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

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.

A Turkish patient with novel AHCY variants and presumed diagnosis of S‐adenosylhomocysteine hydrolase deficiency

“…Cardiomegaly was reported in two sisters (Grubbs et al, ) and hyperplasia of ventricles was noted by postmortem examinations of the present case. Apnea episodes have been reported for the two previous patients (Grubbs et al, ; Vivante et al, ) and both of our patient and her deceased sister also experienced them (Table ).…”

“…The authors stated that the disorder should be suspected in patients with any combination of myopathy with markedly increased CK activity, hypotonia, developmental delay, hypomyelination, behavioral problems, liver disease, coagulation disorders, strabismus, and fetal hydrops with brain abnormalities (Barić et al, ). Two additional patients were also reported after that review (Judkins et al, ; Vivante et al, ).…”

“…The enzyme is encoded by AHCY gene located on chromosome 20q11.22 (Hershfield & Francke, ) and biallelic pathogenic variants of the gene cause AHCY deficiency (OMIM: #613752) which is characterized by myopathy, central nervous system abnormalities, and hepatic insufficiency (Barić et al, ). There are several cases with this disease reported up to now and clinical presentation differed in these patients by the age of onset, major organ involvement, and disease severity (Barić et al, , ; Buist et al, ; Ćuk et al, ; Grubbs et al, ; Honzík et al, ; Judkins et al, ; Stender et al, ; Strauss et al, ; Vivante et al, ).…”

Genetic Evidence Supporting the Role of the Calcium Channel, CACNA1S, in Tooth Cusp and Root Patterning

“…Indeed according to HGMD, 43 mutations involved in seven different diseases have been described in the CACNA1S gene (listed in Supplementary Table S1 and Figure 3 ). These include malignant hyperthermia susceptibility 5, MIM #601887 ( Eltit et al, 2012 ), thyrotoxic periodic paralysis, susceptibility to, 1, MIM #188580 ( Kung, 2006 ), hypokalemic periodic paralysis, type 1, MIM #170400 ( Fialho et al, 2018 ), normokalaemic periodontic paralysis ( Fan et al, 2013 ), myopathy ( Schartner et al, 2017 ), rhabdomyolysis ( Vivante et al, 2017 ), exertional heat illness ( Fiszer et al, 2015 ), and schizophrenia ( Fromer et al, 2014 ; Purcell et al, 2014 ). Six mutations, localized to the first ion transport domain, were previously reported to result in myopathies, malignant hyperthermia, and schizophrenia.…”

Rhabdomyolysis with Kawasaki disease and a family history of rhabdomyolysis

“…Therefore, the present case of rhabdomyolysis could be caused by undetected genetic factors and prolonged high fever. Of the families with a medical history of rhabdomyolysis who had undergone whole exome sequencing, causative mutations were identified in the rhabdomyolysis genes in 43% (9/21 families) . It is difficult for children to describe their subjective symptoms correctly, therefore it is necessary to interview the parents in order to obtain an accurate family medical history of rhabdomyolysis in detail, in cases of persistent high fever including KD, and to check serum CK level without muscle symptoms.…”