Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2
| Autor: | Rabi Tawil, Nicol C. Voermans, Silvère M. van der Maarel, Richard J F L Lemmers, Stephen J. Tapscott, Adolfo López de Munain, Patrick J. van der Vliet, Nienke van der Stoep, Marlinde L. van den Boogaard, Pilar Camaño, Baziel G.M. van Engelen |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Proband musculoskeletal diseases Adult Male congenital hereditary and neonatal diseases and abnormalities Chromosomal Proteins Non-Histone Molecular Sequence Data Gene Expression Penetrance Biology X-inactivation Article 03 medical and health sciences DUX4 Genetic linkage Genetics medicine Facioscapulohumeral muscular dystrophy Missense mutation Humans Age of Onset Muscle Skeletal Genetics (clinical) Aged Homeodomain Proteins Base Sequence Exons DNA Methylation Middle Aged medicine.disease Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] Chromatin Muscular Dystrophy Facioscapulohumeral Pedigree 030104 developmental biology Chromosome 4 Phenotype Genetic Loci Mutation Disease Progression Female Chromosomes Human Pair 4 |
| Zdroj: | European Journal of Human Genetics, 24, 1, pp. 78-85 European Journal of Human Genetics, 24(1), 78-85 European Journal of Human Genetics, 24, 78-85 |
| ISSN: | 1018-4813 |
| Popis: | Item does not contain fulltext Facioscapulohumeral muscular dystrophy (FSHD) predominantly affects the muscles in the face, trunk and upper extremities and is marked by large clinical variability in disease onset and progression. FSHD is associated with partial chromatin relaxation of the D4Z4 repeat array on chromosome 4 and the somatic expression of the D4Z4 encoded DUX4 gene. The most common form, FSHD1, is caused by a contraction of the D4Z4 repeat array on chromosome 4 to a size of 1-10 units. FSHD2, the less common form of FSHD, is most often caused by heterozygous variants in the chromatin modifier SMCHD1, which is involved in the maintenance of D4Z4 methylation. We identified three families in which the proband carries two potentially damaging SMCHD1 variants. We investigated whether these variants were located in cis or in trans and determined their functional consequences by detailed clinical information and D4Z4 methylation studies. In the first family, both variants in trans were shown to act synergistically on D4Z4 hypomethylation and disease penetrance, in the second family both SMCHD1 function-affecting variants were located in cis while in the third family one of the two variants did not affect function. This study demonstrates that having two SMCHD1 missense variants that affect function is compatible with life in males and females, which is remarkable considering its role in X inactivation in mice. The study also highlights the variability in SMCHD1 variants underlying FSHD2 and the predictive value of D4Z4 methylation analysis in determining the functional consequences of SMCHD1 variants of unknown significance. |
| Databáze: | OpenAIRE |
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