A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome
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2020Metadata
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Cuvertino, Sara
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A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome
Author
- Cuvertino, Sara;
- Hartill, Verity;
- Colyer, Alice;
- Garner, Terence;
- Nair, Nisha;
- Al-Gazali, Lihadh;
- Canham, Natalie;
- Faundes Gómez, Víctor;
- Flinter, Frances;
- Hertecant, Jozef;
- Holder Espinasse, Muriel;
- Jackson, Brian;
- Lynch, Sally Ann;
- Nadat, Fatima;
- Narasimhan, Vagheesh M.;
- Peckham, Michelle;
- Sellers, Robert;
- Seri, Marco;
- Montanari, Francesca;
- Southgate, Laura;
- Squeo, Gabriella Maria;
- Trembath, Richard;
- van Heel, David;
- Venuto, Santina;
- Weisberg, Daniel;
- Stals, Karen;
- Ellard, Sian;
- Barton, Anne;
- Kimber, Susan J.;
- Sheridan, Eamonn;
- Merla, Giuseppe;
- Stevens, Adam;
- Johnson, Colin A.;
- Banka, Siddharth;
Abstract
Purpose To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1). Methods Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism. Results The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective software-based facial analysis metrics, and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to -helical transition. Conclusion KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.
Patrocinador
Newlife Charity
Chile's National Commission for Scientific and Technological Research (CONICYT PhD studentship)
Wellcome Trust
British Heart Foundation (Clinical Training fellowship)
Sir Jules Thorn Award for Biomedical Research
Wellcome Trust
Fondazione Telethon
Royal Society Wolfson Laboratory Refurbishment scheme
Wellcome Trust
National Institute for Health Research (NIHR)
Health Innovation Challenge Fund
Wellcome
National Institute for Health Research (NIHR)
NHS England
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Genet Med. 2020 Jan 17.
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