Molecular detection of new mutations, resolution of ambiguous results and complex genetic counseling issues in...

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by expansion of a variable length (CAG)n repeat in the 5' coding region of a novel gene on chromosome 4p16.3. We provide comprehensive molecular analysis of a sporadic case of HD in which a paternally derived normal length allele expanded to an affected length allele. Linkage analysis and paternity testing confirm the paternal origin of the expansion and demonstrate that unequal crossing over during meiosis is an unlikely mechanism for de novo expansion in HD. This case identifies a complex genetic counseling issue for the families of sporadic cases since calculations of recurrence risk are not possible at this time. In addition, we describe utilization of a combination of polymerase chain reaction (PCR) based assays for examination of both the CAG repeat and an adjacent variable length CCG repeat in the huntingtin gene. The combination of these assays can increase the accuracy of molecular diagnosis for HD and may clarify any ambiguous results obtained during molecular testing of HD families.