Phenotypic expansion of KMT2D-related disorder: Beyond Kabuki syndrome.

Abstract

Pathogenic variants in KMT2D, which encodes lysine specific methyltransferase 2D, cause autosomal dominant Kabuki syndrome, associated with distinctive dysmorphic features including arched eyebrows, long palpebral fissures with eversion of the lower lid, large protuberant ears, and fetal finger pads. Most disease-causing variants identified to date are putative loss-of-function alleles, although 15-20% of cases are attributed to missense variants. We describe here four patients (including one previously published patient) with de novo KMT2D missense variants and with shared but unusual clinical findings not typically seen in Kabuki syndrome, including athelia (absent nipples), choanal atresia, hypoparathyroidism, delayed or absent pubertal development, and extreme short stature. These individuals also lack the typical dysmorphic facial features found in Kabuki syndrome. Two of the four patients had severe interstitial lung disease. All of these variants cluster within a 40-amino-acid region of the protein that is located just N-terminal of an annotated coiled coil domain. These findings significantly expand the phenotypic spectrum of features associated with variants in KMT2D beyond those seen in Kabuki syndrome and suggest a possible new underlying disease mechanism for these patients.

• Authors: Dustin Baldridge, Rebecca C Spillmann, Daniel J Wegner, Jennifer A Wambach, Frances V White, Kathleen Sisco, Tomi L Toler, Patricia I Dickson, F Sessions Cole, Vandana Shashi, Dorothy K Grange
• Journal: American journal of medical genetics. Part A (Am J Med Genet A) Vol. 182 Issue 5 Pg. 1053-1065 (05 2020) ISSN: 1552-4833 [Electronic] United States
• PMID: 32083401 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Wiley Periodicals, Inc.

Chemical References

• DNA-Binding Proteins
• KMT2D protein, human
• Neoplasm Proteins

Topics

• Abnormalities, Multiple (diagnostic imaging, genetics, pathology)
• Adolescent
• Adult
• Breast (abnormalities, diagnostic imaging, physiopathology)
• Breast Diseases
• Child
• Congenital Abnormalities (diagnostic imaging, genetics, physiopathology)
• DNA-Binding Proteins (genetics)
• Face (abnormalities, diagnostic imaging, pathology)
• Female
• Genetic Predisposition to Disease
• Hematologic Diseases (diagnostic imaging, genetics, pathology)
• Humans
• Loss of Function Mutation (genetics)
• Male
• Mutation (genetics)
• Neoplasm Proteins (genetics)
• Phenotype
• Vestibular Diseases (diagnostic imaging, genetics, pathology)
• Exome Sequencing
• Young Adult