Horizontal Gaze Palsy with Progressive Scoliosis‐2 with Impaired Intellectual Development (HGPPS2) is a rare congenital disorder characterized by absence of conjugate horizontal eye movements, and progressive scoliosis developing in childhood and adolescence. We report three new patients with HGPPS2 in a consanguineous Pakistani family, presenting varying degrees of progressive scoliosis, developmental delays, horizontal gaze palsy, agenesis of corpus callosum, and absence of cerebral commissures. Analysis of genotyping data identified shared loss of heterozygosity (LOH) region on chromosomes 5p15.33‐15.31, 6q11.2‐12, and 18q21.1‐21.3. A hypothesis‐free, unbiased exome data analysis detected an insertion of nucleotide A (c.2399dupA) in exon 16 of the DCC gene. The insertion is predicted to cause frameshift p.(Asn800Lysfs*11). Interestingly, DCC gene is present in the LOH region on chromosome 18. Variant (c.2399dupA) in the DCC gene is considered as the most probable candidate variant for HGPPS2 based on the presence of DCC in the LOH region, previously reported role of DCC in HGPPS2, perfect segregation of candidate variant with the disease, prediction of variant pathogenicity, and absence of variant in variation databases. Sanger Sequencing confirmed the presence of the novel homozygous mutation in all three patients; the parents were heterozygous carriers of the mutation, in accordance with an autosomal recessive inheritance pattern. DCC encodes a netrin‐1 receptor protein; its role in the development of the CNS has recently been established. Biallelic DCC mutations have previously been shown to cause HGPPS2. A novel homozygous variant in patients of the reported family extend the genotypic and phenotypic spectrum of HGPPS2.

中文翻译：

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巴基斯坦常染色体隐性水平注视麻痹伴进行性脊柱侧凸-2的巴基斯坦家庭DCC基因中的一种新的纯合移码突变，其智力发育受损

患有智力发展受损的进行性脊柱侧凸2的水平凝视麻痹（HGPPS2）是一种罕见的先天性疾病，其特征是缺乏共轭水平眼运动，并在儿童和青少年期发展为脊柱侧弯。我们报告了巴基斯坦近亲家庭中的三名新的HGPPS2患者，表现出不同程度的进行性脊柱侧弯，发育迟缓，水平凝视麻痹，call体发育不全和缺乏脑连合。分析基因分型鉴定染色体上的杂合（LOH）的区域的共享损失数据的5p15.33-15.31，6q11.2-12，和18q21.1-21.3。无假设，无偏见的外显子组数据分析检测到核苷酸A（c.2399dupA）插入了第16外显子。DCC基因。预计插入会导致移码p。（Asn800Lysfs * 11）。有趣的是，DCC基因存在于LOH区域上18号染色体变异（c.2399dupA）在DCC基因被认为是基于存在下HGPPS2最可能的候选变体DCC在LOH区域，先前报道的作用DCC在HGPPS2中，可以将候选变体与疾病完美隔离，预测变体的致病性，并且在变体数据库中不存在变体。桑格测序证实了三位患者中均存在新的纯合突变；根据常染色体隐性遗传模式，亲本是突变的杂合子携带者。DCC编码netrin-1受体蛋白；它在中枢神经系统发展中的作用最近已经确立。先前已显示双等位基因DCC突变可引起HGPPS2。报道的家族患者中的新型纯合变体扩展了HGPPS2的基因型和表型谱。