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Whole-Exome Sequencing Identified Rare Genetic Variants Associated with Undervirilized Genitalia in Taiwanese Pediatric Patients
Disorders/differences of sex development (DSDs) are a group of rare and phenotypically variable diseases. The underlying genetic causes of most cases of 46XY DSDs remains unknown. Despite the advent of genetic testing, current investigations of the causes of DSDs allow genetic-mechanism identificati...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9953256/ https://www.ncbi.nlm.nih.gov/pubmed/36830778 http://dx.doi.org/10.3390/biomedicines11020242 |
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author | Tsai, Meng-Che Weng, Yun-Han Lin, Yu-Fang Wang, Yi-Chieh Yu, Hui-Wen Chou, Yen-Yin Chen, Peng-Chieh |
author_facet | Tsai, Meng-Che Weng, Yun-Han Lin, Yu-Fang Wang, Yi-Chieh Yu, Hui-Wen Chou, Yen-Yin Chen, Peng-Chieh |
author_sort | Tsai, Meng-Che |
collection | PubMed |
description | Disorders/differences of sex development (DSDs) are a group of rare and phenotypically variable diseases. The underlying genetic causes of most cases of 46XY DSDs remains unknown. Despite the advent of genetic testing, current investigations of the causes of DSDs allow genetic-mechanism identification in about 20–35% of cases. This study aimed primarily to establish a rapid and high-throughput genetic test for undervirilized males with and without additional dysmorphic features. Routine chromosomal and endocrinological investigations were performed as part of DSD evaluation. We applied whole-exome sequencing (WES) complemented with multiplex ligation-dependent probe amplification to seek explainable genetic causes. Integrated computing programs were used to call and predict the functions of genetic variants. We recruited 20 patients and identified the genetic etiologies for 14 (70%) patients. A total of seven of the patients who presented isolated DSD phenotypes were found to have causative variants in the AR, MAP3K1, and FLNA genes. Moreover, the other seven patients presented additional phenotypes beyond undervirilized genitalia. Among them, two patients were compatible with CHARGE syndrome, one with Robinow syndrome, and another three with hypogonadotropic hypogonadism. One patient, who carried a heterozygous FLNA mutation, also harbored a heterozygous PTPN11 mutation and thus presented some phenotypes of Noonan syndrome. We identified several genetic variants (12 nonsense mutations and one microdeletion) that account for syndromic and nonsyndromic DSDs in the Taiwanese population. The identification of these causative genes extended our current understanding of sex development and related congenital disorders. |
format | Online Article Text |
id | pubmed-9953256 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-99532562023-02-25 Whole-Exome Sequencing Identified Rare Genetic Variants Associated with Undervirilized Genitalia in Taiwanese Pediatric Patients Tsai, Meng-Che Weng, Yun-Han Lin, Yu-Fang Wang, Yi-Chieh Yu, Hui-Wen Chou, Yen-Yin Chen, Peng-Chieh Biomedicines Article Disorders/differences of sex development (DSDs) are a group of rare and phenotypically variable diseases. The underlying genetic causes of most cases of 46XY DSDs remains unknown. Despite the advent of genetic testing, current investigations of the causes of DSDs allow genetic-mechanism identification in about 20–35% of cases. This study aimed primarily to establish a rapid and high-throughput genetic test for undervirilized males with and without additional dysmorphic features. Routine chromosomal and endocrinological investigations were performed as part of DSD evaluation. We applied whole-exome sequencing (WES) complemented with multiplex ligation-dependent probe amplification to seek explainable genetic causes. Integrated computing programs were used to call and predict the functions of genetic variants. We recruited 20 patients and identified the genetic etiologies for 14 (70%) patients. A total of seven of the patients who presented isolated DSD phenotypes were found to have causative variants in the AR, MAP3K1, and FLNA genes. Moreover, the other seven patients presented additional phenotypes beyond undervirilized genitalia. Among them, two patients were compatible with CHARGE syndrome, one with Robinow syndrome, and another three with hypogonadotropic hypogonadism. One patient, who carried a heterozygous FLNA mutation, also harbored a heterozygous PTPN11 mutation and thus presented some phenotypes of Noonan syndrome. We identified several genetic variants (12 nonsense mutations and one microdeletion) that account for syndromic and nonsyndromic DSDs in the Taiwanese population. The identification of these causative genes extended our current understanding of sex development and related congenital disorders. MDPI 2023-01-17 /pmc/articles/PMC9953256/ /pubmed/36830778 http://dx.doi.org/10.3390/biomedicines11020242 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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/). |
spellingShingle | Article Tsai, Meng-Che Weng, Yun-Han Lin, Yu-Fang Wang, Yi-Chieh Yu, Hui-Wen Chou, Yen-Yin Chen, Peng-Chieh Whole-Exome Sequencing Identified Rare Genetic Variants Associated with Undervirilized Genitalia in Taiwanese Pediatric Patients |
title | Whole-Exome Sequencing Identified Rare Genetic Variants Associated with Undervirilized Genitalia in Taiwanese Pediatric Patients |
title_full | Whole-Exome Sequencing Identified Rare Genetic Variants Associated with Undervirilized Genitalia in Taiwanese Pediatric Patients |
title_fullStr | Whole-Exome Sequencing Identified Rare Genetic Variants Associated with Undervirilized Genitalia in Taiwanese Pediatric Patients |
title_full_unstemmed | Whole-Exome Sequencing Identified Rare Genetic Variants Associated with Undervirilized Genitalia in Taiwanese Pediatric Patients |
title_short | Whole-Exome Sequencing Identified Rare Genetic Variants Associated with Undervirilized Genitalia in Taiwanese Pediatric Patients |
title_sort | whole-exome sequencing identified rare genetic variants associated with undervirilized genitalia in taiwanese pediatric patients |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9953256/ https://www.ncbi.nlm.nih.gov/pubmed/36830778 http://dx.doi.org/10.3390/biomedicines11020242 |
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