Variants in the PNPLA1 Gene in Families with Autosomal Recessive Congenital Ichthyosis Reveal Clinical Significance

Abstract

The term autosomal recessive congenital ichthyosis (ARCI) is the subgroup of ichthyosis, which describes a highly heterogeneous group of genetic disorders of the skin characterized by cornification and defective keratinocytes differentiation associated with mutations in at least 14 genes including <i>PNPLA1</i>. To study the molecular basis of the Pakistani kindreds (A and B) affected by ARCI, whole-exome sequencing (WES) in the DNA samples of affected members was performed followed by Sanger sequencing of the candidate gene to hunt down the disease-causing sequence variant/s. WES data analysis led to the identification of a novel nonsense sequence variant (c.892C&#x3e;T; p.Arg298*, family A) and a recurrent missense variant (c.102C&#x3e;A; p.Asp34Glu, family B) in <i>PNPLA1</i> mapped to the ARCI locus in chromosome 6p21.31. Validation and cosegregation analysis of the variants in the remaining family members of the respective families were confirmed by Sanger sequencing. The current investigation expands the spectrum of <i>PNPLA1</i> mutations and helps establish the proper clinico-genetic diagnosis and correct genotype-phenotype correlation.