Mini-Exome Coupled to Read-Depth Based Copy Number Variation Analysis in Patients with Inherited Ataxias

作者：Marelli Cecilia; Guissart Claire; Hubsch Cecile; Renaud Mathilde; Villemin Jean Philippe; Larrieu Lise; Charles Perrine; Ayrignac Xavier; Sacconi Sabrina; Collignon Patrick; Cuntz Shadfar Danielle; Perrin Laurine; Benarrosh Anelia; Degardin Adrian; Lagha Boukbiza Ouhaid; Mutez Eugenie; Carlander Bertrand; Morales Raul Juntas; Gonzalez Victoria; Carra Dalliere Clarisse; Azakri Souhayla; Mignard Claude; Ollagnon Elisabeth; Pageot Nicolas; Chretien Dominique

来源：Human Mutation, 2016, 37(12): 1340-1353.

DOI：10.1002/humu.23063

• ataxia
• mini-exome
• exome sequencing
• copy number variations
• molecular diagnosis
• trinucleotide repeat expansion

Next-generation sequencing (NGS) has an established diagnostic value for inherited ataxia. However, the need of a rigorous process of analysis and validation remains challenging. Moreover, copy number variations (CNV) or dynamic expansions of repeated sequence are classically considered not adequately detected by exome sequencing technique. We applied a strategy of mini-exome coupled to read-depth based CNV analysis to a series of 33 patients with probable inherited ataxia and onset < 50 years. The mini-exome consisted of the capture of 4,813 genes having associated clinical phenotypes. Pathogenic variants were found in 42% and variants of uncertain significance in 24% of the patients. These results are comparable to those from whole exome sequencing and better than previous targeted NGS studies. CNV and dynamic expansions of repeated CAG sequence were identified in three patients. We identified both atypical presentation of known ataxia genes (ATM, NPC1) and mutations in genes very rarely associated with ataxia (ERCC4, HSD17B4). We show that mini-exome bioinformatics data analysis allows the identification of CNV and dynamic expansions of repeated sequence. Our study confirms the diagnostic value of the proposed genetic analysis strategy. We also provide an algorithm for the multidisciplinary process of analysis, interpretation, and validation of NGS data.

• 出版日期2016-12