Molecular genetic analysis of a New South Wales muscular dystrophy cohort

Duchenne muscular dystrophy (DMD) is an X-linked lethal condition associated with high morbidity and mortality. There is currently no cure for this disease. Several gene-based therapeutic approaches for treating DMD are currently under development but all are dependent on the knowledge of the causative dystrophin gene mutation.A combined mutation detection approach consisting of a quantitative PCR basedanalysis and DNA sequencing of the dystrophin gene resulted in a mutation etectionrate of 96% in the New South Wales (NSW) DMD cohort. The proportion of exonduplication mutations was twice that generally reported for similar patient opulations.The clinical utility of the combined mutation protocol for DMD carrier testing clarified the carrier status of an additional one-third (33%) of female relatives compared to aconventional approach of biochemical, pedigree and linkage studies.The generally accepted view that two-thirds of mothers of isolated cases of DMD are themselves mutation carriers is challenged. Although this assumption is valid forduplication and DNA sequence mutations, it is not valid for deletion mutations in theNSW cohort.The incidence of new cases of DMD in the New South Wales population was educed from approximately 1 in 3594 live male births to 1 in 6022 live male births over a 25year period, indicative of a significant effect of the combination of genetic counselling and improved methods of carrier detection over that period.In a study of a cohort of boys with DMD, who had both psychological and mutationalanalysis, it was shown that mutations affecting the shorter, C-terminal isoforms ofdystrophin are associated with decreased mean intellectual function. A hypothesis ispresented that mutations within the long 5' untranslated region of the Dp140 isoform are unlikely to significantly affect expression of this brain-expressed isoform.During the course of studying the NSW DMD cohort a family was identified whichexhibited X-linkage and a unique clinical presentation involving episodes of severe and prolonged muscle weakness. A novel variant in the pyruvate dehydrogenase E1 alpha subunit (PDHA 1) was identified. The phenotypic effect of this variant is not proven but a body of evidence implicates this as likely to be causative of the observed phenotype