Lecointre Claire, Pichon Olivier, Hamel Antoine, Heloury Yves, Michel-Calemard Laurence, Morel Yves, David Albert, Le Caignec Cédric
CHU Nantes, Service de Génétique Médicale, Nantes, France.
Am J Med Genet A. 2009 Jun;149A(6):1183-9. doi: 10.1002/ajmg.a.32830.
Campomelic dysplasia (CD) is a rare autosomal dominant osteochondrodysplasia with or without XY disorders of sexual development (DSD). Campomelia is absent in about 10% of the cases, referred to as the acampomelic form of CD (ACD). Most CDs are caused by mutations within the SOX9 coding region. Several CD patients with balanced chromosome rearrangements involving the 17q24 region have been reported suggesting the presence of cis-regulatory elements upstream and/or downstream of the gene. Deletions upstream of SOX9 represent a third mechanism of mutation. To date, a 1.5 Mb de novo deletion in the SOX9 upstream region has been identified in a single 46,XY patient with ACD and DSD. We report here for the first time on a familial ACD caused by an inherited deletion mapping upstream of the SOX9 gene. Using high-density oligoarray comparative genomic hybridization (CGH), we showed that the size of the deletion was 960 kb in the XY-DSD child and her mother, both affected. The deletion lying from 517 kb to 1.477 Mb upstream of SOX9 remove several highly conserved elements and reduce the minimum critical size and therefore the number of highly conserved sequence elements responsible for ACD.
弯肢侏儒症（CD）是一种罕见的常染色体显性骨软骨发育不良症，伴有或不伴有性发育异常（DSD）的XY个体。约10%的病例不存在弯肢症状，称为无弯肢型CD（ACD）。大多数CD病例是由SOX9编码区域内的突变引起的。已有数例涉及17q24区域平衡染色体重排的CD患者报道，提示该基因上下游存在顺式调控元件。SOX9上游的缺失是第三种突变机制。迄今为止，在一名患有ACD和DSD的46,XY患者中发现了SOX9上游区域1.5 Mb的新发缺失。我们首次报道了由SOX9基因上游遗传性缺失导致的家族性ACD。使用高密度寡核苷酸阵列比较基因组杂交（CGH），我们发现XY-DSD患儿及其受影响的母亲的缺失大小为960 kb。该缺失位于SOX9上游517 kb至1.477 Mb处，移除了几个高度保守的元件，减小了最小关键尺寸，从而减少了导致ACD的高度保守序列元件的数量。
