TY - JOUR
T1 - Autosomal dominant in cis D4Z4 repeat array duplication alleles in facioscapulohumeral dystrophy
AU - Lemmers, Richard J L F
AU - Butterfield, Russell
AU - van der Vliet, Patrick J
AU - de Bleecker, Jan L
AU - van der Pol, Ludo
AU - Dunn, Diane M
AU - Erasmus, Corrie E
AU - D'Hooghe, Marc
AU - Verhoeven, Kristof
AU - Balog, Judit
AU - Bigot, Anne
AU - van Engelen, Baziel
AU - Statland, Jeffrey
AU - Bugiardini, Enrico
AU - van der Stoep, Nienke
AU - Evangelista, Teresinha
AU - Marini-Bettolo, Chiara
AU - van den Bergh, Peter
AU - Tawil, Rabi
AU - Voermans, Nicol C
AU - Vissing, John
AU - Weiss, Robert B
AU - van der Maarel, Silvère M
N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2024/2/1
Y1 - 2024/2/1
N2 - Facioscapulohumeral dystrophy (FSHD) has a unique genetic aetiology 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 that 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 and 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 and 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 that can easily be missed in routine settings.
AB - Facioscapulohumeral dystrophy (FSHD) has a unique genetic aetiology 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 that 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 and 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 and 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 that can easily be missed in routine settings.
KW - Alleles
KW - Chromatin
KW - Chromosomal Proteins, Non-Histone/genetics
KW - Homeodomain Proteins/genetics
KW - Humans
KW - Muscular Dystrophy, Facioscapulohumeral/genetics
KW - D4Z4
KW - facioscapulohumeral muscular dystrophy
KW - FSHD
KW - duplications
KW - DUX4
UR - http://www.scopus.com/inward/record.url?scp=85184024951&partnerID=8YFLogxK
U2 - 10.1093/brain/awad312
DO - 10.1093/brain/awad312
M3 - Journal article
C2 - 37703328
SN - 0006-8950
VL - 147
SP - 414
EP - 426
JO - Brain : a journal of neurology
JF - Brain : a journal of neurology
IS - 2
ER -