摘要目的:分析2个Hermansky-Pudlak综合征(HPS)家系的基因型及眼部和全身临床表型。方法:采用家系调查研究方法，纳入2020年6月至2021年5月在宁夏回族自治区人民医院就诊的中国汉族和回族HPS家系各1个，收集先证者及其父母的临床资料，父母表型均正常；完善相关眼科及全身检查。采用电子显微镜观察先证者血小板致密颗粒。采集受试者外周静脉血，提取DNA，应用全外显子组测序技术进行致病基因筛查，通过生物信息学分析得到候选致病变异位点。采用Sanger测序进行验证及家系共分离分析，确定致病性变异位点，并探讨HPS相关基因变异与临床特征的关系。结果:家系1和家系2均符合常染色体隐性遗传模式。家系1有近亲结婚家族史，先证者面部皮肤、头发、眉毛、睫毛均无明显色素减退表现，双眼水平眼球震颤，外斜视，轻度视力损伤，虹膜萎缩、透光试验阳性，眼底呈橙色、色素缺失、黄斑发育不良，实验室检查凝血酶原时间延长，电子显微镜检查提示血小板致密颗粒大量减少。家系2先证者头发、眉毛呈棕黄色，重度视力损伤，虹膜色素正常，实验室检查凝血酶时间延长，其余特征与家系1先证者相似。全外显子组测序结果显示，在家系1先证者 HPS3基因上检测到1个新的纯合变异c.2887G>T(p.E963X)。表型正常的父母各携带1个c.2887G>T(p.E963X)杂合变异。家系2先证者 HPS5基因上检测到复合杂合变异：c.2952-2A>C剪接变异和杂合缺失(缺失3 144 bp，位于chr11：18302108-18305251，exon22)。表型正常父母分别携带1个杂合变异。3种变异均为新发变异；根据美国医学遗传学与基因组学学会遗传变异分类标准与指南，均为致病变异。 结论:2个家系分别为HPS-3型和HPS-5型，两型间存在一定的基因型与临床表型对应关系。

abstractsObjective:To analyze the genotypes and clinical phenotypes of two families with Hermansky-Pudlak syndrome (HPS).Methods:The method of pedigree investigation was adopted.A Han Chinese HPS family and a Hui Chinese HPS family were enrolled in People's Hospital of Ningxia Hui Autonomous Region from June 2020 to May 2021.Clinical data of two probands and their phenotypically normal parents were collected.Relevant ocular and systemic examinations were carried out.Platelet dense granules in the two probands were observed with an electron microscope.DNA was extracted from peripheral venous blood collected from the subjects.The pathogenic genes were screened by whole exome sequencing.The potential disease-causing variations were analyzed by bioinformatics analysis.Validation and family cosegregation analysis of the pathogenic variations were performed by Sanger sequencing.The relationship between HPS-related gene variations and clinical characteristics was explored.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Ningxia Eye Hospital, People's Hospital of Ningxia Hui Autonomous Region (No.2016018).Written informed consent was obtained from each subject or custodian before any medical examination.Results:The two families were consistent with autosomal recessive inheritance pattern.In family 1 with a family history of consanguineous marriage, the proband had no obvious hypopigmentation on his facial skin, hair, eyebrows and eyelashes.Horizontal nystagmus, exotropia, mild visual impairment, iris atrophy, positive light transmission, orange fundus, pigment loss, macular hypoplasia, prolonged prothrombin time in laboratory examination, and a significant reduction of platelet dense granules by electron microscopy were observed.The proband in family 2 had pale brown hair and eyebrows, severe visual impairment, normal iris pigment, longer thrombin time in laboratory tests, and characteristics similar to those of the proband in family 1.A novel homozygous variant c. 2887G>T (p.E963X) was detected in the HPS3 gene of the proband in family 1.The parents of the proband from family 1 both carried a heterozygous variant c.2887G>T (p.E963X).Compound heterozygous variants were detected in HPS5 gene of the proband in family 2, c.2952-2A>C splicing variation and heterozygous deletion (a 3 144-bp deletion, located in chr11: 18302108-18305251, exon 22).The parents of the proband from family 2 carried a heterozygous variation.The three novel variations were labeled as pathogenic according to the ACMG standards and guidelines. Conclusions:Family 1 is with HPS-3 and family 2 is with HPS-5.There is a certain genotype-phenotype correspondence in the two types of HPS.