Tetralogy of Fallot with associated surgical interventions.
    explanation: Mixed 8p clinic data document that a minority of cardiac findings required procedural intervention; the passage does not establish a fixed operation or frequency for invdupdel(8p).
  target_mechanisms:
  - target: Congenital Heart Malformation
    treatment_effect: INHIBITS
    description: Symptomatic, lesion-specific management of structural heart disease; the underlying chromosome rearrangement is unchanged.
    evidence:
    - reference: url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
      reference_title: https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Cardiac findings largely did not require surgical interventions; 4 children that did require sur - gical interventions included a pacemaker for supraventricular tachycardia, a child requiring coiling for a patent ductus arteri - osus (PDA), repair for atrial septal defect (ASD), and one child had Tetralogy of Fallot with associated surgical interventions.
      explanation: Mixed 8p clinic data document that a minority of cardiac findings required procedural intervention; the passage does not establish a fixed operation or frequency for invdupdel(8p).
  notes: Congenital diaphragmatic, inguinal, and genitourinary repairs are not targeted because the cited 8p sources document occurrence or surveillance needs, not 8p-specific operative guidance or outcomes for those lesions.
- name: Constipation Management
  description: Treat constipation according to clinical need as part of multidisciplinary supportive care. The syndrome literature does not establish a preferred drug regimen.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
    reference_title: https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Assess for and manage constipation [2].
    explanation: The care table explicitly includes constipation management; a specific agent is not prescribed.
  target_mechanisms:
  - target: Constipation
    treatment_effect: INHIBITS
    description: Symptomatic management of this manifestation; the underlying chromosome rearrangement is unchanged.
    evidence:
    - reference: url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
      reference_title: https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Assess for and manage constipation [2].
      explanation: The care table explicitly includes constipation management; a specific agent is not prescribed.
- name: Genetic Counseling
  description: Discuss the measured rearrangement, variable phenotype, parental testing and possible transmission. A common inversion polymorphism alone does not determine an individual recurrence probability.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
    reference_title: https://project8p.org/wp-content/uploads/2024/10/Clinical-Genetics-2024-Santucci-Chromosome-8p-Syndromes-Clinical-Presentation-and-Management-Guidelines.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Consultation with a clinical geneticist and/or genetic counselor helps the family to understand the diagnosis and consider implications for family planning.
    explanation: Guidance supports counseling; the familial cohort prevents a universal no-recurrence claim.
  action_category: COUNSELING_INFORMATIONAL
progression:
- phase: Infancy and early childhood
  notes: Congenital abnormalities and neonatal hypotonia or feeding difficulties may precede developmental and speech delay. Seizure onset is variable, and selected cohorts cannot provide an individual prognosis.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Neonatal hypotonia was described in 12/28 patients (data not avail- able for five patients; Table 1). Then, 97% of patients ( n = 32/33) developed global development delay including motor delay in 93% (27/29) of patients.
    explanation: Describes the temporal clinical pattern in the cohort.
- phase: Later childhood and adulthood
  notes: Some patients acquire independent walking while speech and adaptive support needs persist. Hypertonia and orthopedic complications can emerge later. Familial adult cases show that survival to reproductive age and transmission are possible; rare severe congenital presentations should not define the whole syndrome.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Patients 16, 17, 18, 19, and 20 were from the same family and included two sibs and their children (Figure 1). All five individuals pres- ented with mild to moderate ID without any major associated malforma- tion.
    explanation: Five affected relatives in two generations carried the rearrangement; all had mild to moderate intellectual disability. This is direct transmission of the unbalanced chromosome, not just inheritance of a benign inversion.
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Hypotonia was accompanied by hypertonia, prominently in the lower extremities, later in life.
    explanation: Later lower-limb hypertonia can coexist with earlier hypotonia.
discussions:
- discussion_id: invdupdel8p_mechanism_and_scope
  prompt: Which formation steps and gene-dosage mechanisms remain unresolved?
  rationale: Constitutional FISH, marker and microarray studies establish rearrangement endpoints, while inversion-loop crossover, dicentric breakage and rescue are mechanistic models. GATA4/SOX7 deletion is not a universal explanation for cardiac disease. The 5.1 Mb callosal candidate interval from Vibert combines selected cases, including pure duplications; it does not identify a proven causal gene. Published duplication-size associations are not validated individual prediction rules. Isolated 8p23 deletion network analyses and single-gene animal models cannot be treated as experimental models of the complete invdupdel chromosome. A single severe RSV case proposed defensin deficiency and impaired NK function, but lacked direct DEF copy-number measurement, acute-infection immune assays or rescue; that hypothesis does not justify a universal immunodeficiency pathway.
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Project-8p-Molecular-Characterization-of-inv-dup-del8p.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: From these ﬁndings, we propose here a model to explain how inv dup del(8p) is formed.
    explanation: The crossover and rescue sequence is an interpretation of FISH and STR findings, not directly observed meiotic intermediates.
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: we prioritized the candidate genes DLGAP2 and CSMD1 for del(8p) distal and the deleted segment of invdupdel(8p), GATA4 and XKR6 for del(8p)_proximal and dup(8p)_proximal, and RHOBTB2 and CHRNA2 for the duplicated segment of invdupdel(8p) (Supplemental Data).
    explanation: Candidate prioritization uses interval content and prior biological knowledge. It does not demonstrate that any one gene accounts for the whole rearrangement phenotype.
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Both GATA4 and SOX7 were copy-number neutral in all individuals with invdupdel(8p) or del(8p)_distal. However, VSD and/or ASD were reported in over one third of individuals with invdupdel(8p) ( n = 15, 38%)
    explanation: The recurrent invdupdel subgroup retained both genes despite septal defects in 15/40 assessed individuals. This directly limits a universal GATA4/SOX7-deletion explanation.
  - reference: url:https://ricerca.uniba.it/retrieve/dd9e0c64-b05b-1e9c-e053-3a05fe0a45ef/6_sdarticle.pdf
    reference_title: https://ricerca.uniba.it/retrieve/dd9e0c64-b05b-1e9c-e053-3a05fe0a45ef/6_sdarticle.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: By high resolution oligo array CGH, we detected the smallest inverted duplication of 8p reported thus far, with additional duplication of 8q24.13/qter on the short arm of the abnormal chromosome 8 (Figs. 1 and 2 A and B).
    explanation: The measured complex chromosome contains an additional terminal 8q duplication on 8p. This is evidence for captured material, not direct observation of the proposed replication process.
  - reference: PMID:35768224
    reference_title: A Case Report of Respiratory Syncytial Virus-Infected 8p Inverted Duplication Deletion Syndrome with Low Natural Killer Cell Activity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: His NK cell activity was measured 9.9% using a 51Cr release assay at an Effector/Target ratio of 20:1
    explanation: Single-patient NK cytotoxicity was measured at five months, after severe RSV at one month. Plasma defensin was measured at eleven months against four older controls; neither measurement proves the proposed acute causal chain.
- discussion_id: invdupdel8p_clinical_evidence_scope
  prompt: How should heterogeneous cohorts and proposed care guidance be interpreted?
  rationale: 'The main clinical sources represent selected cohorts: Okur includes 49 recurrent invdupdel cases within 102 individuals with several 8p rearrangements; Vibert includes 33 postnatal cases and three fetuses, with five relatives; Santucci includes 14 invdupdel cases within a 24-person mixed clinic. Their denominators are not pooled. Proposed management recommendations were not evaluated for efficacy. Internal aggregate MRI and cardiac counts in the Santucci table do not reconcile, so those pooled rates are not used. The prenatal 2025 series includes an inherited interstitial-deletion case retaining the terminal 8p segment; its apparently unaffected five-year outcome is not generalized to classic terminal-deletion invdupdel. The eight-case Yurchenko series also reports different seizure and cardiac observations from the larger cohorts, illustrating selection and age effects rather than defining an invariant phenotype.'
  evidence:
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/s41436-021-01270-2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the shared deleted interval in individuals with invdupdel(8p) was the most distal 6.7 Mb and the shared duplicated interval was approximately 11.1 Mb.
    explanation: CMA-defined shared intervals in the 49-person recurrent subgroup establish simultaneous distal loss and proximal gain; the full duplicated interval varies by individual.
  - reference: url:https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    reference_title: https://project8p.org/wp-content/uploads/2023/08/Clinical-Genetics-2021-Vibert-Neurodevelopmental-phenotype-in-36-new-patients-with-8p-inverted-duplication-deletion-.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Patients 16, 17, 18, 19, and 20 were from the same family and included two sibs and their children (Figure 1). All five individuals pres- ented with mild to moderate ID without any major associated malforma- tion.
    explanation: Five affected relatives in two generations carried the rearrangement; all had mild to moderate intellectual disability. This is direct transmission of the unbalanced chromosome, not just inheritance of a benign inversion.
notes: 'Source scope: Okur, Clinical and genomic characterization of 8p cytogenomic disorders (PMID:34282301); Vibert, Neurodevelopmental phenotype in 36 new patients with 8p inverted duplication-deletion (PMID:34866188); Santucci, Chromosome 8p Syndromes: Clinical Presentation and Management Guidelines (PMID:39390634); Shimokawa, Molecular characterization of inv dup del(8p): analysis of five cases (PMID:15214003); Buysse, Unusual 8p inverted duplication deletion with telomere capture from 8q (PMID:19041960). Public full-text PDF references retain their generated URL titles. No disorder-specific GeneReviews chapter or relevant interventional trial was identified in the review searches. Clinical care guidance and primary cohort observations are distinguished from experimentally tested treatment efficacy.'

