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Diagnostic value of whole-exome sequencing in Chinese pediatric-onset neuromuscular patients
- Source :
- Molecular Genetics & Genomic Medicine, Molecular Genetics & Genomic Medicine, Vol 8, Iss 5, Pp n/a-n/a (2020)
- Publication Year :
- 2019
-
Abstract
- Background Neuromuscular disorders (NMDs) comprise a group of heterogeneous genetic diseases with a broad spectrum of overlapping the clinical presentations that makes diagnosis challenging. Notably, the recent introduction of whole‐exome sequencing (WES) is introducing rapid changes on the genetic diagnosis of NMDs. We aimed to investigate the diagnostic value of WES for pediatric‐onset NMDs. Methods We applied integrated diagnostic approach and performed WES in 50 Chinese subjects (30 males, 20 females) with undiagnosed pediatric‐onset NMDs despite previous specific tests. The patients were categorized in four subgroups according to phenotyping and investigation findings. Variants on NMDs gene list and open exome analysis for those with initial negative findings were identified. Results WES identified causative variants in ACTA1 (n = 2), POMT1, COL6A1 (n = 2), MTMR2, LMNA, SELENON, DNM2, TGFB1, MPZ, IGHMBP2, and LAMA2 in 13 patients. Two subjects have variants of uncertain significance (VUSs) in TTN and SCN11A, unlikely to be pathogenic due to incompatible phenotypes. The mean interval time from symptom onset to genetic diagnosis was 10.4 years (range from 1 month to 33 years). The overall diagnostic yield of WES in our cohort was 26%. Open exome analysis was necessary to identify the pathogenic variant in TGFB1 that caused skeletal dysplasia with neuromuscular presentation. Conclusion Our study shows a clear role of WES in the pathway of integrated diagnostic approach to shorten the diagnostic odyssey in patients with rare NMDs.<br />Our study achieved a diagnostic yield from WES of 26% (13/50). These cases were diagnostically challenging as prior investigations failed to give clues on specific genetic diagnosis. Our findings are compatible to previous studies observing the diagnostic yield tends to be lower in cohorts that have already undergone prior extensive evaluations.
- Subjects :
- 0301 basic medicine
Adult
Male
medicine.medical_specialty
lcsh:QH426-470
Adolescent
Pediatric onset
030105 genetics & heredity
neuromuscular disorders
LMNA
03 medical and health sciences
pediatric‐onset
Predictive Value of Tests
Internal medicine
Exome Sequencing
Genetics
medicine
Humans
In patient
Genetic Testing
Child
Molecular Biology
Exome
Genetics (clinical)
Exome sequencing
business.industry
Infant
Neuromuscular Diseases
Original Articles
medicine.disease
integrated approach
DNM2
lcsh:Genetics
030104 developmental biology
Dysplasia
Genetic Loci
Child, Preschool
Cohort
Mutation
Female
Original Article
whole‐exome sequencing
business
Subjects
Details
- ISSN :
- 23249269
- Volume :
- 8
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Molecular geneticsgenomic medicine
- Accession number :
- edsair.doi.dedup.....bd9023c51b3b0d6516da917af45d1817