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Title: Clinical and Molecular Characterization of Consanguineous Families with Genetic Disorders of The Skin and its Appendages
Authors: Shah, Hajan
Keywords: Biological & Medical Sciences
Issue Date: 2020
Publisher: Sindh Institute of Medical Sciences, SIUT, Karachi
Abstract: The work presented herein is based on the clinical and molecular analysis of 24 large and highly consanguineous Pakistani families (IDs: GSD-01 to GSD-24) from Sindhi ethnic background. All enrolled families suffered from different Mendelian genetic disorders of the skin and its appendages. All clustered into six major groups: nonsyndromic disorders included ichthyosis, PPK, hypotrichosis, tooth agenesis, nail disorders, and syndromic disorders included NFJS/EB and HED (also see, summary chart). By considering the clinical features and mode of transmission in all families the prioritized candidate genes were analyzed, either by linkage analysis or by direct Sanger sequencing. One family “GSD-01” with autosomal recessive congenital ichthyosis (ARCI; MIM# 601277; 242100; 242300; 242500) showed the linkage to ABCA12 gene (MIM# 607800). Sanger sequencing of the ABCA12 gene revealed a homozygous missense mutation c. 4676 G>T (p.Gly1559Val). The candidate genes in other five ACRI families (GSD-02-GSD-06) were excluded by linkage analysis, which strongly suggests the involvement of novel gene(s)-loci implicated with the disease phenotype. The investigation of additional five families (GSD-07-GSD-11) with recessive X-linked ichthyosis (MIM# 308100) showed ~1.24 Mb deletion mutation; the region encompasses the STS (MIM# 3003747) and HDHD1A (MIM# 306480) genes together with several flanking markers. Two other families (GSD-12 and GSD-13), with nonsyndromic palmoplantar keratoderma (PPK; MIM# 125670) were also tested by linkage. In one family (GSD-12) the haplotype analysis showed the persuasive indication of linkage to 18q12.1 locus, which harbors the DSG and DSC genes cluster. Four families (GSD-14-GSD-17) with autosomal recessive woolly hair/ hypotrichosis (ARWH/H; MIM# 604379) showed the linkage to LIPH (MIM# 607365) gene. The mutational analysis revealed a recurrent 2-bp (c.659_660TA) deletion mutation in LIPH gene. A family (GSD-18) with autosomal dominant hypotrichosis (MIM# 605389) showed no conclusive evidence of association to any of the candidate genes. Thus, the exclusion of candidate genes implies the existence of a likely novel gene. In one of the two tooth agenesis (MIM# 167416) families (GSD-19) a novel heterozygous missense mutation c.443C>A (p.Pro148Gln) in PAX9 gene was revealed. While, in the second family (GSD-20) the most promising genes were excluded by Sanger sequencing, which implies the existence of a potential novel gene that need to be discover by WGS. XVII Two multigenerational families with two different types of autosomal dominant congenital nail disorders, including nail/digital clubbing (MIM# 119900) (GSD-21) and koilonychia (MIM# 149300) (GSD-22) were analyzed for putative genes HPGD (MIM# 601688), SLCO2A1 (MIM# 601460) and PLCD1 (MIM# 602142), respectively. But, in both families no clue of linkage was obtained. In an exceptionally large family (GSD-23) showing NFJS-like clinical signs features (MIM# 161000), a rarest form of ectodermal dysplasia (ED) exhibited missing fingerprints together with nail dystrophy and other clinical signs and symptoms, two candidate genes (KRT5 [MIM# 148040] and KRT14 [MIM# 148066]) were analyzed, which showed no alteration. This clearly indicates the involvement of another gene, in this family. In a family (GSD-24) with autosomal recessive HED (MIM# 224900), EDAR (MIM# 604095) gene was analyzed, which showed no any variation. In summary, this study contributed further 24 families from Pakistan with rare genodermatoses. The extensive molecular analysis revealed three known and one novel mutation in some selected genes, in eleven families, including ichthyosis, hypotrichosis and tooth agenesis. Moreover, in thirteen families, we could not ascertain any variation in the candidate genes associated with rare genodermatoses. Hence, exclusion of the candidate genes strongly suggests the involvement of a potential novel gene(s)-loci, at least in these 13 families. Current high throughput whole genome sequencing technologies will help to determine the underlying pathophysiology in these families. We deem this would be an interesting and worthwhile data, which may contribute and support the worldwide coordination system of affected persons, clinicians and researchers, which are looking for the better management or understanding of hereditary skin disorders
Gov't Doc #: 27469
Appears in Collections:PhD Thesis of All Public / Private Sector Universities / DAIs.

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