Non-recurrent SEPT9 duplications cause hereditary neuralgic amyotrophy

Area of Science:

• Genetics
• Molecular Biology
• Neurology

Background:

• Genomic copy number variants (CNVs) are implicated in various genetic diseases.
• A SEPT9 gene duplication was previously identified as a cause of hereditary neuralgic amyotrophy (HNA).
• This founder duplication was found in 12 HNA pedigrees sharing a common haplotype.

Purpose of the Study:

• To identify additional genetic causes of HNA beyond the founder SEPT9 duplication.
• To investigate the role of SEPT9 gene duplications in HNA pathogenesis.

Main Methods:

• Array comparative genomic hybridization (aCGH) was used to detect copy number variations.
• Reverse transcription-PCR and western blotting were employed to analyze SEPT9 transcript and protein products.
• Breakpoint analysis was performed to characterize the identified duplications.

Main Results:

• Six novel, heterogeneous SEPT9 duplications were identified in HNA patients lacking the founder haplotype.
• Five intragenic duplications resulted in altered SEPT9 transcripts and proteins.
• One duplication encompassed the entire SEPT9 gene without producing aberrant products.
• All duplications exhibited unique breakpoints with microhomology regions.
• The duplicated regions included a conserved exon previously linked to HNA missense mutations.

Conclusions:

• A total of seven heterogeneous SEPT9 duplications are now identified as causative for HNA.
• These SEPT9 duplications account for one-third of HNA cases in the study cohort.
• Duplications of varying sizes within the SEPT9 gene are a frequent cause of HNA.