Disease | DiGeorge-like phenotype |
|---|
Inheritance | Autosomal dominant |
Prevalence | Source: |
Rapid or full curation? | |
ClinGen / GenCC / BabySeq / HGMD / OMIM | No ClinGen, GenCC, OMIM curations. HGMD variants below |
Clinical Validity Scoring Notes and points | Gene is highly constrained for LOF (pLI=1, Loeuf=0.18) and missense (z=4.77). It is located within the DiGeorge syndrome 22q11.2 deletion. PMID: 38511226 - paper is a case report but also has good summary of prior patients, all have overlapping features of DiGeorge syndrome. However, I can’t find the primary paper for many of the citations and they aren’t listed in the references section. c.1A>G p.M1? absent gnomAD Variant found via proband only WES, Sanger testing later indicated it was de novo. Patient with tetralogy of Fallot, hypoplasia of corpus callosum, facial featuers, long philtrum, etc. Scoring as common / non-specific 1 POINTS (NMD- AND de novo) c.302+1G>C, 1 allele gnomad, previously reported in Jeanne et al(PMID: 33417013), de novo in a patient with autism spectrum, recurrent infections, DM1. Reviewed the original paper, variant found via WES. Scoring as common phenotype, 1.5 VARIANT POINTS Exon 2-13, OOF previously reported in Jeanne et al (PMID: 33417013) de novo in a patient with psychomotor retardation, ID, diffuse atrophy of whit ematter, microcephaly, facial features. Reviewed the original paper, this variant was found via Array. Scoring as common/non-specific 1.5 points Gln866Ter - previously reported with source “DDD4K.03620 (decipher patient)” in patient with vague HPO term features (abnormalities of cardiovascular, nervous system, integuement), phenotype too vague, not scoring. Cys315SerTer10 - previously reported Homsy et al (I am not sure which paper this is, I see it in a patient with LVO in supp database 2 in PMID: 32368696). de novo in patient with conotruncal defect. Common phenotype, and downgrading since I cant find the original paper. 0.5 POINTS Arg956Ter - reported by Jin et al. in a patient w/ left ventricular outflow tract obstruction, unknown if parents tested. Common phenotype, and downgrading since I cant find the original paper. 0.5 POINT
Experimental Source: |
Clinical Validity Points Total | 6 points Source: |
Clinical Validity Classification | Expand |
|---|
| title | Classifications (pts) |
|---|
| Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed |
| Limited Source: |
Molecular Mechanism | Expand |
|---|
| Loss of function Gain of function Dominant negative Unknown Other |
| Loss of function / Gain of function / Dominant NegativeSuspected LOF, but GDA is limited. |
Penetrance | Expand |
|---|
| Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) |
(list source/PMID) | Source: |
Age of Onset | Expand |
|---|
| Congenital Pediatric Adolescent Adulthood Late adulthood |
(list source/PMID) | |
Severity | Expand |
|---|
| 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 | Expand |
|---|
| - 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 |
| The HIRA gene has been reported in association with a DiGeorge syndrome-like phenotype, with de novo variants reported in individuals with clinical features that overlap with DiGeorge syndrome. Reported features include congenital heart defects (tetralogy of Fallot, left ventricular outflow tract obstruction, conotruncal defect), intellectual disability, microcephaly, brain abnormalities (hypoplasia of corpus callosum, diffuse atrophy of white matter), and facial features (PMID: 38511226, 33417013, 32368696). In addition, there is some limited evidence from animal models, with a knockdown model in mouse hippocampus neurons that showed this gene is mostly expressed in neuritogenesis and dendritogenesis, and a knockout model showing some reduction of the hippocampal molecular layer, corpus callosum, and fornix (PMID: 33417013). This gene is located within the 22q11.2 deletion region and the gene is highly constrained for loss-of-function variants in gnomAD (pLI=1, Loeuf=0.18). In summary, while there is some evidence to suggest that HIRA is a candidate gene for a disorder similar to DiGeorge syndrome, the gene-disease validity is limited. |
Case ID, Curator name, Date, Jira ticket link | |