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Evaluations and curation notes (2)

Review 8p invdupdel mechanisms, cohort scope and clinical care from full sources · 2026-09-21T04:36:13Z · View source

Reviewed the complete original entry and matching deep-research narrative/citations, with full-text reading of the clinical cohorts, proposed care guidance, rearrangement studies, immune case and available prenatal reports. Cache files were generated only through just fetch-reference; the shared 2022 cache now contains its patient-level table and its sole KB consumer passes exact-quote validation. Corrected universal maternal/de novo inheritance and spacer assumptions, distinguished measured FISH/STR/CMA endpoints from proposed recombination/dicentric/rescue mechanisms, and added complex telomere-capture architecture. Ten mechanism nodes separate structural formation and the two opposed dosage changes. Familial unbalanced transmission is retained without inventing a numerical recurrence risk. The full Shimokawa paper distinguishes Japanese allele frequency from inferred heterozygosity; its erroneous abstract frequency and chance calculation are not repeated. Replaced universal GATA4/SOX7 loss with measured copy-neutral recurrent cases and conditional larger-deletion involvement. RHOBTB2 and CHRNA2 remain candidates, not established triplosensitive causes. Removed NEIL2 and defensin overclaims based on differently scoped or single-patient studies. Fifty-four phenotype records preserve cohort-specific denominators, distinguish intellectual disability from developmental delay, and avoid unsupported frequency bands and pooled mixed-8p outcomes. Severe neonatal polyvalvular disease is a case observation, not syndrome lethality. The 2024 mixed-clinic aggregate MRI/cardio counts are internally inconsistent in the actual PDF and are not used. Six care entries and diagnostic surveillance use full proposed guidelines with their limits; symptomatic links are evidence-based, while counseling and diagnostic evaluation are not therapeutic edges. Independent bounded peer review checked inheritance, mechanisms, genetics and care against full sources; removed an unsupported rehabilitation-to-hypotonia inhibition edge and added the primary STR parent-of-origin result. Research completeness: clinical features, architectural subtypes, mechanisms, diagnosis and management addressed. Single-gene Gata4/Tbx5 mouse and sox7 fish studies and isolated 8p23 network analyses do not validate a whole-invdupdel model; no suitable disease-wide experimental model or clinical dataset was identified for addition. The defensin/NK/RSV hypothesis remains discussion with timing, genotype and control limitations. No disease-specific GeneReviews chapter in the committed index; current exact ClinicalTrials.gov searches returned no relevant trial. Population prevalence and individual duplication-size prognosis remain unresolved. No code/schema/provider edits or frozen dataset-accession access. Validation: schema, live ontology terms and 125/125 exact evidence snippets passed before commit; complete curation gates and history checks are recorded in the PR.

