Abstract:

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 pathogenic genes including NEU1 gene to be missed during WES alignment. Conclusions: In clinical diagnosis, autosomal recessive PMA should be paid attention to ST-I which caused by NEU1 gene mutation. For families with hereditary diseases in which WES has not found pathogenic loci, the pathogenic region can be located by combining family genetic mode and genome-wide SNP chip, then the pathogenic genes can be identified by clinical manifestations analysis.

Key words: Progressive myoclonic ataxia, Sialidosis type Ⅰ, Whole exome sequencing, NEU1 gene