TY - JOUR
T1 - Hemizygosity for SMCHD1 in Facioscapulohumeral Muscular Dystrophy Type 2
T2 - Consequences for 18p Deletion Syndrome
AU - Lemmers, Richard J.L.F.
AU - van den Boogaard, Marlinde L.
AU - van der Vliet, Patrick J.
AU - Donlin-Smith, Colleen M.
AU - Nations, Sharon P.
AU - Ruivenkamp, Claudia A.L.
AU - Heard, Patricia
AU - Bakker, Bert
AU - Tapscott, Stephen
AU - Cody, Jannine D.
AU - Tawil, Rabi
AU - van der Maarel, Silvère M.
N1 - Publisher Copyright:
© 2015 WILEY PERIODICALS, INC.
PY - 2015/7/1
Y1 - 2015/7/1
N2 - Facioscapulohumeral muscular dystrophy (FSHD) is most often associated with variegated expression in somatic cells of the normally repressed DUX4 gene within the D4Z4-repeat array. The most common form, FSHD1, is caused by a D4Z4-repeat array contraction to a size of 1-10 units (normal range 10-100 units). The less common form, FSHD2, is characterized by D4Z4 CpG hypomethylation and is most often caused by loss-of-function mutations in the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene on chromosome 18p. The chromatin modifier SMCHD1 is necessary to maintain a repressed D4Z4 chromatin state. Here, we describe two FSHD2 families with a 1.2-Mb deletion encompassing the SMCHD1 gene. Numerical aberrations of chromosome 18 are relatively common and the majority of 18p deletion syndrome (18p-) cases have, such as these FSHD2 families, only one copy of SMCHD1. Our finding therefore raises the possibility that 18p- cases are at risk of developing FSHD. To address this possibility, we combined genome-wide array analysis data with D4Z4 CpG methylation and repeat array sizes in individuals with 18p- and conclude that approximately 1:8 18p- cases might be at risk of developing FSHD. FSHD is caused by derepression of the DUX4 gene within the D4Z4 repeat array (11-100 units). In FSHD1 derepression results from a short (1-10 units) D4Z4 array, in FSHD2 by dominant negative or haploinsufficiency mutations in the repressor SMCHD1 in combination with a semi-short (11-25 units) D4Z4 array. We show that SMCHD1 hemizygosity can also result in FSHD2. Hemizygosity for SMCHD1 is also seen in 18p deletion individuals and about 12% of them carry a semi-short D4Z4 array which puts them at risk for FSHD.
AB - Facioscapulohumeral muscular dystrophy (FSHD) is most often associated with variegated expression in somatic cells of the normally repressed DUX4 gene within the D4Z4-repeat array. The most common form, FSHD1, is caused by a D4Z4-repeat array contraction to a size of 1-10 units (normal range 10-100 units). The less common form, FSHD2, is characterized by D4Z4 CpG hypomethylation and is most often caused by loss-of-function mutations in the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene on chromosome 18p. The chromatin modifier SMCHD1 is necessary to maintain a repressed D4Z4 chromatin state. Here, we describe two FSHD2 families with a 1.2-Mb deletion encompassing the SMCHD1 gene. Numerical aberrations of chromosome 18 are relatively common and the majority of 18p deletion syndrome (18p-) cases have, such as these FSHD2 families, only one copy of SMCHD1. Our finding therefore raises the possibility that 18p- cases are at risk of developing FSHD. To address this possibility, we combined genome-wide array analysis data with D4Z4 CpG methylation and repeat array sizes in individuals with 18p- and conclude that approximately 1:8 18p- cases might be at risk of developing FSHD. FSHD is caused by derepression of the DUX4 gene within the D4Z4 repeat array (11-100 units). In FSHD1 derepression results from a short (1-10 units) D4Z4 array, in FSHD2 by dominant negative or haploinsufficiency mutations in the repressor SMCHD1 in combination with a semi-short (11-25 units) D4Z4 array. We show that SMCHD1 hemizygosity can also result in FSHD2. Hemizygosity for SMCHD1 is also seen in 18p deletion individuals and about 12% of them carry a semi-short D4Z4 array which puts them at risk for FSHD.
KW - D4Z4
KW - Epiallele
KW - Epigenetic modifier
KW - FSHD
KW - SMCHD1
UR - http://www.scopus.com/inward/record.url?scp=84931567031&partnerID=8YFLogxK
U2 - 10.1002/humu.22792
DO - 10.1002/humu.22792
M3 - Article
C2 - 25820463
AN - SCOPUS:84931567031
SN - 1059-7794
VL - 36
SP - 679
EP - 683
JO - Human Mutation
JF - Human Mutation
IS - 7
ER -