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@article{Wright:2021:10.1016/j.ajhg.2021.04.025,
author = {Wright, CF and Quaife, NM and Ramos-Hernández, L and Danecek, P and Ferla, MP and Samocha, KE and Kaplanis, J and Gardner, EJ and Eberhardt, RY and Chao, KR and Karczewski, KJ and Morales, J and Gallone, G and Balasubramanian, M and Banka, S and Gompertz, L and Kerr, B and Kirby, A and Lynch, SA and Morton, JEV and Pinz, H and Sansbury, FH and Stewart, H and Zuccarelli, BD and Genomics, England Research Consortium and Cook, SA and Taylor, JC and Juusola, J and Retterer, K and Firth, HV and Hurles, ME and Lara-Pezzi, E and Barton, PJR and Whiffin, N},
doi = {10.1016/j.ajhg.2021.04.025},
journal = {American Journal of Human Genetics},
pages = {1083--1094},
title = {Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms},
url = {http://dx.doi.org/10.1016/j.ajhg.2021.04.025},
volume = {108},
year = {2021}
}

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TY  - JOUR
AB  - Clinical genetic testing of protein-coding regions identifies a likely causative variant in only around half of developmental disorder (DD) cases. The contribution of regulatory variation in non-coding regions to rare disease, including DD, remains very poorly understood. We screened 9,858 probands from the Deciphering Developmental Disorders (DDD) study for de novo mutations in the 5' untranslated regions (5' UTRs) of genes within which variants have previously been shown to cause DD through a dominant haploinsufficient mechanism. We identified four single-nucleotide variants and two copy-number variants upstream of MEF2C in a total of ten individual probands. We developed multiple bespoke and orthogonal experimental approaches to demonstrate that these variants cause DD through three distinct loss-of-function mechanisms, disrupting transcription, translation, and/or protein function. These non-coding region variants represent 23% of likely diagnoses identified in MEF2C in the DDD cohort, but these would all be missed in standard clinical genetics approaches. Nonetheless, these variants are readily detectable in exome sequence data, with 30.7% of 5' UTR bases across all genes well covered in the DDD dataset. Our analyses show that non-coding variants upstream of genes within which coding variants are known to cause DD are an important cause of severe disease and demonstrate that analyzing 5' UTRs can increase diagnostic yield. We also show how non-coding variants can help inform both the disease-causing mechanism underlying protein-coding variants and dosage tolerance of the gene.
AU  - Wright,CF
AU  - Quaife,NM
AU  - Ramos-Hernández,L
AU  - Danecek,P
AU  - Ferla,MP
AU  - Samocha,KE
AU  - Kaplanis,J
AU  - Gardner,EJ
AU  - Eberhardt,RY
AU  - Chao,KR
AU  - Karczewski,KJ
AU  - Morales,J
AU  - Gallone,G
AU  - Balasubramanian,M
AU  - Banka,S
AU  - Gompertz,L
AU  - Kerr,B
AU  - Kirby,A
AU  - Lynch,SA
AU  - Morton,JEV
AU  - Pinz,H
AU  - Sansbury,FH
AU  - Stewart,H
AU  - Zuccarelli,BD
AU  - Genomics,England Research Consortium
AU  - Cook,SA
AU  - Taylor,JC
AU  - Juusola,J
AU  - Retterer,K
AU  - Firth,HV
AU  - Hurles,ME
AU  - Lara-Pezzi,E
AU  - Barton,PJR
AU  - Whiffin,N
DO  - 10.1016/j.ajhg.2021.04.025
EP  - 1094
PY  - 2021///
SN  - 0002-9297
SP  - 1083
TI  - Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms
T2  - American Journal of Human Genetics
UR  - http://dx.doi.org/10.1016/j.ajhg.2021.04.025
UR  - https://www.ncbi.nlm.nih.gov/pubmed/34022131
UR  - http://hdl.handle.net/10044/1/89704
VL  - 108
ER  -

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