Disease | Heterotaxy |
|---|
Inheritance | Curated for both AD and AR. AD actually had more scorable evidence. |
Prevalence | Rare (1/10,000) Source: https://medlineplus.gov/genetics/condition/heterotaxy-syndrome/#:~:text=The%20prevalence%20of%20heterotaxy%20syndrome,of%20all%20congenital%20heart%20defects. |
Rapid or full curation? | |
ClinGen / GenCC / BabySeq / HGMD / OMIM | No ClinGen curations. GenCC - Strong (Invitae), limited (Ambry). BabySeq (limited). Curated HGMD variants below. |
Clinical Validity Scoring Notes and points | Curated DM variants only that are associated w/ heterotaxy, laterality defects or congenital heart disease. NM_001106.4:c.92A>G;p.(Tyr31Cys). Absent gnomAD v4, REVEL 0.95. PMID: 37644014 in family F7988. Variant is homozygous which doesn’t fit proposed inheritance. Per supplement data 1, phenotype is Supernumerary nipple; Supernumerary ribs; Dextrocardia; Abnormal facial shape; Abnormal heart morphology (complex heart disease); Pulmonary situs ambiguus; Asplenia; midline liver; Bilateral talipes equinovarus; Hypoplasia of the corpus callosum; Wide anterior fontanel; Micrognathia. There was no further segregation / variant information provided. 0.5 POINTS FOR AR
NM_001106.4: c.119G>A; p.R40H - frequency too high in gnomAD, did not score papers. 1.2% in AA (963/75038) with 12 homozygotes. 2 star B/LB in ClinVar. NM_001106.4: c.1057G>T p.G353W, absent gnomAD v4. REVEL 0.72 PMID: 30293987 - variant reported in patient with congenital heart diease but also found in asymptomatic mother (family 150650086). This proband also had a HOM variant in DOCK6 (AR Adams-Oliver syndrome, which has CHD. No points can be applied for this family given the alternate explanation of disease.
NM_001106.4:c.1480G>A p.V494I - 14 alleles gnomAD v4 [0.0005% (12/1180020] European non-FInnish chr. REVEL: 0.374 NM_001106.4: c.925C>T Arg309Cys (DM? in HGMD), frequency in gAD higher than expected for AD, 0.002% (5/91080) S. Asian, also present in other populations. REVEL: 0.594 PMID: 30622330 - this paper had several variant marked as DM? NM_001106.4:c.1147C>T NP_001097.2:p.Arg383Cys - absent gnomAD. Family ID: LAT1543 Observed in patient w/ laterality defect and segregated in 4 affected family members. The diagnosis in the proband was a venous anomaly per table 1, but reviewing supplement 1 the proband had atrial septal defect, Interrupted IVC, TAPV. “Left superior vena cava to coronary sinus, MR,PR, TR, Right ventricular hypertrophy, Right ventricular dilation or enlargement, Dilatation of the main pulmonary artery Unusual systemic venous return from the lower extremities and abdomen with a small (b”. AD EVIDENCE: 0.5 VARIANT POINT, 4 AD SEGREGATION (0 SEGREGATION POINTS) NM_001106.4:c.527C>G P176R in a patient w/ conotruncal defect per table 1, in LAT1333. Per table s1, DORV with the PA arising slightly more anterior than the aorta. BILATERAL GRADE IV VESICOURETERAL REFLUX. but frequency looks too high with 479/1180000 alleles in gAD v4 European chr. https://gnomad.broadinstitute.org/variant/3-38478379-C-G?dataset=gnomad_r4 . No
Mouse: Targeted disruption of mouse Acvr2b gene results in abnormal left-right developments in homozygous knockout. PMID: 9242489. SCORE 2 POINTS AR, 1 POINT FOR AD A knockout mouse of Pitx2, the downstream targeted of Acvr2b, showed an identical phenotype to Acvr2b homozygous knockout mouse PMID: 10499586. Scoring under protein interaction. 1 POINT FOR AR, 0.5 POINT FOR AD.
Pubmed search: |
Clinical Validity Points Total | AD EVIDENCE: 2.5 POINTS AR EVIDENCE: 3.5 POINTS |
Clinical Validity Classification Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed |
| LIMITED |
Molecular Mechanism Loss of function Gain of function Dominant negative Unknown Other |
| Loss of function / Gain of function / Dominant Negative |
Penetrance Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) |
(list source/PMID) | Source: |
Age of Onset Congenital Pediatric Adolescent Adulthood Late adulthood |
(list source/PMID) | |
Severity Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers. |
| |
Clinical Features | Sources: |
HPO Terms https://hpo.jax.org/app/ | |
Gene SOPs & Notes | LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant |
Curation Summary - The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited |
| |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza 03/27/2025 SDSM-AZC - c.1463C>T p.Thr488Ile - HP:0001631 Atrial septal defect, HP:0001643 Patent ductus arteriosus, HP:0001650 Aortic valve stenosis, HP:0005133 Right ventricular dilatation, HP:0012561 Unicuspid aortic valve, HP:0031652 Abnormal aortic valve physiology SDSM-P3M NM_001106.3:c.959+4C>G
|