Lemmers, Richard JLF; Butterfield, Russell; van der Vliet, Patrick J; de Bleecker, Jan L; van der Pol, Ludo; Dunn, Diane M; Erasmus, Corrie E; ... van der Maarel, Silvère M; + view all Lemmers, Richard JLF; Butterfield, Russell; van der Vliet, Patrick J; de Bleecker, Jan L; van der Pol, Ludo; Dunn, Diane M; Erasmus, Corrie E; D'Hooghe, Marc; Verhoeven, Kristof; Balog, Judit; Bigot, Anne; van Engelen, Baziel; Statland, Jeffrey; Bugiardini, Enrico; van der Stoep, Nienke; Evangelista, Teresinha; Marini-Bettolo, Chiara; van den Bergh, Peter; Tawil, Rabi; Voermans, Nicol C; Vissing, John; Weiss, Robert B; van der Maarel, Silvère M; - view fewer (2023) Autosomal dominant in cis D4Z4 repeat array duplication alleles in facioscapulohumeral dystrophy. Brain awad312. 10.1093/brain/awad312.

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Abstract

Facioscapulohumeral dystrophy (FSHD) has a unique genetic etiology resulting in partial chromatin relaxation of the D4Z4 macrosatellite repeat array on 4qter. This D4Z4 chromatin relaxation facilitates inappropriate expression of the transcription factor DUX4 in skeletal muscle. DUX4 is encoded by a retrogene which is embedded within the distal region of the D4Z4 repeat array. In the European population, the D4Z4 repeat array is usually organized in a single array that ranges between 8-100 units. D4Z4 chromatin relaxation and DUX4 derepression in FSHD is most often caused by repeat array contraction to 1-10 units (FSHD1) or by a digenic mechanism requiring pathogenic variants in a D4Z4 chromatin repressor like SMCHD1, combined with a repeat array between 8-20 units (FSHD2). With a prevalence of 1.5% in the European population, in cis duplications of the D4Z4 repeat array, where two adjacent D4Z4 arrays are interrupted by a spacer sequence, are relatively common but their relationship to FSHD is not well understood. In cis duplication alleles were shown to be pathogenic in FSHD2 patients, however, there is inconsistent evidence for the necessity of an SMCHD1 mutation for disease development. To explore the pathogenic nature of these alleles we compared in cis duplication alleles in FSHD patients with or without pathogenic SMCHD1 variant. For both groups we showed duplication-allele-specific DUX4 expression. We studied these alleles in detail using pulsed-field gel electrophoresis-based Southern blotting and molecular combing, emphasizing the challenges in the characterization of these rearrangements. Nanopore sequencing was instrumental to study the composition and methylation of the duplicated D4Z4 repeat arrays and to identify the breakpoints and the spacer sequence between the arrays. By comparing the composition of the D4Z4 repeat array of in cis duplication alleles in both groups, we found that specific combinations of proximal and distal repeat array sizes determine their pathogenicity. Supported by our algorithm to predict pathogenicity, diagnostic laboratories should now be furnished to accurately interpret these in cis D4Z4 repeat array duplications, alleles which can easily be missed in routine settings.

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