Asaf Vivante1,2, Hadas Ityel1, Ben Pode-Shakked2,3,4, Jing Chen1, Shirlee Shril1, Amelie T van der Ven1, Nina Mann1, Johanna Magdalena Schmidt1, Reeval Segel5,6, Adi Aran6,7, Avraham Zeharia3,8, Orna Staretz-Chacham9, Omer Bar-Yosef2,3,10, Annick Raas-Rothschild3,11, Yuval E Landau3,4, Richard P Lifton12,13, Yair Anikster3,4, Friedhelm Hildebrandt14. 1. Division of Nephrology, Department of Medicine, Boston Children's Hospital-Harvard Medical School, 300 Longwood Avenue HU319, Boston, MA, 02115, USA. 2. Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel. 3. Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 4. Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel. 5. Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel. 6. Hadassah Medical School, Hebrew University, Jerusalem, Israel. 7. Pediatric Neurology Unit, Shaare Zedek Medical Center, Jerusalem, Israel. 8. Pediatric Day Hospitalization Department, Schneider Children's Medical Center of Israel, Petah Tikva, Israel. 9. Metabolic Clinic, Pediatric Division, Soroka Medical Center, Ben-Gurion University, Beer Sheva, Israel. 10. Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel. 11. Institute of Rare Diseases, The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer, Israel. 12. Department of Human Genetics, Yale University School of Medicine, New Haven, CT, USA. 13. Howard Hughes Medical Institute, Chevy Chase, MD, USA. 14. Division of Nephrology, Department of Medicine, Boston Children's Hospital-Harvard Medical School, 300 Longwood Avenue HU319, Boston, MA, 02115, USA. Friedhelm.Hildebrandt@childrens.harvard.edu.
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.
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.
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