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 functionaffecting 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.

SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome

“…18). In both models, loss of SMCHD1 repressive activity manifests as a decrease in DNA methylation at SMCHD1 binding sites 16,19–21 . Although SMCHD1 interacts with numerous genetic loci, only the 4q35 D4Z4 macrosatellite array, which contains DUX4 , and the highly homologous 10q26 D4Z4 array are associated with FSHD2, and hypomethylation of these two loci is assessed during diagnostic evaluation 22,23 .…”

A family-based study into penetrance in facioscapulohumeral muscular dystrophy type 1

“…2 We observed a moderate but significant (p < 0.01) inverse correlation between the size of the FSHD allele and the agecorrected CSS (figure 4A), confirming previous studies. 17,28 In addition, we observed a great variability of D4Z4 methylation, both within and between families. Some moderately to severely affected carriers (age-corrected CSS >50) of larger FSHD alleles had very low delta1-methylation values ( figure 4B).…”

Novel key roles for structural maintenance of chromosome flexible domain containing 1 (Smchd1) during preimplantation mouse development

“…Whether reduced term development is solely due to compromised blastocyst viability, or is also partly due to gene programming abnormalities arising during cleavage stages with SMCHD1 deficiency is unknown. In humans, SMCHD1 mutations display autosomal dominance, partial penetrance, and variegated effects (Daxinger et al 2015; Lemmers et al 2012; van den Boogaard et al 2016). While studies of effects of Smchd1 mutations in mice reveal lethal developmental defects and effects on DNA methylation across the genome at later stages, more subtle effects have not been explored.…”