Non-recurrent SEPT9 duplications cause hereditary neuralgic amyotrophy.

[neuralgic amyotrophy]

Genomic copy number variants have been shown to be responsible for multiple genetic diseases . Recently , a duplication in septin 9 (SEPT 9 ) was shown to be causal for hereditary neuralgic amyotrophy (HNA ), an episodic peripheral neuropathy with autosomal dominant inheritance . This duplication was identified in 12 pedigrees that all shared a common founder haplotype .Based on array comparative genomic hybridisation , we identified six additional heterogeneous tandem SEPT 9 duplications in patients with HNA that did not possess the founder haplotype . Five of these novel duplications are intragenic and result in larger transcript and protein products , as demonstrated through reverse transcription-PCR and western blotting . One duplication spans the entire SEPT 9 gene and does not generate aberrant transcripts and proteins . The breakpoints of all the duplications are unique and contain regions of microhomology ranging from 2 to 9 bp in size . The duplicated regions contain a conserved 645 bp exon within SEPT 9 in which HNA-linked missense mutations have been previously identified , suggesting that the region encoded by this exon is important to the pathogenesis of HNA .T ogether with the previously identified founder duplication , a total of seven heterogeneous SEPT 9 duplications have been identified in this study as a causative factor of HNA . These duplications account for one third of the patients in our cohort , suggesting that duplications of various sizes within the SEPT 9 gene are a common cause of HNA .