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A novel likely pathogenic variant in a patient with Hermansky–Pudlak syndrome

Hermansky–Pudlak syndrome (HPS) is a genetic disorder characterized by oculocutaneous albinism and variable pulmonary fibrosis, granulomatous colitis, or immunodeficiency. The diagnosis relies on clinical findings, platelet transmission electron microscopy studies showing absent dense granules, or t...

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Autores principales: Lansdon, Lisa A., Chen, Dong, Rush, Eric T., Engleman, Kendra, Zhang, Lei, Saunders, Carol J., Oroszi, Gabor
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8559624/
https://www.ncbi.nlm.nih.gov/pubmed/34362826
http://dx.doi.org/10.1101/mcs.a006110
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author Lansdon, Lisa A.
Chen, Dong
Rush, Eric T.
Engleman, Kendra
Zhang, Lei
Saunders, Carol J.
Oroszi, Gabor
author_facet Lansdon, Lisa A.
Chen, Dong
Rush, Eric T.
Engleman, Kendra
Zhang, Lei
Saunders, Carol J.
Oroszi, Gabor
author_sort Lansdon, Lisa A.
collection PubMed
description Hermansky–Pudlak syndrome (HPS) is a genetic disorder characterized by oculocutaneous albinism and variable pulmonary fibrosis, granulomatous colitis, or immunodeficiency. The diagnosis relies on clinical findings, platelet transmission electron microscopy studies showing absent dense granules, or the identification of a pathogenic genotype in one of 11 associated genes, including HPS1. We report a 2-wk-old male with significant iris transillumination defects, a pale fundus, and mild corectopia found by clinical exome sequencing to have a previously reported pathogenic variant, c.972dupC p.(Met325HisfsTer128), and a variant of uncertain significance, c.1846G>A p.(Glu616Lys), in HPS1. To determine whether his phenotype was consistent with HPS, follow-up studies of whole blood lumiaggregometry and platelet transmission electron microscopy were performed that revealed absent or markedly reduced platelet ATP secretion and virtually absent platelet dense granules, thus confirming the diagnosis. To the best of our knowledge, our case is the first in which the c.1846G>A p.(Glu616Lys) variant is identified in a patient with HPS. In addition, the case also highlights the importance of leveraging appropriate confirmatory clinical testing and reverse phenotyping, which allowed the care team to establish the clinical diagnosis of HPS and reclassify the previously reported variant of uncertain significance in HPS1 to likely pathogenic.
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spelling pubmed-85596242021-11-10 A novel likely pathogenic variant in a patient with Hermansky–Pudlak syndrome Lansdon, Lisa A. Chen, Dong Rush, Eric T. Engleman, Kendra Zhang, Lei Saunders, Carol J. Oroszi, Gabor Cold Spring Harb Mol Case Stud Research Report Hermansky–Pudlak syndrome (HPS) is a genetic disorder characterized by oculocutaneous albinism and variable pulmonary fibrosis, granulomatous colitis, or immunodeficiency. The diagnosis relies on clinical findings, platelet transmission electron microscopy studies showing absent dense granules, or the identification of a pathogenic genotype in one of 11 associated genes, including HPS1. We report a 2-wk-old male with significant iris transillumination defects, a pale fundus, and mild corectopia found by clinical exome sequencing to have a previously reported pathogenic variant, c.972dupC p.(Met325HisfsTer128), and a variant of uncertain significance, c.1846G>A p.(Glu616Lys), in HPS1. To determine whether his phenotype was consistent with HPS, follow-up studies of whole blood lumiaggregometry and platelet transmission electron microscopy were performed that revealed absent or markedly reduced platelet ATP secretion and virtually absent platelet dense granules, thus confirming the diagnosis. To the best of our knowledge, our case is the first in which the c.1846G>A p.(Glu616Lys) variant is identified in a patient with HPS. In addition, the case also highlights the importance of leveraging appropriate confirmatory clinical testing and reverse phenotyping, which allowed the care team to establish the clinical diagnosis of HPS and reclassify the previously reported variant of uncertain significance in HPS1 to likely pathogenic. Cold Spring Harbor Laboratory Press 2021-10 /pmc/articles/PMC8559624/ /pubmed/34362826 http://dx.doi.org/10.1101/mcs.a006110 Text en © 2021 Lansdon et al.; Published by Cold Spring Harbor Laboratory Press https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.
spellingShingle Research Report
Lansdon, Lisa A.
Chen, Dong
Rush, Eric T.
Engleman, Kendra
Zhang, Lei
Saunders, Carol J.
Oroszi, Gabor
A novel likely pathogenic variant in a patient with Hermansky–Pudlak syndrome
title A novel likely pathogenic variant in a patient with Hermansky–Pudlak syndrome
title_full A novel likely pathogenic variant in a patient with Hermansky–Pudlak syndrome
title_fullStr A novel likely pathogenic variant in a patient with Hermansky–Pudlak syndrome
title_full_unstemmed A novel likely pathogenic variant in a patient with Hermansky–Pudlak syndrome
title_short A novel likely pathogenic variant in a patient with Hermansky–Pudlak syndrome
title_sort novel likely pathogenic variant in a patient with hermansky–pudlak syndrome
topic Research Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8559624/
https://www.ncbi.nlm.nih.gov/pubmed/34362826
http://dx.doi.org/10.1101/mcs.a006110
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