Create: 8p Inverted Duplication Deletion Syndrome · 2026-09-03T19:41:21Z · View source

De novo curation of invdupdel(8p) from primary literature plus one openscientist deep-research run. The pathograph is built around the two-step formation mechanism, with the common maternal 8p23 inversion polymorphism curated as the first node so that the rarity of the syndrome against the commonness of its predisposing haplotype is explicit. Deletion-side gene candidates (GATA4/NEIL2/SOX7, and the defensin cluster) are curated in genetic: as candidates with INDIRECT grading rather than promoted into pathophysiology nodes, because the cardiac attributions come from isolated 8p23.1 cohorts and the immune one from a single case. Four reference_title values were written from memory and corrected against the cache after the validator flagged them, and one snippet needed a bracketed span trimmed. Validated: schema, terms, 31/31 snippets, entity refs, causal targets, duplicate keys, enum values, qualifier terms.

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8p Inverted Duplication/Deletion Syndrome (inv dup del(8p)) — Comprehensive Disease Characterization Report

openscientist-autonomous 20 citations 2026-09-03T19:37:42.824001

8p Inverted Duplication/Deletion Syndrome (inv dup del(8p)) — Comprehensive Disease Characterization Report

Disease: 8p inverted duplication/deletion syndrome MONDO ID: MONDO:0019876 Orphanet: ORPHA:96092 ("Chromosome 8p inverted duplication/deletion") Category: Chromosomal (contiguous-gene) disorder Report basis: 5 autonomous investigation iterations, 11 confirmed findings, 53 primary papers reviewed

Summary

8p inverted duplication/deletion syndrome (inv dup del(8p)) is a rare, almost invariably sporadic (de novo) contiguous-gene chromosomal disorder. It is defined by a single rearranged chromosome 8 that simultaneously carries a terminal 8p deletion (~6.7–11.4 Mb, 8p23.3→8p23.1) and an inverted interstitial duplication (~30–32 Mb, 8p23.1→8p11.1), the two imbalances being separated by a preserved single-copy (disomic) region delimited by the olfactory-receptor (OR) low-copy-repeat clusters (REPD/REPP). The rearrangement arises predominantly by non-allelic homologous recombination (NAHR) during maternal meiosis between these OR repeats, an event strongly predisposed by a common paracentric 8p23.1 inversion polymorphism carried in the heterozygous state by ~26% of individuals of European descent. Because the operative risk factor is the mother's benign inversion-carrier status rather than maternal age, and because the event is de novo, recurrence risk in a family is low.

The dual dosage imbalance drives a highly penetrant, multisystem phenotype. Terminal haploinsufficiency of dosage-sensitive transcription factors — most importantly GATA4 and SOX7 at 8p23.1 — together with triplosensitivity of the large interstitial duplication produces a recognizable clinical picture: developmental delay / intellectual disability in ~97% of patients, anomalies of the corpus callosum (agenesis/hypoplasia) in ~60–65%, infantile hypotonia, characteristic facial dysmorphism, congenital heart defects (notably atrioventricular/atrial septal defects), and seizures in ~30–35% (mean onset ~3.9 years). Severity is graded by the size and breakpoints of the imbalance and is attenuated by somatic mosaicism. Model organisms (mouse Gata4, zebrafish sox7) recapitulate the cardiac and vascular components, validating the dosage mechanism for the heart phenotype, though no model reproduces the whole contiguous imbalance.

Diagnosis is molecular-cytogenetic: chromosomal microarray (CMA/aCGH/SNP-array) defines the deletion+duplication pattern with precise breakpoints, with karyotype (typically add(8)(p23)/der(8)) and FISH confirmation and parental karyotyping to document de novo origin. Prenatally, diagnosis is triggered by ultrasound anomalies (increased nuchal translucency, ventriculomegaly, cardiac and renal defects) that can mimic trisomy 18. There is no curative or disease-specific therapy; management is symptomatic and multidisciplinary, and prevention is limited to genetic counseling and prenatal/preimplantation diagnosis.

Section 1 — Disease Information

Overview. inv dup del(8p) is a recurrent structural chromosomal rearrangement of the short arm of chromosome 8, producing a contiguous-gene syndrome from combined deletion (dosage loss) and inverted duplication (dosage gain). The clinical entity is dominated by neurodevelopmental impairment, brain (corpus callosum) malformation, hypotonia, dysmorphism, and congenital heart disease.

Key identifiers. - MONDO: MONDO:0019876 - Orphanet: ORPHA:96092 ("Chromosome 8p inverted duplication/deletion") - MeSH: concept mapped to Chromosomes, Human, Pair 8 - OMIM: No single dedicated phenotype MIM number; covered under the contiguous-gene 8p23.1 deletion/duplication entries and GATA4 (%607941) - ICD-10: Q99.9 / Q93–Q95 range (chromosomal abnormalities); ICD-11: LD44 (chromosomal anomalies)

Synonyms / alternative names: inv dup del(8p); invdupdel(8p); inverted duplication deletion 8p syndrome; inverted duplication of 8p with terminal deletion; der(8) inverted duplication deletion syndrome; recombinant chromosome 8 (partial).

Information source. The knowledge base for this disorder is derived from aggregated individual case reports and small cohort/case series (the largest being 36 new patients plus a literature review), supplemented by prenatal diagnostic series and disease-level cytogenetic resources (Orphanet, DECIPHER, ClinVar). There is no large population-level EHR dataset.

Section 2 — Etiology

Primary cause (genetic, structural). The disorder is caused by a de novo structural chromosomal rearrangement, not by environmental or infectious factors. The recurrent rearrangement combines a distal terminal deletion (8p23.3→8p23.1) with an inverted interstitial duplication (8p23.1→8p11.1) separated by a disomic region delimited by the OR gene clusters.

Mechanism. The rearrangement arises by NAHR during maternal meiosis between segmental duplications made up of OR gene clusters (REPD/REPP), facilitated by a paracentric 8p23.1 inversion polymorphism present in ~26% of Europeans. A dicentric chromosome intermediate forms, breaks, and the resulting terminal deletion is stabilized by telomere healing (direct addition of telomeric repeats), or rarely by telomere capture from 8q.

