Novel EDAR mutation in tooth agenesis and variable associated features.

Tooth agenesis (TA) is the developmental absence of one or more permanent teeth. We report on 10 members of a Pakistani family afflicted with TA with variable associated features inherited in autosomal dominant fashion with full penetrance. The malformation is bilateral in the majority of cases, and hallmark feature is the absence of lateral and central incisors and canines whereas first and second premolars are involved less often. Affected individuals also have pronounced variable features associated with TA such as diastema between central incisors, overgrown labial frenum, peg-shaped lower incisors, delayed exfoliation, over-erupted upper incisors and malocclusion but have no other signs of ectodermal dysplasia. Through linkage analysis coupled with exome sequencing, we identified novel nonsense variant EDAR c.1302G>A, p.(Trp434*). The variant is deduced to create a premature termination codon that leads to the deletion of the 15 C-terminal residues. Heterozygous EDAR variants most commonly cause hypohydrotic ectodermal dysplasia, but recently one nonsense and 10 missense variants have been reported in nonsyndromic TA, some with few mild features of hypohydrotic ectodermal dysplasia. The phenotype in the family we present, the largest with EDAR-related TA reported to date, is highly variable and without any signs of ectodermal dysplasia.