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 ValidityPoints Total
12
Source:
Clinical ValidityClassification
Definitive (12pts)
Strong (12pts)
Moderate (7-11pts)
Limited (0.1-6pts)
No genetic evidence
Refuted
Disputed
DEFINITIVE
Source: 25298419, 29526280
MolecularMechanism
Loss of function
Gain of function
Dominant negative
Unknown
Other
NOTE: LOF is not mechanism (LOF variants in this gene cause Pitt-Hopkins)
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)