"Inverted 8p duplication deletions are recurrent chromosomal rearrangements that most often arise through non-allelic homologous recombination (NAHR) during maternal meiosis between segmental duplications made up of the olfactory receptor (OR) gene clusters. The presence of a paracentric inversion polymorphism in 8p23.1, found in approximately 26% of European population, may trigger meiotic misalignment and NAHR between the OR gene repeats." — PMID: 24502041

"The terminal deletions are stabilized by direct addition of telomeric repeats, so called telomere healing." — PMID: 19041960

Genetic risk factor. The single established predisposing factor is maternal heterozygosity for the 8p23.1 inversion polymorphism, a benign structural variant that itself causes no phenotype but confers susceptibility to meiotic malsegregation. In the landmark study all 8 mothers of inv dup(8p) probands were inversion carriers (PMID: 11231899).

Environmental risk factors / protective factors / gene-environment interactions. None are established. Because the event is a meiotic recombination error, there are no known environmental risk factors, protective exposures, or gene–environment interactions. Unlike aneuploidies, maternal age is not the operative factor; maternal inversion-carrier status is.

Section 3 — Phenotypes

The phenotype is multisystem and highly penetrant. Frequencies below are drawn primarily from the largest cohort (36 new patients + literature review; PMID: 34866188) and independent case series (PMID: 35327368).

Phenotype	Type	Frequency	Onset	HPO suggestion
Developmental delay / intellectual disability	Neurodevelopmental	~97% (32/33)	Neonatal–infancy	HP:0001263 / HP:0001249
Anomalies of the corpus callosum (agenesis/hypoplasia)	Structural CNS	~63% (17/27 imaged)	Congenital	HP:0001274 / HP:0001338
Muscular hypotonia	Neuromuscular	Very frequent (near-universal in series)	Neonatal	HP:0001252
Dysmorphic facial features	Physical	Present in all cases of one series	Congenital	HP:0001999
Seizures / epilepsy	Neurological	~34%	Mean 3.9 y (2 mo–9 y)	HP:0001250
Congenital heart defects (ASD/AVSD, others)	Cardiovascular	Frequent	Congenital	HP:0001627 / HP:0001671
Psychomotor and language delay	Neurodevelopmental	Very frequent	Infancy	HP:0011342 / HP:0000750
Orthopedic/skeletal anomalies (scoliosis, limb/joint)	Musculoskeletal	Frequent	Childhood	HP:0002751 / HP:0002650
Microcephaly	Physical/CNS	Variable (deletion component)	Congenital	HP:0000252
Behavioral problems	Behavioral	Variable	Childhood	HP:0000708

Prenatal presentation. Can mimic trisomy 18: increased nuchal translucency, ventriculomegaly, cardiac defects (including hypoplastic left heart), renal anomalies, and craniofacial dysmorphism.

Characteristics. Onset is congenital/neonatal; severity is variable (mild to severe); course is generally stable/non-progressive structurally but with lifelong disability; seizures may be episodic. Quality-of-life impact is substantial and lifelong: most survivors have persistent intellectual disability, hypotonia, and require ongoing developmental support, affecting mobility, communication, self-care, and independent living.

"97% (n = 32/33) of patients presented with mild to severe developmental delay/ID and 34% had seizures with mean age of onset of 3.9 years (2 months-9 years). Moreover, out of the 24 patients with brain MRI and 3 fetuses with neuropathology analysis, 63% (n = 17/27) had AnCC." — PMID: 34866188

"The main clinical manifestations in all cases are psychomotor and language delay, muscle hypotonia, and dysmorphic facial features. Malformations of the central nervous system, such as corpus callosum agenesis, were found in five cases." — PMID: 35327368

Section 4 — Genetic / Molecular Information

Causal lesion. A single derivative chromosome 8 carrying a terminal deletion (8p23.3→8p23.1) + an inverted interstitial duplication (8p23.1→8p11.1), separated by a disomic segment bounded by OR clusters. This is a structural (copy-number) variant, classified pathogenic per ACMG/AMP CNV guidelines given established dosage-sensitive gene content.

Key dosage-sensitive genes. - GATA4 (8p23.1; HGNC:4173; OMIM %607941) — cardiac transcription factor; haploinsufficiency in the deletion drives congenital heart defects and contributes to diaphragmatic hernia. - SOX7 (8p23.1; HGNC:18196) — SoxF transcription factor; deletion contributes to cardiac/vascular defects. - NEIL2 (8p23.1) — implicated with GATA4/SOX7 in diaphragmatic defects by protein-interaction network analysis. - Defensin (DEFA/DEFB) cluster (8p23.1) — deletion associated with reduced NK-cell activity and low α-defensin, contributing to infectious vulnerability. - Candidate genes XKR6 and MIR597 proposed for absence seizures within the 8p23.1 interval.

"implicated GATA4, NEIL2, and SOX7 in diaphragmatic defects. Sequence analysis of these genes in 226 chromosomally normal CDH patients, as well as in a small number of deletion 8p23.1 patients, showed rare unreported variants in the coding region" — PMID: 23165946

"This patient showed lower NK cell activity and α-defensin level compared with healthy controls. These results suggest that decreased NK cell activity can result from DEF haploinsufficiency." — PMID: 35768224

Reciprocal / related conditions. The same NAHR mechanism generates reciprocal products: the supernumerary +der(8)(8p23.1pter) marker, the recurrent 8p23.1 interstitial deletion syndrome, and isolated 8p23.1 duplication syndrome (prevalence ~1/58,000), which produces a milder overlapping phenotype with GATA4 gain also linked to CHD.

"The 8p23.1 duplication syndrome (8p23.1 DS) is a recurrent genomic condition with an estimated prevalence of 1 in 58,000." — PMID: 26097203

Modifier genes / epigenetics. No specific trans-acting modifier genes are established for inv dup del(8p); phenotype modulation is driven mainly by rearrangement size/breakpoints and mosaicism (Section 9). No disease-specific epigenetic signature is documented.

Chromosomal abnormality classification. Complex intrachromosomal rearrangement (terminal deletion + inverted interstitial duplication) — cytogenetically add(8)(p23)/der(8). Allele frequencies are not applicable (recurrent de novo structural event, not an SNV). Origin is germline (maternal meiosis); somatic (postzygotic) mosaic forms occur.

Section 5 — Environmental Information

Not applicable. No environmental factors, lifestyle factors, or infectious agents are implicated in causing inv dup del(8p). The disorder is a de novo meiotic recombination error. (Affected individuals have increased vulnerability to infections as a downstream consequence of DEF-cluster haploinsufficiency — see Sections 8 and 11 — but infections do not cause the syndrome.)

