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Multiplexed Assays of Variant Effect and Re-classification of TYR Variants in Chinese Oculocutaneous Albinism Patients

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机构： [1]Department of Dermatology, Beijing Tongren Hospital, Capital Medical University, Beijing, China [2]Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, Beijing, China [3]Genetics and Birth Defects Control Center, National Center for Children’s Health, Beijing, China [4]MOE Key Laboratory of Major Diseases in Children, Beijing Children’s Hospital, Capital Medical University, Beijing, China

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关键词： Oculocutaneous albinism Pathogenicity Sequence variant interpretation TYR Variants of uncertain significance

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Oculocutaneous albinism type 1 (OCA-1), caused by mutations in the tyrosinase (TYR) gene, is the most common form of albinism worldwide. Due to the variants of uncertain significance (VUS) classified by The American College of Medical Genetics and Genomics (ACMG) guidelines, patients who carry these VUS do not receive a definitive molecular diagnosis. In order to clarify the pathogenicity of the VUS variants, we conducted multiplexed assays of variant effect (MAVEs) to re-classify the TYR VUS variants. Protein expression, melanin production, enzyme activity, and subcellular localization were applied to 46 selected variants: 27 VUS from 1243 albinism patients, 14 pathogenic/likely pathogenic (P/LP) and 5 benign/likely benign (B/LB) control variants. OddsPath values were calculated as recommended by Brnich et al (2019). By conducting MAVEs, PS3_moderate or PS3_supporting evidence was applied. 25 out of 27 VUS were re-classified as LP, 3 out of 11 LP variants as P by following the ACMG guidelines. Therefore, 19 out of 20 (95%) previously undiagnosed patients had a molecular diagnosis of OCA-1. In addition, the pathogenic mechanisms of TYR have been elucidated and categorized. These comprehensive MAVEs provide a robust approach for curating TYR VUS. This study advocates MAVEs for validating an accurate genotype-phenotype relationship.Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

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大类 | 2 区医学

小类 | 2 区皮肤病学

最新[2025]版：

大类 | 2 区医学

小类 | 2 区皮肤病学

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第一作者机构： [1]Department of Dermatology, Beijing Tongren Hospital, Capital Medical University, Beijing, China

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通讯机构： [2]Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, Beijing, China [3]Genetics and Birth Defects Control Center, National Center for Children’s Health, Beijing, China [4]MOE Key Laboratory of Major Diseases in Children, Beijing Children’s Hospital, Capital Medical University, Beijing, China

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Multiplexed Assays of Variant Effect and Re-classification of TYR Variants in Chinese Oculocutaneous Albinism Patients

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