Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder that is associated with oculocutaneous albinism, bleeding diathesis, granulomatous colitis, and highly penetrant pulmonary fibrosis in some subtypes. Homozygous or compound heterozygous pathological variants in HPS1, HPS3, HPS4, and several other genes lead to clinical manifestation of the disease. A 57-year-old female was admitted with congenital oculocutaneous albinism, thrombocytopathy and late-onset accelerated pulmonary fibrosis (first symptoms from age 50 onwards). Chest high-resolution computed tomography identified thickening of peribronchovascular interstitium, bronchiectasis, reticulations, honeycombing, ground glass opacities and lung parenchyma consolidations. HPS was clinically suspected. We performed whole exome sequencing (WES), a form of massive parallel sequencing, of proband-parents trio. Whole exome libraries were processed using KAPA Hyper Prep Kit, SeqCap EZ MedExome Enrichment Kit and HyperCap Bead Kit according to the SeqCap EZ HyperCap Workflow. The paired-end 2 × 75 bp sequencing was performed on the Illumina NextSeq 500 Sequencer (Illumina Inc., USA). Furthermore, obtained variants by WES were evaluated using a virtual panel of genes: HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, and PLDN. We identified a compound heterozygous genotype in HPS1 gene in the proband. We identified a pathogenic frameshift variant c.1189delC; p.(Gln397Serfs*2), resulting in a premature stop codon. This variant has been previously associated with HPS. Furthermore, we characterized previously undescribed nonsense variant c.1507C > T; p.(Gln503*), resulting in a premature stop codon and mRNA degradation through nonsense-mediated decay. Sanger sequencing validated the presence of both variants and simultaneously confirmed the heterozygous carrier status of parents. Unfortunately, the patient died due to fulminant progression of pulmonary fibrosis 2 months after diagnostics. Compound heterozygous mutations in HPS1 in the proband lead to disruption of HPS1 gene and clinical manifestation of HPS with severe pulmonary fibrosis. This case illustrates the need to consider HPS in differential diagnostics of pulmonary fibrosis. Pulmonary fibrosis is a common cause of death in HPS patients. Earlier diagnosis may enable better treatment for these patients.

中文翻译：

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HPS1基因的新型遗传变异在Hermansky-Pudlak综合征中显着发展为肺纤维化：一例病例报告

Hermansky-Pudlak综合征（HPS）是一种常染色体隐性遗传疾病，与某些亚型的眼皮肤白化病，血液透析，肉芽肿性结肠炎和高渗透性肺纤维化有关。HPS1，HPS3，HPS4和其他几个基因中的纯合子或复合杂合子病理变异体导致该疾病的临床表现。一名57岁的女性因先天性眼部皮肤白化病，血小板减少症和迟发性加速肺纤维化（从50岁开始出现首发症状）而入院。胸部高分辨率计算机断层扫描发现支气管周围血管间质增厚，支气管扩张，网状结构，蜂窝状，毛玻璃样混浊和肺实质合并。临床上怀疑有HPS。我们执行了全外显子组测序（WES），这是大规模并行测序的一种形式，先证者父母三重奏。根据SeqCap EZ HyperCap工作流程，使用KAPA Hyper Prep Kit，SeqCap EZ MedExome富集试剂盒和HyperCap Bead Kit处理整个外显子库。在Illumina NextSeq 500测序仪（Illumina Inc.，美国）上进行配对末端2×75 bp测序。此外，使用虚拟基因组评估了通过WES获得的变体：HPS1，AP3B1，HPS3，HPS4，HPS5，HPS6，DTNBP1，BLOC1S3和PLDN。我们在先证者的HPS1基因中鉴定出复合杂合基因型。我们确定了一个致病的移码变体c.1189delC；p。（Gln397Serfs * 2），导致终止密码子过早。此变体先前已与HPS相关联。此外，我们表征了先前未描述的废话变体c.1507C> T；第（Gln503 *），通过无意义介导的衰变导致过早的终止密码子和mRNA降解。Sanger测序证实了两种变体的存在，同时证实了亲本的杂合子携带者状态。不幸的是，患者在诊断后2个月因肺纤维化的严重进展而死亡。先证者中HPS1中的复合杂合突变会导致HPS1基因的破坏和具有严重肺纤维化的HPS的临床表现。这种情况说明在肺纤维化的鉴别诊断中需要考虑HPS。肺纤维化是HPS患者的常见死亡原因。早期诊断可以为这些患者提供更好的治疗。Sanger测序证实了两种变体的存在，同时证实了亲本的杂合子携带者状态。不幸的是，患者在诊断后2个月因肺纤维化的严重进展而死亡。先证者中HPS1中的复合杂合突变会导致HPS1基因的破坏和具有严重肺纤维化的HPS的临床表现。这种情况说明在肺纤维化的鉴别诊断中需要考虑HPS。肺纤维化是HPS患者的常见死亡原因。早期诊断可以为这些患者提供更好的治疗。Sanger测序证实了两种变体的存在，同时证实了亲本的杂合子携带者状态。不幸的是，患者在诊断后2个月因肺纤维化的严重进展而死亡。先证者中HPS1中的复合杂合突变会导致HPS1基因的破坏和具有严重肺纤维化的HPS的临床表现。这种情况说明在肺纤维化的鉴别诊断中需要考虑HPS。肺纤维化是HPS患者的常见死亡原因。早期诊断可以为这些患者提供更好的治疗。先证者中HPS1中的复合杂合突变会导致HPS1基因的破坏和具有严重肺纤维化的HPS的临床表现。这种情况说明在肺纤维化的鉴别诊断中需要考虑HPS。肺纤维化是HPS患者的常见死亡原因。早期诊断可以为这些患者提供更好的治疗。先证者中HPS1中的复合杂合突变会导致HPS1基因的破坏和具有严重肺纤维化的HPS的临床表现。这种情况说明在肺纤维化的鉴别诊断中需要考虑HPS。肺纤维化是HPS患者的常见死亡原因。早期诊断可以为这些患者提供更好的治疗。