The First Reported Japanese Case of PNPLA1-Nonsyndromic Epidermal Differentiation Disorder (PNPLA1-nEDD) Associated With an Unreported 92-Base-Pair Duplication Variant

Abstract

Autosomal recessive congenital ichthyosis (ARCI) is a rare inherited skin disorder marked by generalised scaling and erythema. Very recently, diseases formerly diagnosed as ichthyosis, including ARCI, have been renamed nonsyndromic epidermal differentiation disorders (nEDDs). Although pathogenic variants in various genes, including PNPLA1, have been identified as causes, regional and ethnic differences exist in their prevalence. PNPLA1 encodes a unique transacylase essential for acylceramide synthesis, a critical component of the skin barrier. Here, we describe the first reported Japanese case of a PNPLA1-related nonsyndromic epidermal differentiation disorder (PNPLA1-nEDD) caused by a homozygous 92-base-pair duplication variant (c.36_127dup, p.Leu43Profs*46) in PNPLA1. Lipidomic analysis of the stratum corneum revealed marked reductions in ω-O-acylceramides and protein-bound ceramides, alongside the accumulation of non-acylated ceramides—indicating a failure in acylceramide synthesis. This ceramide profile supports the conclusion that the PNPLA1 duplication causes a loss of function. Our findings emphasise the importance of PNPLA1 in the genetic screening of nEDD cases in Japan, regardless of clinical subtype, due to the absence of genotype–phenotype correlations and to broad phenotypic variability.