Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes.
Nat Commun
; 13(1): 5106, 2022 08 30.
Article
in En
| MEDLINE
| ID: mdl-36042188
ABSTRACT
Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Long QT Syndrome
/
Endophenotypes
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Nat Commun
Year:
2022
Document type:
Article