Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Department of Neurology and Psychiatry, Rare Neuromuscular Diseases Center, Sapienza University of Rome, Rome, Italy.
J Med Genet. 2018 Jul;55(7):469-478. doi: 10.1136/jmedgenet-2017-105153. Epub 2018 Mar 21.
18p deletion syndrome is a rare disorder caused by partial or full monosomy of the short arm of chromosome 18. Clinical symptoms caused by 18p hemizygosity include cognitive impairment, mild facial dysmorphism, strabismus and ptosis. Among other genes, structural maintenance of chromosomes flexible hinge domain containing 1 () is hemizygous in most patients with 18p deletions. Digenic inheritance of a mutation and a moderately sized D4Z4 repeat on a facioscapulohumeral muscular dystrophy (FSHD) permissive genetic background of chromosome 4 can cause FSHD type 2 (FSHD2).
Since 12% of Caucasian individuals harbour moderately sized D4Z4 repeats on an FSHD permissive background, we tested if people with 18p deletions are at risk of developing FSHD.
To test our hypothesis we studied different cellular systems originating from individuals with 18p deletions not presenting FSHD2 phenotype for transcriptional and epigenetic characteristics of FSHD at D4Z4. Furthermore, individuals with an idiopathic muscle phenotype and an 18p deletion were subjected to neurological examination.
Primary fibroblasts hemizygous for have a D4Z4 chromatin structure comparable with FSHD2 concomitant with DUX4 expression after transdifferentiation into myocytes. Neurological examination of 18p deletion individuals from two independent families with a moderately sized D4Z4 repeat identified muscle features compatible with FSHD.
18p deletions leading to haploinsufficiency of , together with a moderately sized FSHD permissive D4Z4 allele, can associate with symptoms and molecular features of FSHD. We propose that patients with 18p deletion should be characterised for their D4Z4 repeat size and haplotype and monitored for clinical features of FSHD.
18p 缺失综合征是一种由 18 号染色体短臂部分或全部单体性缺失引起的罕见疾病。18p 杂合性缺失引起的临床症状包括认知障碍、轻度面型异常、斜视和上睑下垂。在其他基因中，结构维持染色体柔性铰链结构域包含 1 （）在大多数 18p 缺失患者中呈杂合性。一个 突变和一个中等大小的 D4Z4 重复在一个面肩肱型肌营养不良症（FSHD）的允许遗传背景染色体 4 上的双基因遗传可以导致 FSHD 型 2（FSHD2）。
由于 12%的白种人在 FSHD 允许的背景下携带中等大小的 D4Z4 重复，我们测试了 18p 缺失的人是否有患 FSHD 的风险。
为了验证我们的假设，我们研究了来自没有 FSHD2 表型的 18p 缺失个体的不同细胞系统，以研究 D4Z4 处 FSHD 的转录和表观遗传特征。此外，还对具有特发性肌肉表型和 18p 缺失的个体进行了神经学检查。
18p 缺失导致 半合子的个体，其 D4Z4 染色质结构与 FSHD2 相媲美，并且在分化为肌细胞后表达 DUX4。对来自两个具有中等大小 D4Z4 重复的 18p 缺失个体的独立家族的神经学检查鉴定出与 FSHD 相兼容的肌肉特征。
导致 单倍不足，以及一个中等大小的 FSHD 允许的 D4Z4 等位基因的 18p 缺失，可以与 FSHD 的症状和分子特征相关。我们建议 18p 缺失的患者应根据其 D4Z4 重复大小和单倍型进行特征描述，并监测 FSHD 的临床特征。
