Mutation identification and prediction for severe cardiomyopathy in Alström syndrome, and review of the literature for cardiomyopathy

Abstract Objective: Alström syndrome (ALMS1)(OMIM# 203800) is a rare autosomal recessive genetic disorder. Dilated cardiomyopathy (DCM) is one of the well-recognized feature of the syndrome ranging from sudden-onset infantile DCM, to adult onset cardiomyopathy, sometimes of the restrictive hypertrophic form with a poor prognosis. We aimed to evaluate severe cardiomyopathy in Alström syndrome in infancy and display susceptible specific mutations of the disease, which may be linked to severe DCM. Secondarily we reviewed published mutations of ALMS1 with cardiomyopathies in the literature. Method: In this patient cohort, we represent new mutagenic alleles related with severe cardiomyopathy and cardiac outcome. We evaluated echocardiographic studies of nine Turkish patients diagnosed with Alström syndrome (between 2014 and 2020, at age two weeks to twenty years). Thus, we made a detailed examination of the cardiac manifestations of a single-center prospective series of nine children with specific ALMS1 mutations and multisystem involvement. All patients underwent genetic testing, biochemical testing, electrocardiogram, and echocardiographic imaging with speckle tracking to evaluate systolic strain.Results: Four of the patients died with cardiomyopathy. Three patients (including three of the four fatalities) with the same novel mutation (c.7911dupC [p. Asn2638Glnfs*24]) had cardiomyopathy with intra-familial variability in severity of cardiomyopathy. Global longitudinal strain, a measure of systolic contractile function, was abnormal in all of patients that can be measured.Conclusion: Cardiac function in ALMS1 patients with infantile cardiomyopathy appears to have different clinical spectrums depending on the mutagenic allele. The c.7911dupC (p. Asn2638Glnfs*24) mutation can be related to severe cardiomyopathy. Parents can be informed and consulted about the progression of serious cardiomyopathy in child carrying this mutagenic allele.