Show simple item record

dc.contributor.authorWright, C. F.
dc.contributor.authorQuaife, N. M.
dc.contributor.authorRamos-Hernández, L.
dc.contributor.authorDanecek, P.
dc.contributor.authorFerla, M. P.
dc.contributor.authorSamocha, K. E.
dc.contributor.authorKaplanis, J.
dc.contributor.authorGardner, E. J.
dc.contributor.authorEberhardt, R. Y.
dc.contributor.authorChao, K. R.
dc.contributor.authorKarczewski, K. J.
dc.contributor.authorMorales, J.
dc.contributor.authorGallone, G.
dc.contributor.authorBalasubramanian, M.
dc.contributor.authorBanka, S.
dc.contributor.authorGompertz, L.
dc.contributor.authorKerr, B.
dc.contributor.authorKirby, A.
dc.contributor.authorLynch, S. A.
dc.contributor.authorMorton, J. E. V.
dc.contributor.authorPinz, H.
dc.contributor.authorSansbury, F. H.
dc.contributor.authorStewart, H.
dc.contributor.authorZuccarelli, B. D.
dc.contributor.authorCook, S. A.
dc.contributor.authorTaylor, J. C.
dc.contributor.authorJuusola, J.
dc.contributor.authorRetterer, K.
dc.contributor.authorFirth, H. V.
dc.contributor.authorHurles, M. E.
dc.contributor.authorLara-Pezzi, E.
dc.contributor.authorBarton, P. J. R.
dc.contributor.authorWhiffin, N.
dc.identifier.citationWright, C. F., Quaife, N. M., Ramos-Hernández, L., Danecek, P., Ferla, M. P., Samocha, K. E., Kaplanis, J., Gardner, E. J., Eberhardt, R. Y., Chao, K. R., Karczewski, K. J., Morales, J., Gallone, G., Balasubramanian, M., Banka, S., Gompertz, L., Kerr, B., Kirby, A., Lynch, S. A., Morton, J. E. V., Pinz, H., Sansbury, F. H., Stewart, H., Zuccarelli, B. D., Cook, S. A., Taylor, J. C., Juusola, J., Retterer, K., Firth, H. V., Hurles, M. E., Lara-Pezzi, E., Barton, P. J. R. and Whiffin, N. (2021) 'Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms', American Journal of Human Genetics, 108(6), pp. 1083-1094.
dc.description.abstractClinical 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.
dc.publisherCell Press
dc.rights© 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
dc.subject*5' Untranslated Regions
dc.subjectCohort Studies
dc.subjectDNA Copy Number Variations
dc.subjectDevelopmental Disabilities/*etiology/pathology
dc.subject*Genetic Predisposition to Disease
dc.subject*Loss of Function Mutation
dc.subjectMEF2 Transcription Factors/genetics
dc.subjectWhole Exome Sequencing
dc.subject*developmental disorders, clinical genetic testing, non-coding region variants, 5'
dc.subjectUTR variants
dc.subjectInc. K.R. holds shares in Opko Health, Inc. B.D.Z. is a member of the speakers
dc.subjectbureau for Biogen, Neurelis, and Supernus. S.A.C. is co-founder and shareholder of
dc.subjectEnleofen Bio Pte Ltd. M.E.H. is co-founder, shareholder, consultant, and
dc.subjectnon-executive director of Congenica Ltd. All other authors declare no competing
dc.titleNon-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms
dc.typeJournal Article
dc.identifier.journalAmerican Journal of Human Genetics
dc.description.noteThe article is available via Open Access. Click on the 'Additional link' above to access the full-text.
dc.description.admin-notePublished version, accepted version (6 month embargo), submitted version

Files in this item


There are no files associated with this item.

This item appears in the following Collection(s)

Show simple item record

© 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Except where otherwise noted, this item's license is described as © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.