{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T16:37:40Z","timestamp":1785688660547,"version":"3.56.0"},"reference-count":30,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T00:00:00Z","timestamp":1672876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004054","name":"Institutional fund Projects","doi-asserted-by":"publisher","award":["IFPIP-1749-141-1443"],"award-info":[{"award-number":["IFPIP-1749-141-1443"]}],"id":[{"id":"10.13039\/501100004054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Hermansky\u2013Pudlak syndrome (HSP) was first reported in 1959 as oculocutaneous albinism with bleeding abnormalities, and now consists of 11 distinct heterogenic genetic disorders that are caused by mutations in four protein complexes: AP-3, BLOC1, BLOC2, and BLOC3. Most of the patients show albinism and a bleeding diathesis; additional features may present depending on the nature of a defective protein complex. The subtypes 3 and 4 have been known for mutations in HSP3 and HSP4 genes, respectively. Methods: In this study, two Pakhtun consanguineous families, ALB-09 and ALB-10, were enrolled for clinical and molecular diagnoses. Whole-exome sequencing (WES) of the index patient in each family followed by Sanger sequencing of all available samples was performed using 3Billion. Inc South Korea rare disease diagnostics services. Results: The affected individuals of families ALB-09 and ALB-10 showed typical phenotypes of HPS such as oculocutaneous albinism, poor vision, nystagmus, nystagmus-induced involuntary head nodding, bleeding diathesis, and enterocolitis; however, immune system weakness was not recorded. WES analyses of one index patient revealed a novel nonsense variant (NM_032383.4: HSP3; c.2766T &gt; G) in family ALB-09 and a five bp deletion (NM_001349900.2: HSP4; c.1180_1184delGTTCC) variant in family ALB-10. Sanger sequencing confirmed homozygous segregation of the disease alleles in all affected individuals of the respective family. Conclusions: The substitution c.2766T &gt; G creates a premature protein termination at codon 922 in HPS3, replacing tyrosine amino acid with a stop codon (p.Tyr922Ter), while the deletion mutation c.1180_1184delGTTCC leads to a reading frameshift and a premature termination codon adding 23 abnormal amino acids to HSP4 protein (p:Val394Pro395fsTer23). To the best of our knowledge, the two novel variants identified in HPS3 and HPS4 genes causing Hermansky\u2013Pudlak syndrome are the first report from the Pakhtun Pakistani population. Our work expands the pathogenic spectrum of HPS3 and HPS4 genes, provides successful molecular diagnostics, and helps the families in genetic counselling and reducing the disease burden in their future generations.<\/jats:p>","DOI":"10.3390\/genes14010145","type":"journal-article","created":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T04:12:56Z","timestamp":1672891976000},"page":"145","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Report of Hermansky\u2013Pudlak Syndrome in Two Families with Novel Variants in HPS3 and HPS4 Genes"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1261-2990","authenticated-orcid":false,"given":"Qaiser","family":"Zaman","sequence":"first","affiliation":[{"name":"Department of Zoology, Government Postgraduate College Dargai, Malakand 23060, Khyber Pakhtunkhwa, Pakistan"},{"name":"Department of Zoology, Abdul Wali Khan University Mardan, Mardan 23200, Khyber Pakhtunkhwa, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Sadeeda","sequence":"additional","affiliation":[{"name":"Department of Zoology, Government Postgraduate College Dargai, Malakand 23060, Khyber Pakhtunkhwa, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Anas","sequence":"additional","affiliation":[{"name":"Department of Zoology, Government Postgraduate College Dargai, Malakand 23060, Khyber Pakhtunkhwa, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8059-9591","authenticated-orcid":false,"given":"Gauhar","family":"Rehman","sequence":"additional","affiliation":[{"name":"Department of Zoology, Abdul Wali Khan University Mardan, Mardan 23200, Khyber Pakhtunkhwa, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qadeem","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Zoology, Government Postgraduate College Dargai, Malakand 23060, Khyber Pakhtunkhwa, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiman","family":"Iftikhar","sequence":"additional","affiliation":[{"name":"Department of Zoology, Government Postgraduate College Dargai, Malakand 23060, Khyber Pakhtunkhwa, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mashal","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Zoology, Government Postgraduate College Dargai, Malakand 23060, Khyber Pakhtunkhwa, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Owais","sequence":"additional","affiliation":[{"name":"Mardan College of Medical Technologies, Mardan 23200, Khyber Pakhtunkhwa, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4845-9227","authenticated-orcid":false,"given":"Ilyas","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Institute for Cardiogenetics, University of Luebeck, 23562 Luebeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3458-1697","authenticated-orcid":false,"given":"Osama","family":"Muthaffar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angham","family":"Abdulkareem","sequence":"additional","affiliation":[{"name":"Faculty of Science, Department of Biochemistry, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fehmida","family":"Bibi","sequence":"additional","affiliation":[{"name":"Special Infectious Agents Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3421-0079","authenticated-orcid":false,"given":"Musharraf","family":"Jelani","sequence":"additional","affiliation":[{"name":"Rare Diseases Genetics and Genomics, Centre for Omic Sciences, Islamia College Peshawar, Peshawar 25120, Khyber Pakhtunkhwa, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Naseer","sequence":"additional","affiliation":[{"name":"Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1203\/00006450-200202000-00006","article-title":"Nonsense mutations in ADTB3A cause complete deficiency of the \u03b23A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2","volume":"51","author":"Huizing","year":"2002","journal-title":"Pediatr. 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