背景:Hermansky-Pudlak综合征(HPS)是一种罕见的常染色体隐性遗传疾病,其特征是眼白化病(OA)或眼皮肤白化病(OCA),血小板功能障碍,和其他症状。本研究旨在分析两个疑似OA的中国家庭的分子缺陷,以及调查HPS6变体的概况及其基因型-表型相关性。
方法:招募了来自两个家庭的7名成员,并接受了临床眼科检查。从外周血白细胞中提取基因组DNA。对JX家族的先证者进行全外显子组测序。在所有可用的家族成员中,基于PCR扩增直接对HPS6的单编码外显子进行Sanger测序。回顾了文献中报道的具有HPS6致病变体的家族或散发性病例的另外46位先证者。
结果:我们在两个独立家族的疑似OA先证者中鉴定了两种不同的HPS6复合杂合截短变体。JX家族的先证者有c.1674dup和c.503-504del变体,CZ家族的另一个先证者有c.1114C>T的无意义变体和c.1556del的移码变体。其中,以前没有报道过HPS6中的c.1674dup和c.1556del变体。因此,我们的患者通过分子诊断被诊断为HPS6病.在HPS6患者的回顾性队列中,我们描绘了HPS6变异体的谱,揭示了CpG岛和HPS6变异体之间的显著重叠,提示DNA甲基化和HPS6变异体之间存在潜在的联系.我们还观察到HPS6蛋白3D结构中变体的空间聚集,暗示这些结构区域可能的功能意义。此外,我们没有发现HPS6的任何显著的基因型-表型相关性,我们也没有观察到HPS6蛋白截短长度与HPS6疾病表型之间的相关性.
结论:我们的研究扩展了HPS6变体的范围,提供了它们的概况的全面描述,并系统地研究了HPS6中的基因型-表型相关性。这些发现可能为研究HPS6发病机制提供潜在的有价值的线索。以及辅助HPS6患者的临床诊断和改善疾病预后。
BACKGROUND: Hermansky-Pudlak syndrome (HPS) is a rare autosomal-recessive disease characterized by ocular albinism (OA) or oculocutaneous albinism (OCA), platelet dysfunction, and other symptoms. This study aimed to analyze the molecular defect in two Chinese families with suspected OA, as well as to investigate the profile of HPS6 variants and their genotype-phenotype correlations.
METHODS: Seven members from two families were recruited and underwent clinical ophthalmologic examinations. The genomic DNA was extracted from peripheral blood leukocytes. Whole-exome sequencing was performed on the proband of family JX. The single coding exon of HPS6 was directly Sanger sequenced based on PCR amplification in all available family members. An additional 46 probands from families or sporadic cases with the pathogenic variants of HPS6 reported in the literature were reviewed.
RESULTS: We identified two different compound heterozygous truncating variants of HPS6 in probands with suspected OA from two independent families. The proband of family JX had c.1674dup and c.503-504del variants, and the other proband from family CZ had a nonsense variant of c.1114C>T and a frameshift variant of c.1556del. Among them, c.1674dup and c.1556del variants in HPS6 have not been reported previously. Therefore, our patients were diagnosed as HPS6 disease by molecular diagnostics. In the retrospective cohort of HPS6 patients, we delineated the profile of HPS6 variants and revealed a significant overlap between CpG islands and the variants of HPS6, suggesting a potential link between DNA methylation and HPS6 variants. We also observed a spatial aggregation of the variants in 3D structure of HPS6 protein, implying the possible functional significance of these structural regions. In addition, we did not find any significant genotype-phenotype correlation of HPS6, and neither did we observe a correlation between the truncation length of the HPS6 protein and the phenotype of HPS6 disease.
CONCLUSIONS: Our research expands the spectrum of HPS6 variants, providing a comprehensive delineation of their profile and systematically investigating genotype-phenotype correlations in HPS6. These findings could offer potentially valuable clues for investigating the molecular mechanism underlying HPS6 pathogenesis, as well as aiding the clinical diagnosis of HPS6 patients and improving disease prognosis.