Mutation Analysis in Ten Cases With <scp> <i>PNPLA1</i> </scp> ‐Nonsyndromic Epidermal Differentiation Disorder: Evidence of a Founder Effect

Autosomal recessive congenital ichthyosis (ARCI) belongs to a heterogeneous group of nonsyndromic epidermal differentiation disorders (nEDD). Variants in PNPLA1, which encodes a transacylase essential for the formation of epidermal lipid barrier, underlie ARCI10. This study aims to unveil the underlying genetic basis in ten Chinese cases diagnosed with ARCI, and to determine the origin of a prevalent variant. Ten cases, encompassing twelve patients with ARCI, were recruited for this study. Whole-exome sequencing combined with Sanger sequencing was used to detect the underlying variants. Haplotype analysis using flanking highly polymorphic SNPs was used to trace the origin of the c.1300delG variant in the PNPLA1 gene. All patients developed generalized fine scales and erythema shortly after birth. Marked phenotypic heterogeneity was observed among the affected individuals, leading to diagnosis of either generalized or localized nEDD. In total, we detected three recurrent variants (c.1300delG, p.A434Hfs*22; c.434 T > C, p.Ile145Thr; c.488C > T, p.Pro163Leu) and five novel variants (c.205 + 1G > A, splicing; c.74C > T, p.Ser25Phe; c.473G > A, p.Cys158Tyr; c.731A > G, p.Tyr244Cys; c.1318C > T, p.Arg440*) in PNPLA1. The c.1300delG variant, prevalent in 7 unrelated ARCI cases, was associated with a common haplotype. Furthermore, we presented the beneficial effect of secukinumab treatment in one of our patients. Our findings suggest that the c.1300delG variant is a highly prevalent variant in Chinese PNPLA1-associated nEDD patients, and indicate that the recurrent variant may originate from a common ancestor in southern China, suggesting a regional founder effect. The observed response with secukinumab in one patient suggests that it might represent a potential therapeutic option for PNPLA1-nEDD patients.