Section 6 — Mechanism / Pathophysiology

Ordered causal chain

A mother carries the 8p23.1 paracentric inversion polymorphism in the heterozygous state (present in ~26% of Europeans) → predisposes to meiotic misalignment.
During maternal meiosis, the OR gene clusters (REPD/REPP) flanking 8p23.1 misalign → NAHR between the repeats.
NAHR results in a dicentric chromosome intermediate (and a reciprocal acentric fragment).
The dicentric breaks asymmetrically → leads to a chromosome bearing a terminal 8p deletion + an inverted interstitial 8p duplication.
The broken terminal end is stabilized by telomere healing (direct telomeric-repeat addition) or, rarely, telomere capture from 8q → yields a stable derivative chromosome 8.
Fertilization transmits the derivative chromosome → the zygote has terminal 8p23 haploinsufficiency + interstitial 8p triplosensitivity.
Haploinsufficiency of GATA4/SOX7/NEIL2 (deletion) → impaired cardiac transcription-factor dosage → results in congenital heart defects and (with diaphragm-expressed genes) diaphragmatic hernia. (Demonstrated in model organisms.)
Haploinsufficiency of the DEF cluster (deletion) → reduced NK-cell activity and α-defensin → leads to immune vulnerability and severe respiratory infections. (Demonstrated in one patient.)
Combined dosage imbalance of many 8p genes (deletion and duplication) → disrupted neurodevelopment → results in corpus callosum anomalies, intellectual disability, hypotonia, and seizures. (Gene-specific causality largely inferred; corpus-callosum-anomaly risk region mapped.)
Structural malformations + neurodevelopmental impairment → lead to the lifelong multisystem clinical phenotype.

Detail by category

Molecular pathways / cellular processes. The cardiac branch converges on cardiac transcription-factor networks (GATA4–TBX5–NKX2-5–HAND2; GATA4–GATA5–GATA6 combinatorial regulation) governing cardiomyocyte proliferation and septation. In mouse models, reduced Gata4 dosage lowers cardiomyocyte proliferation (Cdk4/Cdk2 downregulation; p21/Cdkn1a de-repression via FOG-2/NuRD). The vascular branch involves SoxF–Notch signaling (Sox7 upstream of hey2, efnb2, Dll4/Notch1) in arterial specification.
GO suggestions: heart development (GO:0007507), cardiac septum morphogenesis (GO:0003279), regulation of cardiomyocyte proliferation, arterial endothelial cell differentiation (GO:0060842), corpus callosum morphogenesis / axon guidance, forebrain development.
Protein dysfunction. Loss-of-dosage (haploinsufficiency) of GATA4/SOX7 and gain-of-dosage of interstitial genes; the mechanism is quantitative (gene dosage), not a mutant-protein misfolding mechanism.
Immune involvement. DEF-cluster haploinsufficiency → reduced NK activity/α-defensin → impaired innate antiviral defense.
Cell types (CL suggestions): cardiomyocyte (CL:0000746), endocardial/endothelial cell (CL:0002350/CL:0000115), arterial endothelial cell (CL:1000413), neuron (CL:0000540), natural killer cell (CL:0000623), skeletal muscle myocyte (hypotonia; CL:0000188).

Upstream mechanisms are the meiotic NAHR event and the resulting dosage imbalance; downstream are the organ-specific developmental failures (heart, brain commissures, diaphragm, immune cells).

Section 7 — Anatomical Structures Affected

Organ / body-system level. - Central nervous system (primary): corpus callosum (agenesis/hypoplasia), cerebral ventricles (ventriculomegaly), brain generally — UBERON:0002336 (corpus callosum), UBERON:0000955 (brain), UBERON:0002285 (lateral ventricle). - Cardiovascular system (primary): heart septa and valves, outflow tract, great vessels — UBERON:0000948 (heart), UBERON:0002099 (cardiac septum). - Musculoskeletal system: skeletal muscle (hypotonia), spine (scoliosis), limbs/joints — UBERON:0001134 (skeletal muscle), UBERON:0001130 (vertebral column). - Craniofacial: dysmorphic facial structures — UBERON:0001456 (face). - Diaphragm (secondary, subset): congenital diaphragmatic hernia — UBERON:0001103 (diaphragm). - Renal (secondary, prenatal): kidney anomalies — UBERON:0002113 (kidney). - Immune system (secondary): NK-cell function — UBERON:0002405.

Tissue / cell level. Nervous tissue (callosal projection neurons, glia), cardiac muscle (cardiomyocytes) and endocardium/endothelium, skeletal muscle, NK cells.

Subcellular level (GO CC). Nucleus (transcription-factor localization; GO:0005634) is central given the dosage effect on nuclear transcription factors (GATA4, SOX7). No specific mitochondrial/ER/lysosomal defect is established.

Localization / lateralization. CNS and cardiac malformations are typically midline/bilateral (the corpus callosum is a midline commissure; septal defects are central). Rare laterality defects (dextrocardia with corpus callosum agenesis) are reported (PMID: 20880309).

Section 8 — Temporal Development

Onset: Congenital — the chromosomal imbalance is present from conception; malformations are prenatal/neonatal. Prenatal detection is possible via ultrasound anomalies.
Onset pattern: Chronic/congenital (structural anomalies fixed at birth); seizures have a later, childhood onset (mean 3.9 y, range 2 months–9 years).
Progression: Structural anomalies are stable/non-progressive; the disorder is a chronic, lifelong condition. Developmental delay is persistent; seizures may be episodic and require ongoing management.
Disease course: Non-remitting congenital disorder; no spontaneous remission of core features. Severity is set largely at conception by rearrangement extent (and any mosaicism).
Critical periods: Embryonic organogenesis (cardiac septation, diaphragm formation ~E11.5–12.5 equivalent, commissural/corpus-callosum development) is the window in which the dosage imbalance produces malformations; the principal postnatal intervention window is early developmental intervention and surgical correction of malformations.

Section 9 — Inheritance and Population

Epidemiology. inv dup del(8p) is rare with no established population prevalence (Orphanet lists it among rare chromosomal anomalies). For scale, the reciprocal isolated 8p23.1 duplication syndrome has an estimated prevalence of ~1/58,000. In an unselected pediatric developmental-disorder cohort, pathogenic 8p CNVs occurred in ~1% (10/966), of which inv dup del(8p) is a subset.

