Whole genome sequencing reveals novel non-synonymous mutation in ectodysplasin A (EDA) associated with non-syndromic X-linked dominant congenital tooth agenesis.

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Congenital tooth agenesis in human is characterized by failure of tooth development during tooth organogenesis . 300 genes in mouse and 30 genes in human so far have been known to regulate tooth development . However , candidature of only 5 genes viz . PAX 9 , MSX 1 , AXIN 2 , WNT 10 A and EDA have been experimentally established for congenitally missing teeth like hypodontia and oligodontia . In this study an Indian family with multiple congenital tooth agenesis was identified . Pattern of inheritance was apparently autosomal dominant type with a rare possibility to be X-linked . Whole genome sequencing of two affected individuals was carried out which revealed 119 novel non-synonymous single nucleotide variations (SNVs ) distributed among 117 genes . Out of these only one variation (c .956 G >T ) located at exon 9 of X-linked EDA gene was considered as pathogenic and validated among all the affected and unaffected family members and unrelated controls . This variation leads to p .S er 319 I le change in the TNF homology domain of EDA (transcript variant 1 ) protein . In silico analysis predicts that this Ser 319 is well conserved across different vertebrate species and a part of putative receptor binding site . Structure based homology modeling predicts that this amino acid residue along with four other amino acid residues nearby , those when mutated known to cause selective tooth agenesis , form a cluster that may have functional significance . Taken together these results suggest that c .956 G >T (p .Ser 319 I le ) mutation plausibly reduces the receptor binding activity of EDA leading to distinct tooth agenesis in this family .