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Case Reports
. 2020 Jul;8(7):e1260.
doi: 10.1002/mgg3.1260. Epub 2020 May 12.

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

Barbara Lombardo  1   2 , Valeria D'Argenio  1   2 , Emanuele Monda  3   4 , Andrea Vitale  2   5 , Martina Caiazza  3   4 , Lucia Sacchetti  2 , Lucio Pastore  1   2 , Giuseppe Limongelli  3   4 , Giulia Frisso  1   2 , Cristina Mazzaccara  1   2
Affiliations
Case Reports

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

Barbara Lombardo et al. Mol Genet Genomic Med. 2020 Jul.

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.

Keywords: Alström syndrome; Usher syndrome; array CGH; idiopathic cardiomyopathy; mitochondrial; syndromic dilated cardiomyopathy; whole exome sequencing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Transthoracic echocardiogram from GA patient. Transthoracic echocardiogram from parasternal long‐axis view (M‐mode) (on the left) and from apical four‐chamber view (on the right) showing a severe dilation of the left ventricle (63 mm) and of the left atrium
Figure 2
Figure 2
Familial pedigree. MT‐ND3, PDE4DIP, PCDH15, ALMS1 mutations pattern of the probands and their father and clinical phenotype. II.1: retinitis pigmentosa, bilateral neurosensorial hearing loss, dilated cardiomyopathy, diabetes, hypothyroidism. II.2: retinitis pigmentosa, bilateral neurosensorial hearing loss, dilated cardiomyopathy and diabetes. MT‐ND3: NADH dehydrogenase gene, subunit 3, NC_012920.1; PDE4DIP: Phosphodiesterase 4d‐Interacting Protein gene, NC_000001.11; PCDH15: Protocadherin‐related 15 gene, NC_000010.11; ALMS1: Alström gene, NC_000002.12
See this image and copyright information in PMC

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