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Non-recurrent SEPT9 duplications cause Hereditary Neuralgic Amyotrophy
  1. Angela Collie1,
  2. Megan Landsverk2,*,
  3. Elizabeth Ruzzo1,
  4. Heather Mefford1,
  5. Karen Buysse3,
  6. Jonathan Adkins1,
  7. Dana Knutzen1,
  8. Karen Barnett1,
  9. Robert Brown, Jr4,
  10. Gareth Parry5,
  11. Sabrina Yum6,
  12. David Simpson7,
  13. Richard Olney8,
  14. Patrick Chinnery9,
  15. Evan Eichler1,
  16. Phillip Chance1,
  17. Mark Hannibal1
  1. 1 University of Washington, United States;
  2. 2 Baylor College of Medicine, United States;
  3. 3 Ghent University, United States;
  4. 4 University of Massachusetts Medical School, United States;
  5. 5 University of Minnesota, United States;
  6. 6 University of Pennsylvania School of Medicine, United States;
  7. 7 Michigan Institute for Neurological Disorders, United States;
  8. 8 University of California San Francisco, United States;
  9. 9 Newcastle University, United States
  1. Correspondence to: Megan Landsverk, Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, 77030, United States; meganl{at}bcm.edu

Abstract

Background: Genomic copy number variants (CNVs) have been shown to be responsible for multiple genetic diseases. Recently, a duplication in Septin 9 (SEPT9) 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.

Methods and Results: Based on array comparative genomic hybridization (CGH) we identified six additional heterogeneous tandem SEPT9 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 observed through RT-PCR and Western blotting. One duplication spans the entire SEPT9 gene and generates transcripts and proteins that are normal in size. The breakpoints of all the duplications are unique and contain regions of microhomology ranging from 2 - 9 bp in size. The duplicated regions contain a conserved 645 bp exon within SEPT9 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.

Conclusions: Together with the previously identified founder duplication, we have identified a total of seven heterogeneous SEPT9 duplications as causative for HNA. These duplications account for one-third of the patients in our cohort suggesting that duplications of various sizes within the SEPT9 gene are a common cause of HNA.

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