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

Disease

Prader-Willi-like syndrome

Inheritance

Autosomal dominant

Prevalence

 <1 / 1 000 000

Source: Orphanet

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

No curations for this GDA in ClinGen/GenCC

HGMD reports 7 variants in SIM1 associated with Prader-Willi-like syndrome (6 gross deletions and 1 missense from 2 publications)

Clinical Validity Scoring Notes and points

Variant/Case Evidence:

PMID: 25351778

  • Describes 15 new patients (including 1 fetus) with 6q16 deletions, which is the most common variant in patients exhibiting the PWS-like phenotype

  • Investigated using chromosomal microarray analysis

  • All reported 6q16 deletions occurred de novo in symptomatic patients

  • Other genes also included in these deletions (listed in supplemental information) - unsure if these deletions can be scored

PMID: 26795956

  • Performed genome-wide microarray analysis on a group of 109 PWL patients, and screened 94 patients for variants in SIM1 and MRAP2 using Sanger sequencing

  • SIM1 analysis resulted in the identification of one rare missense variant (p.P352S) in a 10 year old male clinically diagnosed with PWS although this could not be confirmed molecularly as no aberration on chromosome 15q11.2–q13 was detected with MS-MLPA - 0.5 pts

PMID: 23778136

  • Identified 4 rare variants (p.I128T, p.Q152E, p.R581G, and p.T714A) in 4 children with Prader-Willi–like syndrome features - 2 pts

PMID: 24038875

  • De novo interstitial deletion at 6q16.1–q21 (chr6:98,119,288–107,977,239 (hg18)), that included SIM1 and 30 other genes, was identified in a 12 year old male with Prader–Willi-like syndrome - unsure if this deletion can be scored

PMID: 18648397

  • Report 5 patients with overlapping interstitial 6q16 deletions and Prader–Willi-like phenotype - unsure if these deletions can be scored

  • Cases 2 and 3 show heart defects (ductus arteriosus and atrial septal defects in case 2, tetralogy of Fallot in case 3) and are haploinsufficient for the POPDC3 gene

PMID: 12161602

  • Identified a 6q16.1-q21 deletion in a patient with a Prader-Willi-like phenotype

Segregation Evidence:

Case/Control Evidence:

Experimental Evidence:

PMID: 23778136

  • Examined transcriptional activities in stable cell lines using luciferase gene reporter assays, and p.T714A showed strong loss-of-function effects - 1 pt

Source:

Clinical Validity Points Total

Source:

Clinical Validity Classification

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Source:

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

No evidence for haploinsufficiency in ClinGen (2012), but there are pLOF variants reported in ClinVar for SIM1-related disorder

The literature notes that SIM1 loss of function seems to be associated with obesity and may also be associated with PWL-related clinical features (however there is incomplete penetrance)

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

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