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Clinical and molecular spectrum of 46,XY disorders of sex development that harbour MAMLD1 variations: case series and review of literature

BACKGROUND: Mastermind-like domain-containing 1 (MAMLD1) has previously been identified as a causative gene for “46,XY Disorders of Sex Development (DSD)”. Recently, there has been some controversy regarding the causative role of MAMLD1 variations in DSDs. Here we describe a clinical series and revi...

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Autores principales: Li, Lele, Su, Chang, Fan, Lijun, Gao, Fenqi, Liang, Xuejun, Gong, Chunxiu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370409/
https://www.ncbi.nlm.nih.gov/pubmed/32690052
http://dx.doi.org/10.1186/s13023-020-01459-9
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author Li, Lele
Su, Chang
Fan, Lijun
Gao, Fenqi
Liang, Xuejun
Gong, Chunxiu
author_facet Li, Lele
Su, Chang
Fan, Lijun
Gao, Fenqi
Liang, Xuejun
Gong, Chunxiu
author_sort Li, Lele
collection PubMed
description BACKGROUND: Mastermind-like domain-containing 1 (MAMLD1) has previously been identified as a causative gene for “46,XY Disorders of Sex Development (DSD)”. Recently, there has been some controversy regarding the causative role of MAMLD1 variations in DSDs. Here we describe a clinical series and review the reported cases to evaluate the role of MAMLD1 variants in children with 46,XY DSD. Cases of 46,XY DSD harbouring MAMLD1 variants from unrelated families were recruited from the Beijing Children’s Hospital in China (N = 10) or identified through a literature search (N = 26). The clinical manifestations and genetic variants of all the patients were evaluated. RESULTS: Hypospadias was the most prevalent phenotype among our 10 cases (8 out of 10 cases) and in all the previously reported ones. Central precocious puberty and isolated micropenis were observed for the first time. Among the 10 cases, nine variants were identified, including three nonsense (p.R356X, p.Q152X, and p.Q124X) and six missense (p.P334S, p.S662R, p.A421P,p.T992I, p.P542S, and p.R927L) variants. In silico analysis showed that the variants p.P334S, p.P542S, p.S662R, and p.R927Lmight lead to drastic changes in the interaction force of the amino acid chain and the flexibility of the spatial structure, and such changes may affect protein function. CONCLUSION: Patients with 46,XY DSD harbouring MAMLD1variants manifest a broad spectrum of phenotypes and mostly present with hypospadias. The six novel variants reported here enrich the mutation database and contribute to our understanding of the pathogenesis of 46,XY DSD.
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spelling pubmed-73704092020-07-21 Clinical and molecular spectrum of 46,XY disorders of sex development that harbour MAMLD1 variations: case series and review of literature Li, Lele Su, Chang Fan, Lijun Gao, Fenqi Liang, Xuejun Gong, Chunxiu Orphanet J Rare Dis Research BACKGROUND: Mastermind-like domain-containing 1 (MAMLD1) has previously been identified as a causative gene for “46,XY Disorders of Sex Development (DSD)”. Recently, there has been some controversy regarding the causative role of MAMLD1 variations in DSDs. Here we describe a clinical series and review the reported cases to evaluate the role of MAMLD1 variants in children with 46,XY DSD. Cases of 46,XY DSD harbouring MAMLD1 variants from unrelated families were recruited from the Beijing Children’s Hospital in China (N = 10) or identified through a literature search (N = 26). The clinical manifestations and genetic variants of all the patients were evaluated. RESULTS: Hypospadias was the most prevalent phenotype among our 10 cases (8 out of 10 cases) and in all the previously reported ones. Central precocious puberty and isolated micropenis were observed for the first time. Among the 10 cases, nine variants were identified, including three nonsense (p.R356X, p.Q152X, and p.Q124X) and six missense (p.P334S, p.S662R, p.A421P,p.T992I, p.P542S, and p.R927L) variants. In silico analysis showed that the variants p.P334S, p.P542S, p.S662R, and p.R927Lmight lead to drastic changes in the interaction force of the amino acid chain and the flexibility of the spatial structure, and such changes may affect protein function. CONCLUSION: Patients with 46,XY DSD harbouring MAMLD1variants manifest a broad spectrum of phenotypes and mostly present with hypospadias. The six novel variants reported here enrich the mutation database and contribute to our understanding of the pathogenesis of 46,XY DSD. BioMed Central 2020-07-20 /pmc/articles/PMC7370409/ /pubmed/32690052 http://dx.doi.org/10.1186/s13023-020-01459-9 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Li, Lele
Su, Chang
Fan, Lijun
Gao, Fenqi
Liang, Xuejun
Gong, Chunxiu
Clinical and molecular spectrum of 46,XY disorders of sex development that harbour MAMLD1 variations: case series and review of literature
title Clinical and molecular spectrum of 46,XY disorders of sex development that harbour MAMLD1 variations: case series and review of literature
title_full Clinical and molecular spectrum of 46,XY disorders of sex development that harbour MAMLD1 variations: case series and review of literature
title_fullStr Clinical and molecular spectrum of 46,XY disorders of sex development that harbour MAMLD1 variations: case series and review of literature
title_full_unstemmed Clinical and molecular spectrum of 46,XY disorders of sex development that harbour MAMLD1 variations: case series and review of literature
title_short Clinical and molecular spectrum of 46,XY disorders of sex development that harbour MAMLD1 variations: case series and review of literature
title_sort clinical and molecular spectrum of 46,xy disorders of sex development that harbour mamld1 variations: case series and review of literature
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370409/
https://www.ncbi.nlm.nih.gov/pubmed/32690052
http://dx.doi.org/10.1186/s13023-020-01459-9
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