Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases
- 5 August 2017
- journal article
- research article
- Published by Springer Science and Business Media LLC in Pediatric Nephrology
- Vol. 32 (12), 2273-2282
- https://doi.org/10.1007/s00467-017-3755-8
Abstract
Background Rhabdomyolysis is a clinical emergency that may cause acute kidney injury (AKI). It can be acquired or due to monogenic mutations. Around 60 different rare monogenic forms of rhabdomyolysis have been reported to date. In the clinical setting, identifying the underlying molecular diagnosis is challenging due to nonspecific presentation, the high number of causative genes, and current lack of data on the prevalence of monogenic forms. Methods We employed whole exome sequencing (WES) to reveal the percentage of rhabdomyolysis cases explained by single-gene (monogenic) mutations in one of 58 candidate genes. We investigated a cohort of 21 unrelated families with rhabdomyolysis, in whom no underlying etiology had been previously established. Results Using WES, we identified causative mutations in candidate genes in nine of the 21 families (43%). We detected disease-causing mutations in eight of 58 candidate genes, grouped into the following categories: (1) disorders of fatty acid metabolism (CPT2), (2) disorders of glycogen metabolism (PFKM and PGAM2), (3) disorders of abnormal skeletal muscle relaxation and contraction (CACNA1S, MYH3, RYR1 and SCN4A), and (4) disorders of purine metabolism (AHCY). Conclusions Our findings demonstrate a very high detection rate for monogenic etiologies using WES and reveal broad genetic heterogeneity for rhabdomyolysis. These results highlight the importance of molecular genetic diagnostics for establishing an etiologic diagnosis. Because these patients are at risk for recurrent episodes of rhabdomyolysis and subsequent risk for AKI, WES allows adequate prophylaxis and treatment for these patients and their family members and enables a personalized medicine approach.Keywords
Funding Information
- Foundation for the National Institutes of Health (DK088767)
- March of Dimes
- Yale Center for Mendelian Genomics (U54HG006504)
- German Research Foundation (VE916/1-1)
This publication has 35 references indexed in Scilit:
- Disease mutations in the ryanodine receptor N-terminal region couple to a mobile intersubunit interfaceNature Communications, 2013
- Unusual presentation of phosphoglycerate mutase deficiency due to two different mutations in PGAM-M geneNeuromuscular Disorders, 2009
- The Sequence Alignment/Map format and SAMtoolsBioinformatics, 2009
- HomozygosityMapper--an interactive approach to homozygosity mappingNucleic Acids Research, 2009
- A Systematic Approach to Mapping Recessive Disease Genes in Individuals from Outbred PopulationsPLoS Genetics, 2009
- S‐Adenosylhomocysteine hydrolase deficiency in a 26‐year‐old manJournal of Inherited Metabolic Disease, 2006
- Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndromeNature Genetics, 2006
- Central core disease is due to RYR1 mutations in more than 90% of patientsBrain, 2006
- Identification of a common mutation in the carnitine palmitoyltransferase II gene in familial recurrent myoglobinuria patientsNature Genetics, 1993
- Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenitaNeuron, 1992