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

TY - JOUR

T1 - Mono-allelic loss of YTHDF3 and neurodevelopmental disorder

T2 - clinical features of four individuals with 8q12.3 deletions

AU - Terkelsen, Thorkild

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

N1 - This article is protected by copyright. All rights reserved.

PY - 2022/2

Y1 - 2022/2

N2 - The YTH domain family member 3 gene (YTHDF3) encodes a reader of the abundant N6-methyladenosine (m6 A) 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 to 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 (m6 A) 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 to 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.

KW - DECAY

KW - M(6)A

KW - MESSENGER-RNA

KW - TRANSLATION

KW - YTHDF3 protein

KW - chromosome deletion

KW - developmental delay

KW - heterozygote

KW - human

KW - intellectual disability

U2 - 10.1111/cge.14083

DO - 10.1111/cge.14083

M3 - Journal article

C2 - 34708403

SN - 0009-9163

VL - 101

SP - 208

EP - 213

JO - Clinical Genetics

JF - Clinical Genetics

IS - 2

ER -