Citation: Zaman, Q.; Sadeeda; Anas, M.; Rehman, G.; Khan, Q.; Iftikhar, A.; Ahmad, M.; Owais, M.; Ahmad, I.; Muthaffar, O.Y.; et al. Report of Hermansky–Pudlak Syndrome in Two Families with Novel Variants in HPS3 and HPS4 Genes. Genes 2023, 14, 145. https://doi.org/10.3390/ genes14010145 Academic Editors: Muhammad Umair and Ahmed Waqas Received: 1 December 2022 Revised: 28 December 2022 Accepted: 2 January 2023 Published: 5 January 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). genes G C A T T A C G G C A T Article Report of Hermansky–Pudlak Syndrome in Two Families with Novel Variants in HPS3 and HPS4 Genes Qaiser Zaman 1,2 , Sadeeda 1 , Muhammad Anas 1 , Gauhar Rehman 2 , Qadeem Khan 1 , Aiman Iftikhar 1 , Mashal Ahmad 1 , Muhammad Owais 3 , Ilyas Ahmad 4 , Osama Yousef Muthaffar 5 , Angham Abdulrhman Abdulkareem 6,7 , Fehmida Bibi 8,9 , Musharraf Jelani 7,10, * and Muhammad Imran Naseer 7,9, * ,† 1 Department of Zoology, Government Postgraduate College Dargai, Malakand 23060, Khyber Pakhtunkhwa, Pakistan 2 Department of Zoology, Abdul Wali Khan University Mardan, Mardan 23200, Khyber Pakhtunkhwa, Pakistan 3 Mardan College of Medical Technologies, Mardan 23200, Khyber Pakhtunkhwa, Pakistan 4 Institute for Cardiogenetics, University of Luebeck, 23562 Luebeck, Germany 5 Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia 6 Faculty of Science, Department of Biochemistry, King Abdulaziz University, Jeddah 21589, Saudi Arabia 7 Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia 8 Special Infectious Agents Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah 21589, Saudi Arabia 9 Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia 10 Rare Diseases Genetics and Genomics, Centre for Omic Sciences, Islamia College Peshawar, Peshawar 25120, Khyber Pakhtunkhwa, Pakistan * Correspondence: mjelani@icp.edu.pk (M.J.); minaseer@kau.edu.sa or mimrannaseer@yahoo.com (M.I.N.); Tel.: +0092-3335207053 (M.J.) † Current address: Centre for Omic Sciences, Islamia College Peshawar, Peshawar 25120, Khyber Pakhtunkhwa, Pakistan. Abstract: Background: Hermansky–Pudlak syndrome (HSP) was first reported in 1959 as oculocu- taneous 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 depend- ing 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 in- dividuals 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 > 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 > 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– Pudlak 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. Genes 2023, 14, 145. https://doi.org/10.3390/genes14010145 https://www.mdpi.com/journal/genes