title: Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2.
abstract: 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.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marlinde L
authors.initials: ML
authors.lastname: van den Boogaard
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Richard J F L
authors.initials: RJ
authors.lastname: Lemmers
authors.affiliation: Neurosciences, BioDonostia Health Research Institute, Hospital Donostia, San Sebastián, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Camaño
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: van der Vliet
authors.affiliation: Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Nicol
authors.initials: N
authors.lastname: Voermans
authors.affiliation: Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Baziel G M
authors.initials: BG
authors.lastname: van Engelen
authors.affiliation: Neurosciences, BioDonostia Health Research Institute, Hospital Donostia, San Sebastián, Spain.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Lopez de Munain
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tapscott
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Nienke
authors.initials: N
authors.lastname: van der Stoep
authors.affiliation: Department of Neurology, University of Rochester Medical Center, Rochester, MN, USA.
authors.forename: Rabi
authors.initials: R
authors.lastname: Tawil
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D001483:Base Sequence; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D002894:Chromosomes, Human, Pair 4; D019175:DNA Methylation; D018450:Disease Progression; D005091:Exons; D005260:Female; D015870:Gene Expression; D056426:Genetic Loci; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000145:classification / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype
chemical_list: D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; C578241:SMCHD1 protein, human