Mono-allelic loss of YTHDF3 and neurodevelopmental disorder: clinical features of four individuals with 8q12.3 deletions

Thorkild Terkelsen; Charlotte Brasch-Andersen; Niels Illum; Tiffany Busa; Chantal Missirian; Kate Chandler; Simon T. Holden; Uffe Birk Jensen; Christina R. Fagerberg

doi:10.1111/cge.14083

Mono-allelic loss of YTHDF3 and neurodevelopmental disorder: clinical features of four individuals with 8q12.3 deletions

Thorkild Terkelsen, Charlotte Brasch-Andersen, Niels Illum, Tiffany Busa, Chantal Missirian, Kate Chandler, Simon T. Holden, Uffe Birk Jensen, Christina R. Fagerberg^*

^*Kontaktforfatter

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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Abstract

The YTH domain family member 3 gene (YTHDF3) encodes a reader of the abundant N6-methyladenosine (m⁶A) modification of eukaryotic mRNA, which plays an essential role in regulating mRNA stability and is necessary to achieve normal development of the central nervous system in animal models. YTHDF3 has not previously been implicated in Mendelian disease despite a high probability of loss of function intolerance and statistical evidence of enrichment for gene-disruptive de novo variants in large-scale studies of individuals with intellectual disability and/or developmental delay. We report four individuals with deletion of 8q12.3, deletion size 1.38–2.60 Mb, encompassing YTHDF3, three of them were de novo, and in one case, the inheritance was unknown. Common features of the individuals (age range, 4–22 years) were developmental delay and/or intellectual disability. Two individuals underwent squint surgery. We suggest that haploinsufficiency of YTHDF3 causes a neurodevelopmental disorder with developmental delay and intellectual disability of variable degree.

Originalsprog	Engelsk
Tidsskrift	Clinical Genetics
Vol/bind	101
Udgave nummer	2
Sider (fra-til)	208-213
ISSN	0009-9163
DOI	https://doi.org/10.1111/cge.14083
Status	Udgivet - feb. 2022

Bibliografisk note

Funding Information:
We wish to thank the patients and their families for taking part in the study. This study makes use of data generated by the DECIPHER community. A full list of centers who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from [email protected] . Funding for the Decipher project was provided by the Wellcome Trust. This work was supported by The fund to support clinical research careers in the Region of Southern Denmark (Christina R. Fagerberg) and Aarhus University (Thorkild Terkelsen). The funding sources had no involvement in the study. 11

Publisher Copyright:
© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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10.1111/cge.14083

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Citationsformater

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title = "Mono-allelic loss of YTHDF3 and neurodevelopmental disorder: clinical features of four individuals with 8q12.3 deletions",

abstract = "The YTH domain family member 3 gene (YTHDF3) encodes a reader of the abundant N6-methyladenosine (m6A) modification of eukaryotic mRNA, which plays an essential role in regulating mRNA stability and is necessary to achieve normal development of the central nervous system in animal models. YTHDF3 has not previously been implicated in Mendelian disease despite a high probability of loss of function intolerance and statistical evidence of enrichment for gene-disruptive de novo variants in large-scale studies of individuals with intellectual disability and/or developmental delay. We report four individuals with deletion of 8q12.3, deletion size 1.38–2.60 Mb, encompassing YTHDF3, three of them were de novo, and in one case, the inheritance was unknown. Common features of the individuals (age range, 4–22 years) were developmental delay and/or intellectual disability. Two individuals underwent squint surgery. We suggest that haploinsufficiency of YTHDF3 causes a neurodevelopmental disorder with developmental delay and intellectual disability of variable degree.",

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author = "Thorkild Terkelsen and Charlotte Brasch-Andersen and Niels Illum and Tiffany Busa and Chantal Missirian and Kate Chandler and Holden, \{Simon T.\} and Jensen, \{Uffe Birk\} and Fagerberg, \{Christina R.\}",

note = "Funding Information: We wish to thank the patients and their families for taking part in the study. This study makes use of data generated by the DECIPHER community. A full list of centers who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from [email protected] . Funding for the Decipher project was provided by the Wellcome Trust. This work was supported by The fund to support clinical research careers in the Region of Southern Denmark (Christina R. Fagerberg) and Aarhus University (Thorkild Terkelsen). The funding sources had no involvement in the study. 11 Publisher Copyright: {\textcopyright} 2021 John Wiley \& Sons A/S. Published by John Wiley \& Sons Ltd.",

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AU - Brasch-Andersen, Charlotte

AU - Illum, Niels

AU - Busa, Tiffany

AU - Missirian, Chantal

AU - Chandler, Kate

AU - Holden, Simon T.

AU - Jensen, Uffe Birk

AU - Fagerberg, Christina R.

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N2 - The YTH domain family member 3 gene (YTHDF3) encodes a reader of the abundant N6-methyladenosine (m6A) modification of eukaryotic mRNA, which plays an essential role in regulating mRNA stability and is necessary to achieve normal development of the central nervous system in animal models. YTHDF3 has not previously been implicated in Mendelian disease despite a high probability of loss of function intolerance and statistical evidence of enrichment for gene-disruptive de novo variants in large-scale studies of individuals with intellectual disability and/or developmental delay. We report four individuals with deletion of 8q12.3, deletion size 1.38–2.60 Mb, encompassing YTHDF3, three of them were de novo, and in one case, the inheritance was unknown. Common features of the individuals (age range, 4–22 years) were developmental delay and/or intellectual disability. Two individuals underwent squint surgery. We suggest that haploinsufficiency of YTHDF3 causes a neurodevelopmental disorder with developmental delay and intellectual disability of variable degree.

AB - The YTH domain family member 3 gene (YTHDF3) encodes a reader of the abundant N6-methyladenosine (m6A) modification of eukaryotic mRNA, which plays an essential role in regulating mRNA stability and is necessary to achieve normal development of the central nervous system in animal models. YTHDF3 has not previously been implicated in Mendelian disease despite a high probability of loss of function intolerance and statistical evidence of enrichment for gene-disruptive de novo variants in large-scale studies of individuals with intellectual disability and/or developmental delay. We report four individuals with deletion of 8q12.3, deletion size 1.38–2.60 Mb, encompassing YTHDF3, three of them were de novo, and in one case, the inheritance was unknown. Common features of the individuals (age range, 4–22 years) were developmental delay and/or intellectual disability. Two individuals underwent squint surgery. We suggest that haploinsufficiency of YTHDF3 causes a neurodevelopmental disorder with developmental delay and intellectual disability of variable degree.

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Mono-allelic loss of YTHDF3 and neurodevelopmental disorder: clinical features of four individuals with 8q12.3 deletions

Abstract

Bibliografisk note

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