Nontruncating FRMD7 Variants Are More Penetrant than Truncating Variants in Heterozygous Female Carriers of Infantile Nystagmus.

FRMD7

Pathogenic FRMD7 variants whose class — truncating or nontruncating — modulates clinical penetrance in heterozygous female carriers

The authors set out to determine whether variant class modifies clinical penetrance in heterozygous female carriers of pathogenic FRMD7 variants. This retrospective multicohort pedigree analysis covered 560 heterozygous female carriers from 126 pedigrees — 100 pedigrees with 477 carriers from 40 published reports identified by systematic search, and 26 pedigrees with 83 carriers from two UK clinical genetics cohorts — each carrier classified as affected or unaffected on clinical examination. Pooled penetrance was 30.1% for truncating variants (74 of 246, 95% CI 24.7% to 36.1%) and 49.7% for nontruncating variants (156 of 314, 95% CI 44.2% to 55.2%). Cluster-aware analysis using generalized estimating equations with pedigree as the cluster confirmed higher odds of clinical manifestation for nontruncating variants (odds ratio 2.12, 95% CI 1.32 to 3.40, P = 0.002), robust to leave-one-pedigree-out and leave-one-publication-out sensitivity analyses and directionally concordant between the literature and institutional cohorts.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Moving from a single penetrance figure to two figures by variant class, 30% versus 50%, concretely changes what is said in a counselling session with a female carrier. The methodology is careful — clustering by pedigree, leave-one-out sensitivity analyses — which is rare in penetrance work aggregating published literature. The main limitation remains ascertainment bias in published cohorts, which mechanically overrepresent multiplex families and therefore probably inflate penetrance in both groups.

Analysis by Dr Thibaut Benquey