"found 10 individuals with pathogenic copy number variants (CNVs) on the short arm of chromosome 8 (8p), representing approximately 1% of the patients analyzed" — PMID: 20461109

Inheritance. De novo, sporadic, arising in maternal meiosis. Parental karyotypes are typically normal. The predisposing factor is maternal heterozygosity for the benign 8p23.1 inversion (~26% of Europeans). Recurrence risk is low. Rare somatic-mosaic forms occur postzygotically.

"Since inv dup(8p)s originate consistently in maternal meiosis, we investigated the maternal chromosomes 8 in eight mothers of subjects with inv dup(8p) ... All the mothers were heterozygous for an 8p submicroscopic inversion that was delimited by the 8p-OR gene clusters and was present, in heterozygous state, in 26% of a population of European descent." — PMID: 11231899

Penetrance / expressivity. Penetrance is high for the classic rearrangement; expressivity is highly variable, scaling with imbalance size/breakpoints and attenuated by mosaicism (below). No genetic anticipation (not a repeat-expansion disorder). Founder effects and consanguinity are not relevant. "Carrier frequency" in the classic sense does not apply; the relevant population parameter is the ~26% maternal inversion-polymorphism frequency (a susceptibility, not a disease-carrier state).

Demographics. Both sexes affected (autosomal; no strong sex bias reported). The inversion polymorphism is documented at ~26% in European-descent populations; the operative maternal factor is inversion-carrier status, not maternal age. The 8p23.1 segmental-duplication architecture is also a general genomic-instability hotspot (e.g., somatic 8p loss in ~31% of multiple myeloma).

Section 10 — Diagnostics

Definitive diagnosis is molecular-cytogenetic. - Chromosomal microarray (CMA; aCGH or SNP-array): first-line; defines precise breakpoints and the characteristic pattern — terminal 8p deletion + interstitial inverted duplication separated by a single-copy disomic region. - G-banded karyotype: typically shows add(8)(p23) or der(8). - Metaphase FISH: confirms the inverted duplication and 8p subtelomere deletion; subtelomeric/centromeric/whole-chromosome painting probes. - Parental karyotyping: documents de novo origin and can reveal the maternal 8p23.1 inversion.

"aCGH detected an 11.35 Mb deletion in 8p23.3-p23.1 encompassing SOX7 and GATA4, and a 31.99 Mb duplication in 8p23.1-p11.1 in the fetus. Metaphase FISH confirmed inv dup del(8p)." — PMID: 27343326

Prenatal diagnosis. Invasive testing (CVS/amniocentesis) with CMA is prompted by ultrasound findings — increased NT, ventriculomegaly, cardiac defects, renal/craniofacial anomalies — that can mimic trisomy 18. In prenatal SNP-array cohorts, multisystem ultrasound anomalies confer the highest CMA yield (~27%) and increased NT is the strongest soft-marker predictor of chromosomal pathology.

"multisystem anomalies conferred the highest risk (27.3%), driven predominantly by aneuploidies; among soft markers, increased nuchal translucency (NT) emerged as the strongest predictor of chromosomal pathology" — PMID: 42067806

Supporting clinical work-up. Brain MRI (corpus callosum anomalies, ventriculomegaly); echocardiography (septal/valve defects); orthopedic/skeletal evaluation; immune work-up (NK-cell activity, α-defensin) where infections recur. Prenatal WGS and low-coverage WGS can also detect the large CNVs with performance comparable to CMA.

Differential diagnosis. Trisomy 18 (prenatal overlap), isolated 8p23.1 deletion or duplication syndromes, other contiguous-gene syndromes with corpus callosum agenesis and CHD, Kabuki-like phenotypes; distinguished by the characteristic dual deletion+duplication CMA signature.

Screening. No population/newborn screening exists for inv dup del(8p); detection is via diagnostic (not screening) CMA prompted by phenotype, or prenatally by ultrasound-triggered testing.

Section 11 — Outcome / Prognosis

Nature. Chronic, lifelong congenital disorder; no cure; management supportive.

Mortality. Prognosis is dominated by malformation severity. Congenital heart defects (including hypoplastic left heart) and congenital diaphragmatic hernia are the principal life-threatening complications; neonatal death occurs with severe cardiac malformation (e.g., severe polyvalvular dysplasia, death at day 12).

"the present case had severe polyvalvular dysplasia and the infant deceased at day 12 of life" — PMID: 28211984

"Recurrent interstitial deletion of a region of 8p23.1 flanked by the low copy repeats 8p-OR-REPD and 8p-OR-REPP is associated with a spectrum of anomalies that can include congenital heart malformations and congenital diaphragmatic hernia (CDH). Haploinsufficiency of GATA4 is thought to play a critical role in the development of these birth defects." — PMID: 19606479

Morbidity. Survivors have persistent intellectual disability, hypotonia, orthopedic problems (scoliosis, joint/limb anomalies), and require lifelong developmental support. Immune vulnerability (DEF haploinsufficiency) predisposes to severe respiratory infections (severe RSV bronchiolitis; a severe COVID-19 case requiring 26-day hospitalization with 9 days in PICU and mechanical ventilation).

"This patient showed lower NK cell activity and α-defensin level compared with healthy controls." — PMID: 35768224

Prognostic factors. Rearrangement size/breakpoints, presence and severity of CHD/CDH, and mosaicism. Milder outcomes occur with smaller duplications, isolated terminal deletions distal to GATA4, or somatic mosaicism.

