Mini‐Exome Coupled to Read‐Depth Based Copy Number Variation Analysis in Patients with Inherited Ataxias: Influence Statistics

Expert Impact

Concepts for which they have has direct influence: Inherited ataxia , Sequence analysis , Ataxia genes , Exome sequencing , Analysis dna , Ataxia child , Variation analysis .

Key People For Inherited Ataxia

Top KOLs in the world
#1
Alexandra Dürr
huntington disease cerebellar ataxia spastic paraplegia
#2
Alexis Brice
parkinson disease cerebellar ataxia age onset
#3
Stefano Di Donato
molecular diagnosis huntington disease efns guidelines
#4
Massimo Pandolfo
friedreich ataxia frataxin deficiency sticky dna
#5
Ludger Schöls
spinocerebellar ataxia type friedreich ataxia spastic paraplegia
#6
Alessandro Filla
friedreich ataxia southern italy age onset

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

Abstract

. 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.