Cis D4Z4 repeat duplications associated with facioscapulohumeral muscular dystrophy type 2. (22nd June 2018)

• Record Type: Journal Article
• Authors: Lemmers, Richard J L F; van der Vliet, Patrick J; Vreijling, Jeroen P; Henderson, Don; van der Stoep, Nienke; Voermans, Nicol; van Engelen, Baziel; Baas, Frank; Sacconi, Sabrina; Tawil, Rabi; van der Maarel, Silvère M
• Is Part Of: Human molecular genetics. Volume 27:Number 20(2018:Oct. 15)
• Page Start: 3488
• Page End: 3497
• Publication Date: 2018-06-22
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddy236
• Languages: English
• ISSNs: 0964-6906

Abstract

Abstract: Facioscapulohumeral muscular dystrophy, known in genetic forms FSHD1 and FSHD2, is associated with D4Z4 repeat array chromatin relaxation and somatic derepression of DUX4 located in D4Z4. A complete copy of DUX4 is present on 4qA chromosomes, but not on the D4Z4-like repeats of chromosomes 4qB or 10. Normally, the D4Z4 repeat varies between 8 and 100 units, while in FSHD1 it is only 1–10 units. In the rare genetic form FSHD2, a combination of a 4qA allele with a D4Z4 repeat size of 8–20 units and heterozygous pathogenic variants in the chromatin modifier SMCHD1 causes DUX4 derepression and disease. In this study, we identified 11/79 (14%) FSHD2 patients with unusually large 4qA alleles of 21–70 D4Z4 units. By a combination of Southern blotting and molecular combing, we show that 8/11 (73%) of these unusually large 4qA alleles represent duplication alleles in which the long D4Z4 repeat arrays are followed by a small FSHD-sized D4Z4 repeat array duplication. We also show that these duplication alleles are associated with DUX4 expression. This duplication allele frequency is significantly higher than in controls (2.9%), FSHD1 patients (1.4%) and in FSHD2 patients with typical 4qA alleles of 8–20 D4Z4 units (1.5%). Segregation analysis shows that, similar to typical 8–20 units FSHD2 alleles, duplication alleles only cause FSHD in combination with a pathogenic variant in SMCHD1 . We conclude that cis duplications of D4Z4 repeats explain DUX4 expression and disease presentation in FSHD2 families with unusual long D4Z4 repeats on 4qA chromosomes.