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Genetic analysis resolves differential diagnosis of a familial syndromic dilated cardiomyopathy: A new case of Alstrom syndrome.

ABSTRACT: BACKGROUND:Syndromic dilated cardiomyopathy (DCM) includes a group of complex disorders with a very heterogeneous genetic etiology, leading to delay in definitive diagnosis. Conversely, an early genetic diagnosis is very important in determining the disease course, the prognosis, and may guide personalized treatments and family counseling. METHODS:We analyzed two brothers with a multisystemic disorder, including dilated cardiomyopathy, diabetes, bilateral neurosensorial hearing loss, and optic atrophy, using different genetic approaches, namely mitochondrial DNA sequencing, comparative genomic hybridization-array (a-CGH) and whole exome sequencing (WES). RESULTS:Sequencing of the wide mitochondrial genome revealed, in both brothers, the known homoplasmic variant rs2853826 in the subunit 3 of the NADH dehydrogenase gene (MT-ND3), whose pathogenicity was conflicting. Comparative genomic hybridization-array analysis revealed in both patients and their father two heterozygous deletions in Phosphodiesterase 4d-Interacting Protein (PDE4DIP) and Protocadherin-related 15 (PCDH15) genes, respectively. The use of WES detected a pathogenetic mutation in ALMS1, enabling the definitive diagnosis of Alström syndrome. CONCLUSION:We demonstrated how the diagnosis of a complex heterogeneous disease may be difficult, due to several overlapping manifestations and the possible interaction of more genetic variants that could lead to a more severe and complex phenotype. This paper strongly evidences how genomics is revolutionizing the diagnosis of rare complex disease, representing one of the most essential steps to enable a definitive diagnosis and to establish the etiology for diseases, such as syndromic DCM.

SUBMITTER: Lombardo B

PROVIDER: S-EPMC7336746 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Genetic analysis resolves differential diagnosis of a familial syndromic dilated cardiomyopathy: A new case of Alström syndrome.

Lombardo Barbara B D'Argenio Valeria V Monda Emanuele E Vitale Andrea A Caiazza Martina M Sacchetti Lucia L Pastore Lucio L Limongelli Giuseppe G Frisso Giulia G Mazzaccara Cristina C

Molecular genetics & genomic medicine 20200512 7

<h4>Background</h4>Syndromic dilated cardiomyopathy (DCM) includes a group of complex disorders with a very heterogeneous genetic etiology, leading to delay in definitive diagnosis. Conversely, an early genetic diagnosis is very important in determining the disease course, the prognosis, and may guide personalized treatments and family counseling.<h4>Methods</h4>We analyzed two brothers with a multisystemic disorder, including dilated cardiomyopathy, diabetes, bilateral neurosensorial hearing lo ...[more]

PMID: 32396277

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Project description:Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by ventricular dilatation and impaired systolic function. Patients with DCM suffer from heart failure, arrhythmia, and are at risk of premature death. DCM has a prevalence of one case out of 2500 individuals with an incidence of 7/100,000/year (but may be under diagnosed). In many cases the disease is inherited and is termed familial DCM (FDC). FDC may account for 20-48% of DCM. FDC is principally caused by genetic mutations in FDC genes that encode for cytoskeletal and sarcomeric proteins in the cardiac myocyte. Family history analysis is an important tool for identifying families affected by FDC. Standard criteria for evaluating FDC families have been published and the use of such criteria is increasing. Clinical genetic testing has been developed for some FDC genes and will be increasingly utilized for evaluating FDC families. Through the use of family screening by pedigree analysis and/or genetic testing, it is possible to identify patients at earlier, or even presymptomatic stages of their disease. This presents an opportunity to invoke lifestyle changes and to provide pharmacological therapy earlier in the course of disease. Genetic counseling is used to identify additional asymptomatic family members who are at risk of developing symptoms, allowing for regular screening of these individuals. The management of FDC focuses on limiting the progression of heart failure and controlling arrhythmia, and is based on currently accepted treatment guidelines for DCM. It includes general measures (salt and fluid restriction, treatment of hypertension, limitation of alcohol intake, control of body weight, moderate exercise) and pharmacotherapy. Cardiac resynchronization, implantable cardioverter defibrillators and left ventricular assist devices have progressively expanding usage. Patients with severe heart failure, severe reduction of the functional capacity and depressed left ventricular ejection fraction have a low survival rate and may require heart transplant.

Dataset Information

Genetic analysis resolves differential diagnosis of a familial syndromic dilated cardiomyopathy: A new case of Alstrom syndrome.

Publications

Genetic analysis resolves differential diagnosis of a familial syndromic dilated cardiomyopathy: A new case of Alström syndrome.

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