DETECTION OF DE-NOVO MUTATIONS AND ANALYSIS OF THEIR ORIGIN IN FAMILIES WITH X-LINKED HYPOHIDROTIC ECTODERMAL DYSPLASIA

Hypohidrotic ectodermal dysplasia (EDA) has been localised to the q12- q13.1 region of the X chromosome by both physical and genetic mapping methods. Although linkage analysis using closely linked flanking marke rs can clarify the carrier status for many females at risk for the dis order, knowledge of the origin of the mutation in instances of possibl e de novo mutation is critical for accurate genetic counselling of fam ilies. Two methods have been used to confirm de novo mutation in famil ies with EDA and to trace their origin. Direct detection of three de n ovo molecular deletions, one arising during oogenesis and the other tw o during spermatogenesis, was achieved by Southern analyses using cosm ids isolated from the EDA region as probes. Seven de novo mutations ar ising during spermatogenesis, and two possible de novo mutations durin g oogenesis, were identified by an analysis of the cosegregation of th e disorder with polymorphic markers closely linked to and flanking the EDA locus. The confirmation and analysis of the origin of the 10 de n ovo mutations greatly assisted genetic counselling in these families. The apparent 3.5:1 excess of male to female origin of mutation in fami lies studied with unidentified types of mutation is similar to other s tudies of X linked disorders, and suggests that the majority of these mutations may involve single base pair substitutions.