Clinicla and Molecular Characterization of Human Hereditary Skin Disorders in Consanguineous Families

Abstract

A study, presented in the dissertation, described clinical and genetic characterization of nineteen consanguineous families (A-S) featuring various forms of inherited skin disorders. Fifteen of these families (A-I, K-P) showed various forms of isolated skin anomalies, while the remaining four families (J, Q-S) exhibited distinct forms of syndromic conditions. Isolated X-linked ichthyosis (XLI) was identified in four families (A-D). Initial marker analysis revealed two distinct interstitial deletions at chromosome Xp22.3. SNP array fine mapped the underlying deletions to ~ 1.67 Mb (family A, B, C) and ~ 1.62 Mb (family D). Different forms of isolated scaling skin phenotype, with autosomal recessive inheritance, was identified in five consanguineous families (E-I). Genotyping using microsatellite markers and haplotype analysis established linkage in the family E, segregating ichthyosis vulgaris, to a previously known gene FLG at chromosome 1q21.3. Subsequently, Sanger sequencing identified a novel homozygous nonsense variant (c.10459A>T; p.Arg3487*) in the third exon of the FLG gene in affected individuals. In family F, with ichthyosiform erythroderma, genetic delineation by exome sequencing revealed a previously reported nonsense variant (c.1630C>T; p.Gln544*) in the ALOXE3 gene. In the third family, segregating scaling phenotype, SNP genotyping and exome sequencing identified a novel gene CLUH carrying a homozygous missense variant (c.2852G>A; p.Arg951His) in affected members. Two other families (H and I), segregating autosomal recessive form of ichthyosis, failed to show linkage to the known genes. Abstract Clinical and Molecular Characterization of Human Hereditary Skin Disorders in Consanguineous Families XXVIII Pure hair and nail ectodermal dysplasia, with autosomal recessive transmission, was observed in an inbred family J. Genotyping established linkage in the family at chromosome 12p11.1-q21.1. Sanger sequencing identified a novel homozygous nonsense variant (c.404C>A; p.Ser135*) in the HOXC13 gene. Clinically various forms of isolated hypotrichosis was observed in six consanguineous families (K-P). Sequencing of a panel of genes failed to reveal potential pathogenic variants in two families (K, L), segregating autosomal dominant form of hair loss disorders. Direct sequencing of the gene LPAR6 in the family M identified a previously defined missense variant (c.562A>T; P.Ile188Phe) causing hypotrichosis with wooly hair. The in-silico studies of mutated LPAR6 protein verified aberrant receptor activity and downstream phospholipid signaling resulting in hair disorder, with curly phenotype. The conventional homozygosity mapping using microsatellites failed to identify linkage to known genes/loci in two other families (N, O). Exome sequencing in the family P wasn’t successful in identifying a homozygous pathogenic sequence variant causing hair loss. The study, described in the dissertation, elaborated genetic characterization of three consanguineous families segregating syndromic forms of hair loss disorders. In the family Q, with hypotrichosis and Juvenile Macular Dystrophy, haplotype analysis established linkage to gene CDH3 on chromosome 16q. Sequence analysis identified a novel homozygous in-frame deletion variant (c.764_766delACT; p.255delTyr) in the CDH3 gene. In family R and S clinical investigation found the condition Woodhouse Sakati syndrome (WSS) and Nonphotosensitive trichothiodystrophy (TTDN), respectively. Exome sequencing identified a novel truncating homozygous variant Abstract Clinical and Molecular Characterization of Human Hereditary Skin Disorders in Consanguineous Families XXIX (c.270delA; p.Lys90Asnfs8*) in the gene DCAF17 and splice site variant c.339+1G>A in the gene MPLKIP in the family S. Structural investigation of mutated CDH3 p.255delTyr and DCAF17 p.Lys90Asnfs8* predicted atypical interactions with associated proteins. cDNA analysis of mutated MPLKIP c.339+1G>A verified unusual splicing event resulting in intron retention and setting up syndromic attributes in the family S.