Nontruncating

Purpose: To determine whether mutation class (truncating versus nontruncating) modifies clinical penetrance in heterozygous female carriers of pathogenic Design: Retrospective multicohort pedigree analysis with cluster-aware statistical modeling. Subjects: There are 560 heterozygous female carriers from 126 pedigrees with pathogenic or likely pathogenic Methods: Heterozygous female carriers were classified as affected or unaffected for infantile nystagmus based on clinical examination, and variants were stratified into truncating and nontruncating classes. Penetrance was compared between variant classes using generalized estimating equations with a logistic link and pedigree as the cluster variable. Sensitivity analyses comprised a mixed-effects logistic regression with a pedigree-level random intercept, together with leave-one-pedigree-out and leave-one-publication-out influence diagnostics. Main Outcome Measures: Clinical penetrance of infantile nystagmus, defined as the proportion of heterozygous female carriers meeting clinical criteria, compared between mutation classes. Results: Pooled penetrance was 30.1% (74/246; Wilson 95% confidence interval [CI] 24.7%-36.1%) for truncating variants and 49.7% (156/314; Wilson 95% CI 44.2%-55.2%) for nontruncating variants. Cluster-aware analysis confirmed higher odds of clinical manifestation for nontruncating than truncating variants (odds ratio [OR] 2.12, 95% CI 1.32-3.40, Conclusions: Mutation class is a robust modifier of clinical penetrance in heterozygous female carriers of pathogenic Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article.