1. A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct fromKabuki syndrome
- Author
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Karen Stals, Sara Cuvertino, Víctor Faundes, Frances Flinter, Lihadh Al-Gazali, Santina Venuto, Vagheesh M. Narasimhan, Laura Southgate, Colin A. Johnson, Eamonn Sheridan, Nisha Nair, Anne Barton, Alice Colyer, Susan J. Kimber, Brian R. Jackson, Adam Stevens, Daniel Weisberg, Natalie Canham, Giuseppe Merla, Gabriella Maria Squeo, Richard C. Trembath, Sally Ann Lynch, Fatima Nadat, Terence Garner, Robert Sellers, Sian Ellard, Muriel Holder-Espinasse, David A. van Heel, Michelle Peckham, Francesca Montanari, Siddharth Banka, Verity L. Hartill, Marco Seri, Jozef Hertecant, Cuvertino, S., Hartill, V., Colyer, A., Garner, T., Nair, N., Al-Gazali, L., Canham, N., Faundes, V. Flinter F., Hertecant, J., Holder-Espinasse, M., Jackson, B., Lynch, Sa, Nadat, F., Narasimhan, V., Peckham, M., Sellers, R., Seri, M., Montanari, F., Southgate, L., Squeo, Gm, Trembath, R., van Heel, D., Venuto, S., Weisberg, D., Stals, K., Ellard, S., The, 100, Barton, A., Kimber, S., Sheridan, E., Merla, G, Stevens, A., Johnson, Ca, Banka, S., Cuvertino S., Hartill V., Colyer A., Garner T., Nair N., Al-Gazali L., Canham N., Faundes V., Flinter F., Hertecant J., Holder-Espinasse M., Jackson B., Lynch S.A., Nadat F., Narasimhan V.M., Peckham M., Sellers R., Seri M., Montanari F., Southgate L., Squeo G.M., Trembath R., van Heel D., Venuto S., Weisberg D., Stals K., Ellard S., Barton A., Kimber S.J., Sheridan E., Merla G., Stevens A., Johnson C.A., and Banka S.
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Genetics ,0303 health sciences ,Kabuki syndrome ,Hearing loss ,KMT2D ,Choanal atresia ,Biology ,intrinsically disordered region ,medicine.disease ,Article ,Human genetics ,multiple congenital anomaly ,03 medical and health sciences ,Exon ,0302 clinical medicine ,030220 oncology & carcinogenesis ,DNA methylation ,medicine ,Missense mutation ,medicine.symptom ,histone 3 lysine 4 methyltransferase ,Haploinsufficiency ,Genetics (clinical) ,030304 developmental biology - 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 alpha 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.
- Published
- 2020
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