"This female has developmental delay, but lacks congenital anomalies that are associated with either 8p abnormality in non-mosaic form. The attenuated phenotype in this individual may be due to compensation of one cell line for imbalances in the other cell line." — PMID: 20830805

"unlike the inv dup del(8p), the phenotype in our case is milder with no central nervous system malformations or cardiac defects" — PMID: 18302246

Section 12 — Treatment

No disease-specific or curative therapy exists. There are no pharmacological, gene, or cell therapies targeting the rearrangement, and no registered disease-specific clinical trials. Management is supportive and multidisciplinary:

Domain	Intervention	NCIT suggestion
Development	Early developmental intervention; physical, occupational, speech therapy	Rehabilitation Therapy (NCIT:C15917)
Cardiac	Surgical repair of congenital heart defects	Cardiac Surgery (NCIT:C157664)
Diaphragm	Surgical repair of diaphragmatic hernia	Surgical Procedure (NCIT:C15329)
Epilepsy (~34%)	Anti-seizure medication	Anticonvulsant Agent (NCIT:C264)
Orthopedic	Management of scoliosis/limb/joint anomalies	Orthopedic Procedure
Nutrition/feeding	Feeding support	Nutritional Support (NCIT:C15311)
Infections	Intensive/critical care (mechanical ventilation, dexamethasone, remdesivir in severe COVID-19)	Supportive Care (NCIT:C15277)

"There, she was mechanically ventilated, received dexamethasone and remdesivir, and was hospitalized for 26 days, nine of which were in the pediatric intensive care unit." — PMID: 37829974

Pharmacogenomics, advanced therapeutics, targeted/immunotherapy, personalized medicine: none applicable/available for this disorder.

Section 13 — Prevention

Primary prevention: Not possible (de novo meiotic event). No vaccination or risk-factor modification prevents the rearrangement.
Secondary prevention: Prenatal diagnosis by CMA (prompted by ultrasound anomalies/increased NT) enables informed reproductive decisions and delivery planning. Preimplantation genetic testing is an option for known inversion carriers.
Tertiary prevention: Prevent complications — surgical correction of malformations, seizure control, and infection prophylaxis (COVID-19 vaccination and RSV prophylaxis are advised given the DEF-related immune vulnerability).
Genetic counseling: Central preventive measure. Because the event arises de novo from a common benign maternal inversion polymorphism, recurrence risk is low, but the same NAHR mechanism can generate reciprocal deletion/duplication products, so prenatal monitoring is recommended.

"Prenatal diagnosis should be performed to monitor the recurrent risk of inv dup del(8p), as well as the other three harmful consequences resulted from the same NAHR mechanism." — PMID: 20677137

Section 14 — Other Species / Natural Disease

There is no naturally occurring animal disease equivalent to inv dup del(8p) — the specific human 8p23.1 OR-cluster/inversion architecture and NAHR-driven rearrangement are human-specific. However, the individual dosage-sensitive genes are evolutionarily conserved and modeled experimentally (Section 15): - Mouse Gata4 (NCBI Gene 14463) — ortholog of human GATA4. - Zebrafish sox7, sox18 — orthologs of the human SOXF family. - Taxonomy: Mus musculus (NCBI:txid10090), Danio rerio (NCBI:txid7955).

No zoonotic potential or cross-species transmission (non-infectious genetic disorder). No breed-specific (VBO) associations.

Section 15 — Model Organisms

No single model reproduces the entire inv dup del(8p) contiguous imbalance, but gene-specific models recapitulate the cardiac and vascular components, validating the dosage mechanism.

Mouse (mammalian): - Gata4 is a core cardiac transcription factor; disruption causes congenital heart defects. Gata4(+/-);Tbx5(+/-) embryos show decreased atrial/ventricular myocardial thickness and atrioventricular septation defects with reduced cardiomyocyte proliferation (Cdk4/Cdk2 downregulation). - Gata4/Gata5 compound heterozygotes develop double-outlet right ventricle, VSDs, and valve defects.

"Gata4(+/-);Tbx5(+/-) mouse embryos display decreased atrial and ventricular myocardial thickness at E11.5, prior to cardiac septation." — PMID: 24858909

Zebrafish: - sox7 mutants show a "short circulatory loop" from aberrant artery–vein connections; Sox7 acts upstream of Notch (hey2, efnb2) in arterial specification. Combined Sox7/Sox18 loss ablates the dorsal aorta.

"sox7 mutants display a short circulatory loop around the heart as a result of aberrant connections between the lateral dorsal aorta (LDA) and either the venous primary head sinus (PHS) or the common cardinal vein (CCV)" — PMID: 25834021

Model characteristics. These models faithfully reproduce the cardiac septal/outflow and vascular defects of the 8p23.1-deletion component. Limitations: they capture only single-gene dosage effects, not the combined deletion+duplication imbalance, the neurodevelopmental/corpus-callosum phenotype, or the immune (defensin) component. Resources: MGI (mouse Gata4), ZFIN (zebrafish sox7/sox18).

Mechanistic Model (Synthesis)

Maternal 8p23.1 inversion polymorphism (heterozygous, ~26% Europeans)
    │  predisposes to
    ▼
   Meiotic misalignment of OR repeats (REPD/REPP) at 8p23.1
    │  NAHR
    ▼
Dicentric chromosome 8 intermediate
    │  asymmetric breakage
    ▼
  der(8): TERMINAL 8p DELETION  +  INVERTED INTERSTITIAL 8p DUPLICATION
    │  stabilized by telomere healing / (rare) 8q capture
    ▼
     ┌──────────────┴───────────────┬──────────────────────┐
     ▼                              ▼                      ▼
 GATA4/SOX7/NEIL2 loss        DEF cluster loss      Global 8p dosage imbalance
 (deletion, dosage↓)          (deletion)            (deletion + duplication)
     │                              │                      │
     ▼                              ▼                      ▼
 Congenital heart defects     ↓NK activity,         Corpus callosum anomalies,
 ± diaphragmatic hernia       ↓α-defensin           ID, hypotonia, seizures,
 [model-validated]            → severe infections    dysmorphism [largely inferred]
     └──────────────┬───────────────┴──────────────────────┘
    ▼
Lifelong multisystem clinical phenotype

Upstream = the maternal inversion + NAHR + dosage imbalance. Downstream = organ-specific developmental failures. The cardiac and vascular branches are experimentally demonstrated (mouse/zebrafish); the neurodevelopmental branch is well correlated but gene-level causality remains largely inferred.

