Large-Scale Population Analysis Challenges the Current Criteria for the Molecular Diagnosis of Fascioscapulohumeral Muscular Dystrophy
Contribuinte(s) |
UNIVERSIDADE DE SÃO PAULO |
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Data(s) |
14/10/2013
14/10/2013
2012
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Resumo |
Facioscapulohumeral muscular dystrophy (FSHD) is a common hereditary myopathy causally linked to reduced numbers (<= 8) of 3.3 kilobase D4Z4 tandem repeats at 4q35. However, because individuals carrying D4Z4-reduced alleles and no FSHD and patients with FSHD and no short allele have been observed, additional markers have been proposed to support an FSHD molecular diagnosis. In particular a reduction in the number of D4Z4 elements combined with the 4A(159/161/168)PAS haplotype (which provides the possibility of expressing DUX4) is currently used as the genetic signature uniquely associated with FSHD. Here, we analyzed these DNA elements in more than 800 Italian and Brazilian samples of normal individuals unrelated to any FSHD patients. We find that 3% of healthy subjects carry alleles with a reduced number (4-8) of D4Z4 repeats on chromosome 4q and that one-third of these alleles, 1.3%, occur in combination with the 4A161PAS haplotype. We also systematically characterized the 4q35 haplotype in 253 unrelated FSHD patients. We find that only 127 of them (50.1%) carry alleles with 1-8 D4Z4 repeats associated with 4A161PAS, whereas the remaining FSHD probands carry different haplotypes or alleles with a greater number of D4Z4 repeats. The present study shows that the current genetic signature of FSHD is a common polymorphism and that only half of FSHD probands carry this molecular signature. Our results suggest that the genetic basis of FSHD, which is remarkably heterogeneous, should be revisited, because this has important implications for genetic counseling and prenatal diagnosis of at-risk families. Telethon [GUP08004, GUP11009] Telethon Association Francaise Contre les Myopathies Association Francaise Contre les Myopathies [14339] National Institute of Health-National Institutes of Neurological Disorders and Stroke [RO1 NS047584] National Institute of HealthNational Institutes of Neurological Disorders and Stroke Centros de Pesquisa, Inovacao e Difusao/Fundacao de Amparo a Pesquisa do Estado de Sao Paulo Centros de Pesquisa, Inovacao e Difusao/Fundacao de Amparo a Pesquisa do Estado de Sao Paulo Institutos Nacionais de Ciencia e Tecnologia Institutos Nacionais de Ciencia e Tecnologia Conselho Nacional de Desenvolvimento Cientifico e Tecnologico Conselho Nacional de Desenvolvimento Cientifico e Tecnologico |
Identificador |
AMERICAN JOURNAL OF HUMAN GENETICS, CAMBRIDGE, v. 90, n. 4, supl. 1, Part 3, pp. 628-635, APR 6, 2012 0002-9297 http://www.producao.usp.br/handle/BDPI/34535 10.1016/j.ajhg.2012.02.019 |
Idioma(s) |
eng |
Publicador |
CELL PRESS CAMBRIDGE |
Relação |
AMERICAN JOURNAL OF HUMAN GENETICS |
Direitos |
restrictedAccess Copyright CELL PRESS |
Palavras-Chave | #DNA REARRANGEMENTS #4Q35 DELETION #FSHD #PHENOTYPE #LOCUS #D4Z4 #CHROMOSOME-4 #D4F104S1 #FRAGMENT #FAMILY #GENETICS & HEREDITY |
Tipo |
article original article publishedVersion |