Non-truncating FRMD7 variants are more penetrant than truncating variants in heterozygous female carriers of infantile nystagmus

Purpose

To determine whether mutation class (truncating versus nontruncating) modifies clinical penetrance in heterozygous female carriers of pathogenic FRMD7 variants.

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 FRMD7 variants: 100 pedigrees (477 carriers) from 40 published reports identified by systematic literature search and 26 pedigrees (83 carriers) from 2 UK institutional clinical genetics cohorts.

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, P = 0.002). The result was robust to leave-one-pedigree-out (OR range 2.02–2.28) and leave-one-publication-out (OR range 1.84–2.28) sensitivity analyses and was directionally concordant in literature and institutional cohorts (interaction P = 0.49).

Conclusions

Mutation class is a robust modifier of clinical penetrance in heterozygous female carriers of pathogenic FRMD7 variants. These variant-class specific estimates may refine genetic counseling in FRMD7-associated infantile nystagmus beyond the conventional single penetrance figure.

Financial Disclosure(s)

The authors have no proprietary or commercial interest in any materials discussed in this article.