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Neuromuscul Disord. 2015 Jul;25(7):533-41. doi: 10.1016/j.nmd.2015.03.011. Epub 2015 Mar 30.

Next generation sequencing on patients with LGMD and nonspecific myopathies: Findings associated with ANO5 mutations.

Author information

1
Telethon Institute of Genetics and Medicine, Pozzuoli (NA), Italy; Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università di Napoli, Napoli, Italy.
2
Fondazione Don Gnocchi, Italy.
3
Dipartimento di Neuroscienze e Scienze riproduttive ed odontostomatologiche, Università di Napoli "Federico II", Napoli, Italy.
4
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
5
Department of Neurology, Ghent University Hospital, Ghent, Belgium.
6
Biochimie et génétique moléculaire, Centre hospitalier Cochin, Paris, France.
7
Dipartimento di Neuroscienze, Università di Messina, Messina, Italy.
8
Dipartimento di Neuroscienze, Università di Padova, Padova, Italy.
9
Centre de Référence Maladies Neuromusculaires - SLA, Hôpital Archet 1, CHU de Nice, Nice, France.
10
Dipartimento di Medicina Sperimentale, Seconda Università di Napoli, Napoli, Italy.
11
Telethon Institute of Genetics and Medicine, Pozzuoli (NA), Italy; Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università di Napoli, Napoli, Italy. Electronic address: vinnigro@gmail.com.

Abstract

We studied 786 undiagnosed patients with LGMD or nonspecific myopathic features to investigate the role of ANO5 mutations in limb-girdle muscular dystrophies (LGMDs) and in nonspecific myopathies using the next generation sequencing (NGS) approach. In 160 LGMD patients, we first sequenced hotspot exons 5 and 20 and then sequenced the remaining part of the coding region. Another 626 patients, recruited using broader inclusion criteria, were directly analyzed by targeted NGS. By combining NGS and Sanger sequencing, we identified 33/786 (4%) patients carrying putative pathogenic changes in both alleles and 23 ANO5 heterozygotes (3%). The phenotypic spectrum is broader than expected, from hyperCKemia to myopathies, with lack of genotype/phenotype correlations. In particular, this is currently the largest screening of the ANO5 gene. The large number of heterozygotes for damaging mutations suggests that anoctaminopathies should be frequent and often nonpenetrant. We propose the multiple genetic testing by targeted NGS as a first step to analyze patients with nonspecific myopathic presentations. This represents a straightforward approach to overcome the difficulties of clinical heterogeneity of ANO5 patients, and to test, at the same time, many other genes involved in neuromuscular disorders.

KEYWORDS:

Anoctamin; LGMD2L; Limb girdle muscular dystrophy; Muscular dystrophy; NGS screening; Next generation sequencing; Targeted resequencing

PMID:
25891276
PMCID:
PMC4502439
DOI:
10.1016/j.nmd.2015.03.011
[Indexed for MEDLINE]
Free PMC Article

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