Porsch Robert M, Merello Elisa, De Marco Patrizia, Cheng Guo, Rodriguez Laura, So Manting, Sham Pak C, Tam Paul K, Capra Valeria, Cherny Stacey S, Garcia-Barcelo Maria-Mercè, Campbell Desmond D
Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR.
Istituto Giannina Gaslini, Genoa, Italy.
BMC Med Genet. 2016 Dec 22;17(1):98. doi: 10.1186/s12881-016-0359-2.
Caudal regression syndrome (CRS) or sacral agenesis is a rare congenital disorder characterized by a constellation of congenital caudal anomalies affecting the caudal spine and spinal cord, the hindgut, the urogenital system, and the lower limbs. CRS is a complex condition, attributed to an abnormal development of the caudal mesoderm, likely caused by the effect of interacting genetic and environmental factors. A well-known risk factor is maternal type 1 diabetes.
Whole exome sequencing and copy number variation (CNV) analyses were conducted on 4 Caucasian trios to identify de novo and inherited rare mutations.
In this pilot study, exome sequencing and copy number variation (CNV) analyses implicate a number of candidate genes, including SPTBN5, MORN1, ZNF330, CLTCL1 and PDZD2. De novo mutations were found in SPTBN5, MORN1 and ZNF330 and inherited predicted damaging mutations in PDZD2 (homozygous) and CLTCL1 (compound heterozygous). Importantly, predicted damaging mutations in PTEN (heterozygous), in its direct regulator GLTSCR2 (compound heterozygous) and in VANGL1 (heterozygous) were identified. These genes had previously been linked with the CRS phenotype. Two CNV deletions, one de novo (chr3q13.13) and one homozygous (chr8p23.2), were detected in one of our CRS patients. These deletions overlapped with CNVs previously reported in patients with similar phenotype.
Despite the genetic diversity and the complexity of the phenotype, this pilot study identified genetic features common across CRS patients.
尾椎退化综合征（CRS）或骶骨发育不全是一种罕见的先天性疾病，其特征是一系列影响尾椎和脊髓、后肠、泌尿生殖系统及下肢的先天性尾端异常。CRS是一种复杂病症，归因于尾端中胚层的异常发育，可能是由相互作用的遗传和环境因素所致。一个众所周知的风险因素是母亲患1型糖尿病。
对4个白种人三联体进行全外显子组测序和拷贝数变异（CNV）分析，以鉴定新生和遗传的罕见突变。
在这项初步研究中，外显子组测序和拷贝数变异（CNV）分析涉及多个候选基因，包括SPTBN5、MORN1、ZNF330、CLTCL1和PDZD2。在SPTBN5、MORN1和ZNF330中发现了新生突变，在PDZD2（纯合子）和CLTCL1（复合杂合子）中发现了遗传的预测有害突变。重要的是，在PTEN（杂合子）、其直接调节因子GLTSCR2（复合杂合子）和VANGL1（杂合子）中鉴定出预测有害突变。这些基因先前已与CRS表型相关联。在我们的一名CRS患者中检测到两个CNV缺失，一个是新生的（3号染色体q13.13），一个是纯合的（8号染色体p23.2）。这些缺失与先前在具有相似表型的患者中报道的CNV重叠。
尽管表型存在遗传多样性和复杂性，但这项初步研究确定了CRS患者共有的遗传特征。
