Asian Research Thesis Index

Abstract

Genodermatoses include a large group of inherited dermatological disorders that is often present with multisystem involvement resulting in various clinical manifestations due to genetic heterogeneity with pathogenic variations in more than 500 genes. Most genodermatoses occur early, during the neonatal period, infancy or early childhood, some conditions may appear later in life during adolescence or adulthood. Diagnosis of genodermatoses has been a major challenge and requires both clinical and investigational correlation to reach a diagnosis. Sometimes, even with comprehensive investigations, a definitive diagnosis cannot be achieved. With the arrival of new investigational. methods such as next generation sequencing, which not only successfully identified the molecular basis of many genodermatoses but also play important role in clinical use to help in the diagnosis of patients with suspected genodermatoses. In the current study, whole exome sequencing and Sanger sequencing were used to investigate genetic defects of nine Pakistani families affected with pseudoxanthoma elasticum (Families: A and B) and epidermolysis bullosa (Families: C,D E,F,G,H,I). Whole exome sequencing identified a novel homozygous frameshift variant (c.1799_1805dupGTCTGGT; p. Thr603fs*11) in ABCC6 in family A, a compound heterozygous variant (c.2294G>A; p.Arg765Gln and c.2974G>A; p.Gly992Arg) in ABCC6 in family B, a single nucleotide insertion variant (c.151insG; p.Gln226fs*) in LAMA3 in family C, two novel missense variants c.1285G>T (p.Asp429Tyr) and c.3373G>A (p.Gly1125Ser) in ITGB4 in family D, a novel homozygous missense variant c.1828A>G (p.Arg610Gly) in PLEC in family E, a heterozygous missense variant c.6209G>A (p.Gly2070Glu) in COL7A1 in family F, a homozygous frameshift variant c.676dupC (p.Gln226fs) in FERMT1 in family G, a homozygous nonsense variant c. C1705T in LAMB3 in family H and a homozygous nonsense variant c.C1573T (p.R525X) in COL7A1 in family I. In conclusion, two families affected with pseudoxanthoma elasticum and seven families affected with epidermolysis bullosa were identified with novel variants in ABCC6, ITGB4, and PLEC1. It should be assistive in the genetic counseling and prenatal diagnosis of the families as well as for the designing of improved diagnostic and therapeutic approaches.

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