Kohmoto Tomohiro, Naruto Takuya, Watanabe Miki, Fujita Yuji, Ujiro Sae, Okamoto Nana, Horikawa Hideaki, Masuda Kiyoshi, Imoto Issei
Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
Am J Med Genet A. 2017 Apr;173(4):1082-1086. doi: 10.1002/ajmg.a.38122.
Mesomelia-synostoses syndrome (MSS) is a rare, autosomal-dominant, syndromal osteochondrodysplasia characterized by mesomelic limb shortening, acral synostoses, and multiple congenital malformations due to a non-recurrent deletion at 8q13 that always encompasses two coding-genes, SULF1 and SLCO5A1. To date, five unrelated patients have been reported worldwide, and MMS was previously proposed to not be a genomic disorder associated with deletions recurring from non-allelic homologous recombination (NAHR) in at least two analyzed cases. We conducted targeted gene panel sequencing and subsequent array-based copy number analysis in an 11-year-old undiagnosed Japanese female patient with multiple congenital anomalies that included mesomelic limb shortening and detected a novel 590 Kb deletion at 8q13 encompassing the same gene set as reported previously, resulting in the diagnosis of MSS. Breakpoint sequences of the deleted region in our case demonstrated the first LINE-1s (L1s)-mediated unequal NAHR event utilizing two distant L1 elements as homology substrates in this disease, which may represent a novel causative mechanism of the 8q13 deletion, expanding the range of mechanisms involved in the chromosomal rearrangements responsible for MSS.
中肢-关节强直综合征（MSS）是一种罕见的常染色体显性遗传性综合征性骨软骨发育不良，其特征为中肢肢体缩短、肢端关节强直，以及由于8q13处的非重复性缺失导致的多种先天性畸形，该缺失总是包含两个编码基因SULF1和SLCO5A1。迄今为止，全球已报道了5例无亲缘关系的患者，并且在至少两例分析病例中，先前曾提出MSS不是与非等位基因同源重组（NAHR）反复出现的缺失相关的基因组疾病。我们对一名11岁未确诊的日本女性患者进行了靶向基因panel测序及随后基于阵列的拷贝数分析，该患者有多种先天性异常，包括中肢肢体缩短，并在8q13处检测到一个新的590 Kb缺失，其包含与先前报道相同的基因集，从而确诊为MSS。我们病例中缺失区域的断点序列显示，在该疾病中首次出现了利用两个远距离L1元件作为同源底物的LINE-1s（L1s）介导的不等位NAHR事件，这可能代表了8q13缺失的一种新的致病机制，扩大了导致MSS的染色体重排所涉及的机制范围。
