Misdiagnosis by whole exome sequencing in progressive myoclonic ataxia consanguineous families: causes and strategies

• Published in: Zhenduanxue Lilun yu Shijian Vol. 21; no. 4; pp. 456 - 461
• Main Author: YANG Hui, LI Yunlu, YANG Kang, LI Shiju, HE Jin
• Format: Journal Article
• Language: Chinese
• Published: Editorial Office of Journal of Diagnostics Concepts & Practice 01.08.2022
• Subjects: progressive myoclonic ataxia|sialidosis type Ⅰ|whole exome sequencing|neu1 gene
• ISSN: 1671-2870
• DOI: 10.16150/j.1671-2870.2022.04.007

Objective: To investigate the causes and strategies of missed diagnosis of progressive myoclonic ataxia (PMA) consanguineous families by whole exome sequencing (WES). Methods: Five PMA consanguineous families with no disease causative variants detected by WES were enrolled, and homozygosity mapping and haplotype analysis for locating disease related region were performed. Further combined with myoclonus and ataxia phenotypes, the possible pathogenic genes were identified. Sanger sequencing was used to verify the candidate mutation and perfomed family co-segregation in five families. Finally, the reasons for missed diagnosis were analyzed by tracing to the SAM and BAM files from WES alignment process. Results: By homozygous regional mapping and reanalysis of WES, 5 families with progressive myoclonic ataxia were identified as sialidosis type I (ST-I) caused by homozygous mutation of NEU1 gene c.544A >G(p.S182G). It was also found that ALT contig in human genome reference sequence could cause multiple pathogeni