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Gene-disease assertions not curated here (add link or write note): Loss of function variants cause Pitt-Hopkins syndrome (Definitive in ClinGen)

Disease

Fuchs endothelial corneal dystrophy type 3 (SUSCEPTIBILITY)

Inheritance

Autosomal dominant

Prevalence

 Common: Affects 4% of Caucasian population in US, and 75% are associated w/ triplet repeat expansion

Source: PMID: 31276570

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

Clingen - none. GenCC - strong by G2P. HGMD variants/papers in Clinical validity scoring notes.

Clinical Validity Scoring Notes and points

  • Weiben 2019 PMID: 31276570

    • No interruptions of the expanded CAG repeat was found. But novel variants within the AGG repeats that flank the CAG were found in 2/5 unaffected patients w/ expansions.

    • Table 1, smallest expansion in affected individuals with an expansion is 64 repeats

    • In the control group of 63 individuals, 95% of the subjects had below 40 repeats and 5% over 50 repeats

  • Bhattacharyya 2024 PMID: 38713708

    • Previously demonstrated in large cohort that an expanded copy defined as ≥ 50 copies confers a <76-fold increased risk for developing FECD, cites Zarouchlioti PMID: 29526280. Data shown in figure 1 of that paper.

  • Zarouchlioti 2018 PMID: 29526280

    • A highly significant association between expansion of the CTG18.1 trinucleotide repeat (conservatively defined as R50 repeats) and FECD was identified (OR ¼ 76.47; 95% CI: 47.45–123.2; p ¼ 5.69 3 10 71) in the white European-only portion of the cohort. 6 POINTS CASE-CONTROL

    • Fig 1 - 450 individuals with FECD and 550 individuals with age related macular degeneration (AMD) tested for TCF4 expansion. Fig shows that expansion on 1 or both alleles are enriched in patients with FECD. Fig 1A shows evidence that expanded alleles are 50 or more repeats in length.

    • ASO treatment led to reduction in incidence of nuclear foci, splicing factor proteins recruited to the foci, downstream aberrant splicing defects, suggesting functional rescue.

    • They note a threshold for the length of expansion and association with FECD is not yet defined. They suggest that a CTG length ≤32 should be considered as FECD associated (this is based on some clinical evidence and evidence from cellular studies on nuclear foci in cell lines)

  • Xing 2014 PMID 25298419

    • Expanded allele associated w/ FECD (P = 4.7 × 10(-14)), with the odds ratio of each copy of the expanded allele estimated to be 66.5 (95% confidence interval: 12.6-350.1). 57 cases and 121 controls. 6 POINTS CASE-CONTROL

Source:

Clinical Validity Points Total

12

Source:

Clinical Validity Classification

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

DEFINITIVE

Source: 25298419, 29526280

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

NOTE: LOF is not mechanism (LOF variants in this gene cause Pitt-Hopkins)

Short tandem repeat - CAG in intron 1

  • Normal: ≤31

  • Uncertain risk:

  • Pathogenic (risk susceptibility): ≥50

  • Cutoff: 32

  • Primary citation: PMID: 29526280

Review:

  • Stripy: normal ≤31, pathogenic ≥50

  • Strchive: Normal 10 - 40, Pathogenic ≥50

  • Mayo not available

  • gnomad: Normal ≤ 31, Pathogenic ≥ 50. Note: many alleles >50 repeats.

  • Nirvana annotation: Normal 0-39, expanded 40-inf

    • Though this wouldn’t catch the alleles below 40, this is fine because it is uncertain whether alleles between 31 and 39 actually confer risk.

  • 1676829

  • 21245398

  • 25168903

  • Weiben 2019 PMID: 31276570

    • No interruptions of the expanded CAG repeat was found. But novel variants within the AGG repeats that flank the CAG were found in 2/5 unaffected patients w/ expansions.

    • Table 1, smallest expansion in affected individuals with an expansion is 64 repeats

    • In the control group of 63 individuals, 95% of the subjects had below 40 repeats and 5% over 50 repeats

  • Bhattacharyya 2024 PMID: 38713708

    • Previously demonstrated in large cohort that an expanded copy defined as ≥ 50 copies confers a <76-fold increased risk for developing FECD, cites Zarouchlioti PMID: 29526280. Data shown in figure 1 of that paper.

  • Zarouchlioti 2018 PMID: 29526280

    • A highly significant association between expansion of the CTG18.1 trinucleotide repeat (conservatively defined as R50 repeats) and FECD was identified (OR ¼ 76.47; 95% CI: 47.45–123.2; p ¼ 5.69 3 10 71) in the white European-only portion of the cohort.

    • Fig 1 - 450 individuals with FECD and 550 individuals with age related macular degeneration (AMD) tested for TCF4 expansion. Fig shows that expansion on 1 or both alleles are enriched in patients with FECD. Fig 1A shows evidence that expanded alleles are 50 or more repeats in length.

    • ASO treatment led to reduction in incidence of nuclear foci, splicing factor proteins recruited to the foci, downstream aberrant splicing defects, suggesting functional rescue.

    • They note a threshold for the length of expansion and association with FECD is not yet defined. They suggest that a CTG length ≤32 should be considered as FECD associated (this is based on some clinical evidence and evidence from cellular studies on nuclear foci in cell lines)

Penetrance

 options

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Reduced and age related

Source:

Age of Onset

 options

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Adulthood, 5th-6th decade

PMID: 38713708

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.

Mild-Moderate

Clinical Features

Age-related cause of vision loss

  • Corneal edema and opacity

Sources: 38713708

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

Andrea Oza, 05.17.24 BCL-168 - Getting issue details... STATUS

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