Phenotypic and Genotypic Study of Patients with Hermansky- Pudlak Syndrome


Hermansky-Pudlak syndrome (HPS) represents a group of autosomal recessive disorders due to mutations in genes involved in oculocutaneous albinism and bleeding diathesis. There are 10 genetic subtypes of HPS: type 1 (due to mutations in HPS1), type 2 (AP3B1), type 3 (HPS3), type 4 (HPS4), type 5 (HPS5), type 6 (HPS6), type 7 (DTNBP1), type 8 (BLOC1S3), type 9 (BLOC1S6), and type 10 (AP3D1). Eventually all patients with HPS1, 2 and 4 develop pulmonary fibrosis and may require lung transplant. Since severe platelet dense granule deficiency is considered a characteristic feature of of HPS, platelet whole mount transmission electron microscopy (PTEM) has been considered a good initial screening test. Potential HPS positive cases detected by PTEM still need to be confirmed and further classified by genetic testing. The goal of this study is to assess the HPS gene mutation status of the
PTEM identified HPS cases in our institution.


Nine patients with PTEM documented severe dense granule deficiencies and one patient with ocular albinism but normal dense granules by PTEM were included in this study. Next Generation Sequencing (NGS) was performed using a targeted panel (Agilent Technologies) encompassing 9 of the HPS genes (HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, and BLOC1S6). DNA library preparation was performed using the SureSelectXT Target Enrichment System for Illumina Paired-End Multiplexed Sequencing Library (Agilent Technologies). The enriched
indexed DNA sample was then sequenced on an Illumina MiSeq or HiSeq 2500 platform. The CLC Bio Genomics Server was used for sequence alignment and variant calling, which was then uploaded into NGS Workbench (Mayo Clinic) for review. All sequence variants were classified following the current American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines.


All 10 patients had oculocutaneous albinism and bleeding diathesis (age range 8-80 years, 3
male). The average mean dense granules/plt of the 9 PTEM positive patients was less than 0.1 (normal range >1.2). Pathogenic mutations were found in all 9 PTEM positive patients, HPS1 (n=5), HPS3 (n=2), HPS5 (n=1) and HPS6 (n=1). These included both reported (n=5) and novel mutations (n=4). No pathogenic mutations were found in the
patient with ocular albinism but negative PTEM findings.


An algorithmic approach of employing both PTEM and genetic testing can accurately identify and classify Hermansky-Pudlak syndrome to assist clinical management in such patients. The late diagnosis of many HPS patients in this cohort underscores the importance of availability of both PTEM and molecular genetic testing in clinical laboratories.

J.A. Majerus, L.M. Coon, R.K. Pruthi, R. He, D.M. Warad, D. Chen
Mayo Clinic, Rochester, MN.

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