Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
Am J Med Genet A. 2018 Dec;176(12):2819-2823. doi: 10.1002/ajmg.a.40514. Epub 2018 Oct 4.
Heřmanský-Pudlák syndrome (HPS), a rare autosomal recessive disorder, manifests with oculocutaneous albinism and a bleeding diathesis. However, severity of disease can be variable and is typically related to the genetic subtype of HPS; HPS type 6 (HPS-6) is an uncommon subtype generally associated with mild disease. A Caucasian adult female presented with a history of severe bleeding; ophthalmologic examination indicated occult oculocutaneous albinism. The patient was diagnosed with a platelet storage pool disorder, and platelet whole mount electron microscopy demonstrated absent delta granules. Genome-wide SNP analysis showed regions of homozygosity that included the HPS1 and HPS6 genes. Full length HPS1 transcript was amplified by PCR of genomic DNA. Targeted next-generation sequencing identified a novel homozygous missense variant in HPS6 (c.383 T > C; p.V128A); this was associated with significantly reduced HPS6 mRNA and protein expression in the patient's fibroblasts compared to control cells. These findings highlight the variable severity of disease manifestations in patients with HPS, and illustrate that HPS can be diagnosed in patients with excessive bleeding and occult oculocutaneous albinism. Genetic analysis and platelet electron microscopy are useful diagnostic tests in evaluating patients with suspected HPS. Clinical Trial registration: Registrar: ClinicalTrials.gov Website: www.clinicaltrials.gov Registration Numbers: NCT00001456 and NCT00084305.
赫曼斯基-普达拉克综合征（HPS）是一种罕见的常染色体隐性遗传病，表现为眼皮肤白化病和出血倾向。然而，疾病的严重程度可能存在差异，通常与 HPS 的遗传亚型有关；HPS 型 6（HPS-6）是一种不常见的亚型，通常与轻度疾病相关。一名白人成年女性因严重出血史就诊；眼科检查显示隐匿性眼皮肤白化病。该患者被诊断为血小板贮存池缺陷，血小板整体电子显微镜检查显示δ颗粒缺失。全基因组 SNP 分析显示存在包括 HPS1 和 HPS6 基因在内的纯合区域。通过对基因组 DNA 的 PCR 扩增全长 HPS1 转录本。靶向下一代测序鉴定了 HPS6 中的一种新型纯合错义变异（c.383T>C;p.V128A）；与对照细胞相比，该变异与患者成纤维细胞中 HPS6 mRNA 和蛋白表达显著降低相关。这些发现强调了 HPS 患者疾病表现严重程度的可变性，并表明 HPS 可以在有过度出血和隐匿性眼皮肤白化病的患者中诊断。遗传分析和血小板电子显微镜检查是评估疑似 HPS 患者的有用诊断测试。临床试验注册：注册机构：ClinicalTrials.gov 网站：www.clinicaltrials.gov 注册编号：NCT00001456 和 NCT00084305。
