Skip to end of metadata
Go to start of metadata

You are viewing an old version of this content. View the current version.

Compare with Current View Version History

« Previous Version 2 Current »

Gene-disease assertions not curated here (add link or write note):

Disease

DiGeorge-like phenotype

Inheritance

Autosomal dominant

Prevalence

 

Source:

Rapid or full curation?

  • Rapid
  • Full

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

  • Jeanne et al PMID: 33417013

    • Hira knockdown in mouse hippocampal neurons which indicated it is mostly expressed during neuritogenesis and dendritogenesis stages. 0.5 point

    • Hira +/- knockout mice - minor anomalies were found, including reduced height of hipocampus at molecular layer, marginally reduced area of the corpus callosum and fornix. Only scoring this as 0.5 point since the abnormalities seemed minor and didn’t fully replicate the human phenotype..

Source:

Clinical Validity Points Total

6 points

Source:

Clinical Validity Classification

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Limited

Source:

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function / Gain of function / Dominant Negative

Penetrance

 options

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

 options

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

 Options

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

 Examples

- 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

  • No labels