The contribution of X-linked coding variation to severe developmental disordersCitation formats

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  • Deciphering Developmental Disorders Study

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The contribution of X-linked coding variation to severe developmental disorders. / Deciphering Developmental Disorders Study.

In: Nature Communications, Vol. 12, No. 1, 627, 27.01.2021.

Research output: Contribution to journalArticlepeer-review

Harvard

Deciphering Developmental Disorders Study 2021, 'The contribution of X-linked coding variation to severe developmental disorders', Nature Communications, vol. 12, no. 1, 627. https://doi.org/10.1038/s41467-020-20852-3

APA

Deciphering Developmental Disorders Study (2021). The contribution of X-linked coding variation to severe developmental disorders. Nature Communications, 12(1), [627]. https://doi.org/10.1038/s41467-020-20852-3

Vancouver

Deciphering Developmental Disorders Study. The contribution of X-linked coding variation to severe developmental disorders. Nature Communications. 2021 Jan 27;12(1). 627. https://doi.org/10.1038/s41467-020-20852-3

Author

Deciphering Developmental Disorders Study. / The contribution of X-linked coding variation to severe developmental disorders. In: Nature Communications. 2021 ; Vol. 12, No. 1.

Bibtex

@article{f6570c6e13b040e2944828afa04b8f48,
title = "The contribution of X-linked coding variation to severe developmental disorders",
abstract = "Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.",
keywords = "Chromosomes, Human, X/genetics, Developmental Disabilities/genetics, Female, Genes, Recessive, Genes, X-Linked, Genetic Diseases, X-Linked/genetics, Genetic Variation, Humans, Inheritance Patterns/genetics, Male, Multifactorial Inheritance/genetics, Mutation/genetics, Phenotype, Sex Characteristics",
author = "{Deciphering Developmental Disorders Study} and Martin, {Hilary C} and Gardner, {Eugene J} and Samocha, {Kaitlin E} and Joanna Kaplanis and Nadia Akawi and Alejandro Sifrim and Eberhardt, {Ruth Y} and Tavares, {Ana Lisa Taylor} and Neville, {Matthew D C} and Niemi, {Mari E K} and Giuseppe Gallone and Jeremy McRae and Wright, {Caroline F} and FitzPatrick, {David R} and Firth, {Helen V} and Hurles, {Matthew E}",
note = "Funding Information: We thank the DDD families for participating, the DDD clinicians for recruiting patients, the Sanger Sample Management and Sequencing pipelines teams for generating the data, the Sanger Human Genome Informatics team for helping to process the exome data, and Nicola Whiffin for helpful comments on the manuscript. The study was approved by the UK Research Ethics Committee (10/H0305/83, granted by the Cambridge South Research Ethics Committee and GEN/284/12, granted by the Republic of Ireland Research Ethics Committee). This work has been conducted using the UK Biobank Resource under Application Number 44165. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the UK Department of Health, and the Wellcome Trust Sanger Institute (grant WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the UK Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South Research Ethics Committee and GEN/284/12, granted by the Republic of Ireland Research Ethics Committee). The research team acknowledges the support of the National Institutes for Health Research, through the Comprehensive Clinical Research Network. This study makes use of DECIPHER (http://decipher.sanger.ac.uk), which is funded by the Wellcome Trust. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = jan,
day = "27",
doi = "10.1038/s41467-020-20852-3",
language = "English",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Springer Nature",
number = "1",

}

RIS

TY - JOUR

T1 - The contribution of X-linked coding variation to severe developmental disorders

AU - Deciphering Developmental Disorders Study

AU - Martin, Hilary C

AU - Gardner, Eugene J

AU - Samocha, Kaitlin E

AU - Kaplanis, Joanna

AU - Akawi, Nadia

AU - Sifrim, Alejandro

AU - Eberhardt, Ruth Y

AU - Tavares, Ana Lisa Taylor

AU - Neville, Matthew D C

AU - Niemi, Mari E K

AU - Gallone, Giuseppe

AU - McRae, Jeremy

AU - Wright, Caroline F

AU - FitzPatrick, David R

AU - Firth, Helen V

AU - Hurles, Matthew E

N1 - Funding Information: We thank the DDD families for participating, the DDD clinicians for recruiting patients, the Sanger Sample Management and Sequencing pipelines teams for generating the data, the Sanger Human Genome Informatics team for helping to process the exome data, and Nicola Whiffin for helpful comments on the manuscript. The study was approved by the UK Research Ethics Committee (10/H0305/83, granted by the Cambridge South Research Ethics Committee and GEN/284/12, granted by the Republic of Ireland Research Ethics Committee). This work has been conducted using the UK Biobank Resource under Application Number 44165. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the UK Department of Health, and the Wellcome Trust Sanger Institute (grant WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the UK Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South Research Ethics Committee and GEN/284/12, granted by the Republic of Ireland Research Ethics Committee). The research team acknowledges the support of the National Institutes for Health Research, through the Comprehensive Clinical Research Network. This study makes use of DECIPHER (http://decipher.sanger.ac.uk), which is funded by the Wellcome Trust. Publisher Copyright: © 2021, The Author(s).

PY - 2021/1/27

Y1 - 2021/1/27

N2 - Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.

AB - Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.

KW - Chromosomes, Human, X/genetics

KW - Developmental Disabilities/genetics

KW - Female

KW - Genes, Recessive

KW - Genes, X-Linked

KW - Genetic Diseases, X-Linked/genetics

KW - Genetic Variation

KW - Humans

KW - Inheritance Patterns/genetics

KW - Male

KW - Multifactorial Inheritance/genetics

KW - Mutation/genetics

KW - Phenotype

KW - Sex Characteristics

U2 - 10.1038/s41467-020-20852-3

DO - 10.1038/s41467-020-20852-3

M3 - Article

C2 - 33504798

VL - 12

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 627

ER -