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The traditional understanding of genetic disease, that, with the exception of aneuploidy, it is due primarily to single base pair changes or small deletions and duplications has been challenged over the last decade. This challenge has been spearheaded by increasing evidence of the frequency and significance of larger genomic rearrangements. It now appears that a substantial proportion of Mendelian conditions are caused by deletions and duplications that involve the copy number of one or more contiguous genes. It is becoming apparent too that de novo chromosomal events are much more frequent than spontaneous point mutations and that chromosomal rearrangement is likely to account for the vast majority of sporadic disease.

Abstract: LGMD is predominantly inherited in an autosomal recessive manner; however autosomal dominant and X-linked subtypes have also been described. To date, most mutations that have been reported in LGMD patients have been point mutations, and these lie in approximately 17 genes. There are occasional reports of deletions in autosomal recessive LGMD genes, often only discovered when a single point mutation has been found in a gene known to cause autosomal recessive LGMD. We sought to determine whether deletions and duplications are a common cause of LGMD that have been routinely missed by standard sequencing approaches. We designed a bespoke Roche Nimblegen 12x135K CGH array that allowed for the simultaneous targeted interrogation of all coding exons of 17 LGMD genes, with additional widely-spaced backbone probes providing coverage across the whole genome. Dosage changes were confirmed by real-time quantitative PCR. We used DNA from 50 undiagnosed LGMD patients ascertained at Auckland City Hospital and 100 undiagnosed patients from the INMR laboratory, Children’s Hospital at Westmead with congenital myopathy and LGMD who had been screened for most of the common genetic causes. We found copy number variations in a handful of patients and are verifying these with real-time quantitative PCR. The data suggest a low incidence of deletion and duplication mutations. In conclusion, large deletions and duplications are uncommon in the known LGMD genes in undiagnosed LGMD patients and screening for deletions and duplications is unlikely to be a useful approach, unless single recessive mutations are found or standard gene sequencing protocols fail to identify the causative mutation. Sequencing e.g. by Next Generation Sequencing methods is likely to play a significant role in ascertaining a genetic diagnosis for these patients in an affordable and timely manner. [Copyright &y& Elsevier]