Search for the Sequence Variants in Hairless Gene in Three Consanguineous Families with Hypotrichosis

Abstract

The human skin is the outermost covering of the body with nails, teeth, glands, and hair as the main appendages. Hair is mainly composed of keratinized cells and provides different functions including protection, camouflage, sweat dispersion, thermoregulation, social interaction, and sensory activity. Human hair is the utter epitome of aesthetics in our culture. Sequence variations in genes involved in hair follicle morphogenesis, growth, and cycling have been linked to hair disorders. Hypotrichosis is a genetic hair disorder, characterized by thinning and progressive hair loss, inherited in isolated or syndromic forms, and is segregated in both recessive and dominant inheritance patterns. The study, presented in the dissertation, potentially searched the sequence variants in the HR gene in three Pakistani families (A, B, and C) with hypotrichosis. Family A was tested for linkage analysis to nine genes including HR (8p21.3), LIPH (3q27.2), DSG4 (18q21.1), LPAR6/P2RY5 (13q14.2), CDH3 (16q22.1), KRT25 (17q21.2), C3ORF52 (3q13.2), DSP (6p24.3), and LSS (21q22.3) involved in autosomal recessive form of hypotrichosis. Following the exclusion of the reported genes from linkage, the DNA of the affected member (IV-2) in family A was subjected to whole exome sequencing, which revealed a novel frameshift deletion (c.2921-2936del) in exon 14 of the HR gene. The variant was found homozygous in the affected member, while heterozygous in phenotypically normal parents. In family B and C, Sanger sequencing of all coding exons and exon-intron borders of the HR gene was performed by the dideoxy chain termination method which revealed no pathogenic variant. In conclusion, the present study identified a novel variant only in family A. In searching for disease-causing variants in family B and C, it is recommended to use whole genome/exome sequencing to identify the variants in regulatory regions of the known gene or might be involvement of a novel gene. The current study will help in prenatal screening, carrier testing, and genetic counseling of the affected individuals, and families carrying similar features in the Pakistani population.