Department of Rare Skeletal Disorders, IRCCS Istituto Ortopedico Rizzoli, 40131 Bologna, Italy.
Genes (Basel). 2024 Sep 5;15(9):1169. doi: 10.3390/genes15091169.
Multiple osteochondromas (MO) is an autosomal dominant disorder and the most common genetic skeletal dysplasia, characterized by the growth of bone outgrowths capped by cartilage, called osteochondromas. Most MO cases are caused by mutations in the exostosin-1 () and exostosin-2 () genes. Only 5% of MO-causative variants are represented by single or multiple exon deletions; to date, no pathogenic large duplication has been described in the literature. In the present study, we describe the novel in-tandem intragenic duplication c.(1128_1202)_(1284+29_1344)dup involving exon 4 of (NM_000127.2), detected in a three-generation family with MO. The variant has been detected by MLPA (multiplex ligation-dependent probe amplification) and then confirmed with qPCR (quantitative PCR). Our finding expands the spectrum of MO-causing variants describing a pathogenic large duplication, underlying the importance of quantitative analysis in patients with negative sequencing.
多发性外生骨疣（MO）是一种常染色体显性遗传疾病，也是最常见的遗传性骨骼发育不良，其特征是骨生长突变为软骨覆盖的骨赘，称为外生骨疣。大多数 MO 病例是由外生骨蛋白 1（）和外生骨蛋白 2（）基因突变引起的。只有 5%的 MO 致病变异是由单个或多个外显子缺失引起的；迄今为止，文献中尚未描述致病性大片段重复。在本研究中，我们描述了一种新的基因内串联内含子重复 c.（1128_1202）_（1284+29_1344）dup，涉及 MO 三代表型家族中的外显子 4 （NM_000127.2）。该变体已通过 MLPA（多重连接依赖性探针扩增）检测到，然后通过 qPCR（定量 PCR）进行确认。我们的发现扩展了 MO 致病变异的范围，描述了一种致病性大片段重复，这突显了对测序阴性患者进行定量分析的重要性。