Evidence Base — Key Literature

PMID	Contribution	Evidence type
24502041	NAHR/maternal-meiosis/OR-cluster mechanism; 26% inversion frequency	Human, cytogenetic
11231899	Landmark: maternal meiotic origin; all mothers inversion carriers	Human, cytogenetic
19041960	Telomere healing stabilizes terminal deletion; 8q telomere capture	Human, case
34866188	Largest cohort (36 pts): ID 97%, seizures 34%, AnCC 63%	Human, cohort
35327368	8-case series: psychomotor/language delay, hypotonia, dysmorphism, CC agenesis	Human, series
23165946	GATA4/NEIL2/SOX7 → diaphragmatic (and cardiac) defects	Human + network
35768224	DEF haploinsufficiency → low NK activity/α-defensin → severe RSV	Human, case
26097203	Reciprocal 8p23.1 duplication prevalence ~1/58,000	Human, cohort
28533195	8p23.1 deletion syndrome spectrum (CHD, ID, behavior, microcephaly, epilepsy)	Human, review/case
18393291	GATA4 as causal gene for cardiac phenotype	Human, mapping
24858909	Mouse Gata4/Tbx5: myocardial/septation defects	Mouse model
25834021	Zebrafish sox7: cardiovascular defects, Sox7 upstream of Notch	Zebrafish model
27343326	aCGH + FISH diagnostic workflow (SOX7/GATA4 deletion)	Human, prenatal
42067806	Prenatal CMA yield; NT strongest predictor	Human, cohort
28211984	Neonatal mortality from severe polyvalvular dysplasia	Human, case
19606479	8p23.1 deletion → CHD + CDH; GATA4 haploinsufficiency critical	Human, series
37829974	Severe COVID-19 in affected infant; intensive care	Human, case
20677137	Prenatal diagnosis/counseling as prevention	Human, case
20830805	Mosaicism attenuates phenotype	Human, case
18302246	Tandem vs inverted duplication modulates severity	Human, case
20461109	Pathogenic 8p CNVs ~1% of developmental-disorder cohort	Human, cohort
20880309	Dextrocardia + corpus callosum agenesis (laterality)	Human, case

Limitations and Knowledge Gaps

No prevalence estimate. The disorder's true incidence/prevalence is unknown; evidence is from case reports and small series, biasing toward severe/recognizable cases.
Neurodevelopmental gene-level causality is inferred, not demonstrated. While the cardiac (GATA4/SOX7) and immune (DEF) branches are mechanistically supported by models/patient data, the specific genes responsible for corpus callosum anomalies, intellectual disability, and seizures within the large duplication/deletion intervals are not individually proven.
No whole-syndrome animal model. Existing models capture single-gene dosage effects only; the combined deletion+duplication imbalance and the neurodevelopmental phenotype are not modeled.
Genotype–phenotype correlation is incomplete. One 8-case series found no clear correlation between molecular-cytogenetic variants and clinical severity, though a corpus-callosum-anomaly risk region has been mapped.
No natural-history/QoL data. Longitudinal outcome, life-expectancy, and standardized quality-of-life data are lacking.
Epigenetic and multi-omic characterization absent. No transcriptomic, proteomic, metabolomic, or methylation profiling specific to inv dup del(8p) is available.

Proposed Follow-up Experiments / Actions

Establish an international registry to define prevalence, natural history, mortality, and QoL with standardized instruments.
Breakpoint–phenotype mapping across large CMA cohorts to refine the corpus-callosum, seizure, and ID critical regions and to test dosage of specific candidate genes (XKR6, MIR597, and duplication-interval genes).
Neurodevelopmental modeling: generate patient-derived iPSCs / cerebral organoids carrying the rearrangement (or engineered 8p dosage changes) to test corpus-callosum/neuronal phenotypes and identify driver genes.
Systematic immune phenotyping (NK activity, α-defensin, infection history) across a patient cohort to determine how consistently DEF haploinsufficiency causes clinically relevant immunodeficiency and to guide prophylaxis (RSV, COVID-19 vaccination).
Prospective cardiac outcome study correlating GATA4/SOX7 deletion status with CHD type/severity and surgical outcomes.
Transcriptomic/methylation profiling of patient tissues (or organoids) to search for a diagnostic episignature and downstream dysregulated pathways.

Report compiled from 5 investigation iterations, 11 confirmed findings, and 53 primary papers. Evidence types are distinguished throughout as human clinical, model organism, in vitro, or computational.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	22
Resolved	22
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	20
Quoted claims found in source	20
Quoted claims not found in source	0
References weighed for topical relevance	22
On topic	16
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	47
Resolved	44
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	3
Terms whose name was checked	22
Terms named correctly	11
Terms named as a different term	8
Terms whose name is worth a second look	3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0001252 (1 mention) - the report calls it "Neonatal"; HP calls it Hypotonia
HP:0001999 (1 mention) - the report calls it "Congenital"; HP calls it Abnormal facial shape
HP:0001250 (1 mention) - the report calls it "Mean 3.9 y (2 mo–9 y)"; HP calls it Seizure
HP:0000252 (1 mention) - the report calls it "Congenital"; HP calls it Microcephaly
HP:0000708 (1 mention) - the report calls it "Childhood"; HP calls it Atypical behavior
NCIT:C157664 (1 mention) - the report calls it "Cardiac Surgery"; NCIT calls it Poorly Marginated Nodule
NCIT:C15311 (1 mention) - the report calls it "Nutritional Support"; NCIT calls it Quality Control
NCIT:C15277 (1 mention) - the report calls it "Supportive Care"; NCIT calls it Mastectomy

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0007507 (1 mention) - the report calls it "GO suggestions: heart development"; GO calls it heart development
UBERON:0001134 (1 mention) - the report calls it "skeletal muscle"; UBERON calls it skeletal muscle tissue, and lists "skeletal muscle" among its other names
NCIT:C15917 (1 mention) - the report calls it "Rehabilitation Therapy"; NCIT calls it Arterial Embolization

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Source YAML

References & Deep Research

Deep Research

8p Inverted Duplication/Deletion Syndrome (inv dup del(8p)) — Comprehensive Disease Characterization Report

Summary

Section 1 — Disease Information

Section 2 — Etiology

Section 3 — Phenotypes

Section 4 — Genetic / Molecular Information

Section 5 — Environmental Information

Section 6 — Mechanism / Pathophysiology

Ordered causal chain

Detail by category

Section 7 — Anatomical Structures Affected

Section 8 — Temporal Development

Section 9 — Inheritance and Population

Section 10 — Diagnostics

Section 11 — Outcome / Prognosis

Section 12 — Treatment

Section 13 — Prevention

Section 14 — Other Species / Natural Disease

Section 15 — Model Organisms

Mechanistic Model (Synthesis)

Evidence Base — Key Literature

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver