Abstract：
Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare, autosomal recessive inherited disorder caused by mutations in ROBO3 gene. The clinical features of HGPPS include horizontal gaze palsy, progressive scoliosis, other oculomotor abnormalities such as strabismus and nystagmus. Whole-exome sequencing (WES) is used to diagnose rare Mendelian disorders, when routine standard tests have failed to make a formal pathological diagnosis. However, WES may identify variants of uncertain significance (VUS) that may add further ambiguity to the diagnosis. We report the case of a 4-year-old boy with horizontal gaze palsy, progressive scoliosis, microcephaly, and mild developmental delay. WES identified an intronic VUS in ROBO3 gene. We performed minigene splicing functional analysis to confirm the pathogenicity of this VUS. This report illustrates that WES data analysis with supportive functional analysis provides an effective approach to improve the diagnostic yield for unsolved clinical cases. This case also highlights the phenotypic heterogeneity in patients with HGPPS.
摘要：
水平凝视麻痹伴进行性脊柱侧凸（HGPPS）是一种罕见的，ROBO3基因突变引起的常染色体隐性遗传障碍。HGPPS的临床特征包括水平凝视麻痹，进行性脊柱侧弯,其他眼球运动异常，如斜视和眼球震颤。全外显子组测序（WES）用于诊断罕见的孟德尔疾病，当常规标准测试未能做出正式的病理诊断时。然而,WES可以识别具有不确定意义的变体(VUS),其可以进一步增加诊断的歧义。我们报告了一个4岁男孩患有水平凝视麻痹的病例，进行性脊柱侧弯,小头畸形,轻度发育迟缓.WES在ROBO3基因中鉴定了内含子VUS。我们进行了小基因剪接功能分析以确认该VUS的致病性。该报告说明，具有支持性功能分析的WES数据分析为提高未解决的临床病例的诊断率提供了有效的方法。该病例还突出了HGPPS患者的表型异质性。
