我们的临床遗传学团队已经跟踪了两个姐妹(16岁和15岁)几年。两个女孩都有严重的智力障碍,低张力,癫痫发作,和独特的颅面特征。父母很健康,没有其他孩子。Oligo阵列,脆性X测试,许多单基因检测结果均为阴性。所有四个家庭成员都接受了研究外显子组测序,揭示了ASXL3中的杂合无义突变(p。R1036X)与疾病隔离。外显子组数据和独立的Sanger测序证实该变体是从头的,表明父母一方可能存在种系镶嵌现象。在健康人群中从未观察到p.R1036X变体,并且先前已报道为致病性突变。截短ASXL3中的从头突变导致Bainbridge-Ropers综合征(BRPS),一种与Bohring-Opitz综合征相似的发育障碍。文献中描述了不到30名BRPS患者;据我们所知,这是两个相关个体的疾病的首次报告。我们的发现为智力残疾提供了进一步的支持,缺席演讲,自闭症特征,低张力,独特的面部外观是Bainbridge-Ropers综合征的常见新兴特征。
Two sisters (ages 16 yr and 15 yr) have been followed by our clinical genetics team for several years. Both girls have severe intellectual disability, hypotonia, seizures, and distinctive craniofacial features. The parents are healthy and have no other children. Oligo array, fragile X testing, and numerous single-gene tests were negative. All four family members underwent research exome sequencing, which revealed a heterozygous nonsense mutation in ASXL3 (p.R1036X) that segregated with disease. Exome data and independent Sanger sequencing confirmed that the variant is de novo, suggesting possible germline mosaicism in one parent. The p.R1036X variant has never been observed in healthy human populations and has been previously reported as a pathogenic mutation. Truncating de novo mutations in ASXL3 cause Bainbridge-Ropers syndrome (BRPS), a developmental disorder with similarities to Bohring-Opitz syndrome. Fewer than 30 BRPS patients have been described in the literature; to our knowledge, this is the first report of the disorder in two related individuals. Our findings lend further support to intellectual disability, absent speech, autistic traits, hypotonia, and distinctive facial appearance as common emerging features of Bainbridge-Ropers syndrome.