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

DEFINITIVE

Source: 25298419, 29526280

Molecular Mechanism

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

(list source/PMID)

Reduced and age related

Source:

Age of Onset

(list source/PMID)

Adulthood, 5th-6th decade

PMID: 38713708

Severity

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

Case ID, Curator name, Date, Jira ticket link

Andrea Oza, 05.17.24