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Kelley Paris

Kelley Paris

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Disease

Prader-Willi-like syndrome

Inheritance

Autosomal dominant

Prevalence

Expand
titlePossible sources

Orphanet

Medline Plus Genetics

 <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

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

Expand
titleClassifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Source:

Molecular Mechanism

Expand
titleMechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of functionNo 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

Expand
titleoptions

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

Expand
titleoptions

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

Expand
titleOptions

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
titleExamples

- 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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