Genetic and Metabolic Central Laboratory, Guangxi Birth Defects Research and Prevention Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
Guangxi Clinical Research Center for Pediatric Diseases, Guangxi Key Laboratory of Reproductive Health and Birth Defects Prevention, Guangxi Key Laboratory of Precision Medicine for Genetic Diseases, Guangxi Key Laboratory of Birth Defects and Stem Cell Biobank, Guangxi Key Laboratory of Birth Defects Research and Prevention, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
Mol Genet Genomic Med. 2023 Sep;11(9):e2215. doi: 10.1002/mgg3.2215. Epub 2023 Jun 18.
Homozygous or compound heterozygous ROBO3 gene mutations cause horizontal gaze palsy with progressive scoliosis (HGPPS). This is an autosomal recessive disorder that is characterized by congenital absence or severe restriction of horizontal gaze and progressive scoliosis. To date, almost 100 patients with HGPPS have been reported and 55 ROBO3 mutations have been identified.
We described an HGPPS patient and performed whole-exome sequencing (WES) to identify the causative gene.
We identified a missense variant and a splice-site variant in the ROBO3 gene in the proband. Sanger sequencing of cDNA revealed the presence of an aberrant transcript with retention of 700 bp from intron 17, which was caused by a variation in the noncanonical splicing site. We identified five additional ROBO3 variants, which were likely pathogenic, and estimated the overall allele frequency in the southern Chinese population to be 9.44 × 10 , by a review of our in-house database.
This study has broadened the mutation spectrum of the ROBO3 gene and has expanded our knowledge of variants in noncanonical splicing sites. The results could help to provide more accurate genetic counseling to affected families and prospective couples. We suggest that the ROBO3 gene should be included in the local screening strategy.
ROBO3 基因纯合或复合杂合突变导致水平眼球麻痹伴进行性脊柱侧弯（HGPPS）。这是一种常染色体隐性疾病，其特征为先天性水平眼球缺失或严重受限以及进行性脊柱侧弯。迄今为止，已有近 100 例 HGPPS 患者被报道，发现了 55 种 ROBO3 突变。
我们描述了一名 HGPPS 患者，并进行了全外显子组测序（WES）以鉴定致病基因。
我们在先证者的 ROBO3 基因中发现了一个错义变异和一个剪接位点变异。cDNA 的 Sanger 测序显示存在一个异常转录本，其中包含来自内含子 17 的 700bp 的保留，这是由非规范剪接位点的变异引起的。我们鉴定了另外五个可能致病的 ROBO3 变体，并通过对我们内部数据库的回顾，估计南方中国人中该变体的总体等位基因频率为 9.44×10-5。
本研究拓宽了 ROBO3 基因的突变谱，并扩展了我们对非规范剪接位点变异的认识。这些结果有助于为受影响的家庭和潜在夫妇提供更准确的遗传咨询。我们建议将 ROBO3 基因纳入当地的筛查策略中。
