Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases.

TitleExome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases.
Publication TypeJournal Article
Year of Publication2017
AuthorsVivante, A, Ityel, H, Pode-Shakked, B, Chen, J, Shril, S, van der Ven, AT, Mann, N, Schmidt, JMagdalena, Segel, R, Aran, A, Zeharia, A, Staretz-Chacham, O, Bar-Yosef, O, Raas-Rothschild, A, Landau, YE, Lifton, RP, Anikster, Y, Hildebrandt, F
JournalPediatr Nephrol
Date Published2017 Dec
KeywordsAdolescent, Adult, Arabs, Child, Exome, Genetic Predisposition to Disease, Humans, Jews, Mutation, Rhabdomyolysis, Whole Exome Sequencing

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.

Alternate JournalPediatr. Nephrol.
PubMed ID28779239
PubMed Central IDPMC5903869
Grant ListR01 DK088767 / DK / NIDDK NIH HHS / United States
P30 DK079310 / DK / NIDDK NIH HHS / United States
S10 OD018521 / OD / NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
T32 DK007726 / DK / NIDDK NIH HHS / United States