摘要目的:观察并分析2个水平注视麻痹伴进行性脊柱侧弯(HGPPS)家系的临床特征和致病基因。方法:采用家系调查研究，纳入2023年11月至2024年4月于河南省儿童医院眼科检查确诊的HGPPS 2个家系各2代3人。详细询问先证者及家系成员病史及家族史，并行视力、屈光度、眼前节、眼压、广角激光扫描眼底照相、光学相干断层扫描、视觉诱发电位(VEP)、视网膜电图(ERG)、眼部B型超声、全脊柱正位＋侧位片、眼眶＋头颅＋颈椎＋胸椎＋腰骶椎磁共振成像(MRI)平扫。采集受试者外周静脉血2 ml，提取全基因组DNA，应用全外显子组测序(WES)技术进行基因测序。对可疑的致病变异位点通过Sanger测序进行验证，并根据ACMG指南致病变异分级标准分析基因变异位点的致病性。结果:家系1先证者男，3岁2个月，6月龄时发现头向左歪，脊柱以T11-12为中心右凸侧弯，VEP和ERG检查未见明显异常；家系2先证者男，3岁4个月，左眼内斜视，脊柱以T12为中心左凸侧弯。2例先证者均出现水平注视麻痹，眼球不能外转，内转轻度受限，左眼上斜视，轻度水平眼球震颤，垂直方向眼球运动正常，大动作发育落后，视力、眼前节及眼底正常；MRI检查均显示延髓呈蝴蝶状，延髓中央可见一处脑干裂隙。基因检测结果显示，家系1先证者 ROBO3基因第7、8号外显子分别存在c.1054delC(p.Gln352Serfs *90)(M1)和c.1219G>T(p.Gly407Cys)(M2)复合杂合变异；先证者父亲携带M1变异，母亲携带M2变异。家系2先证者 ROBO3基因第12、17号外显子分别存在c.1888C>T(p.R630X)(M3)和c.2684C>A(p.A895E)(M4)复合杂合变异；先证者父亲携带M3变异，母亲携带M4变异。M1和M3为可能致病性变异，M2和M4为临床意义未明变异，预测软件预测M2和M4均为有害变异。 结论:2个HGPPS家系均以水平注视麻痹和进行性脊柱侧弯为主要临床特征，伴有眼球震颤和斜视，MRI检查延髓中央有脑干裂隙。本研究新发现4个 ROBO3基因变异，增加了HGPPS的致病变异谱。

abstractsObjective:To observe and analyze the ocular clinical features and pathogenic genes of horizontal gaze palsy with progressive scoliosis (HGPPS).Methods:A pedigree study was conducted.Two families with HGPPS diagnosed by ophthalmology examination at Henan Children's Hospital from November 2023 to April 2024 were included, with 3 people from two generations in each family.Medical history and family history of the subjects were inquired.Vision acuity, diopter, anterior segment, intraocular pressure, wide-angle laser scanning ophthalmoscopy, optical coherence tomography, visual evoked potential (VEP), electroretinogram (ERG), ocular B-ultrasound, full spine AP+ lateral view, orbit+ skull+ cervical spine+ thoracic spine+ lumbosacral spine MRI plain scan were performed on the subjects.Whole genomic DNA was extracted from 2 ml of peripheral venous blood collected from the subjects, and gene sequencing was performed using whole exome sequencing (WES) technology.Suspicious pathogenic variant loci were verified by Sanger sequencing, and the pathogenicity of gene variant loci was analyzed according to the ACMG standards and guidelines for the interpretation of sequence variants.This study followed the Declaration of Helsinki.The study protocol was reviewed and approved by the Ethics Committee of Henan Children's Hospital (No.2024-KY-0024).All subjects and guardians signed informed consent forms and were informed of relevant matters before genetic testing.Results:The proband from family 1 was male, 3 years and 2 months old.At the age of 6 months, he was found to have head tilted to the left with a right scoliosis of the spine centered on T11-12 and no obvious abnormalities on VEP and ERG examinations.The proband from family 2 was male, 3 years and 4 months old, with a left scoliosis of the spine centered on T12.Both probands developed horizontal fixation paralysis, unable to rotate eye outward, slightly limited inward rotation, left eye hypertropia, mild horizontal nystagmus, normal vertical eye movement, backward development of major movements, and normal vision, anterior segment and fundus.MRI examination showed that the medulla oblongata was butterfly shaped, and a brainstem fissure could be seen in the center of the medulla oblongata.The genetic testing showed that the proband from family 1 had compound heterozygous variations c. 1054delC/p.Gln352Serfs *90 (M1) in exon 7 and c. 1219G>T/p.Gly407Cys (M2) in exon 8 of ROBO3 gene.The father of the proband carried M1 and the mother of the proband carried M2.The proband from family 2 had compound heterozygous variations c. 1888C>T/p.R630X (M3) in exon 12 and c. 2684C>A/p.A895E (M4) in exon 17 of ROBO3 gene.M1 and M3 were possible pathogenic, and M2 and M4 were of unknown clinical significance, and prediction software predicted M2 and M4 were harmful variations. Conclusions:The main clinical features of two HGPPS pedigree are horizontal fixation paralysis and progressive scoliosis, accompanied by nystagmus and strabismus.MRI shows brainstem fissure in the central medullary area.Four variants are novel variants, which increases the variation spectrum of ROBO3 gene.