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Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

ABSTRACT: We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

SUBMITTER: O'Donnell-Luria AH

PROVIDER: S-EPMC6556837 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

O'Donnell-Luria Anne H AH Pais Lynn S LS Faundes Víctor V Wood Jordan C JC Sveden Abigail A Luria Victor V Abou Jamra Rami R Accogli Andrea A Amburgey Kimberly K Anderlid Britt Marie BM Azzarello-Burri Silvia S Basinger Alice A AA Bianchini Claudia C Bird Lynne M LM Buchert Rebecca R Carre Wilfrid W Ceulemans Sophia S Charles Perrine P Cox Helen H Culliton Lisa L Currò Aurora A Demurger Florence F Dowling James J JJ Duban-Bedu Benedicte B Dubourg Christèle C Eiset Saga Elise SE Escobar Luis F LF Ferrarini Alessandra A Haack Tobias B TB Hashim Mona M Heide Solveig S Helbig Katherine L KL Helbig Ingo I Heredia Raul R Héron Delphine D Isidor Bertrand B Jonasson Amy R AR Joset Pascal P Keren Boris B Kok Fernando F Kroes Hester Y HY Lavillaureix Alinoë A Lu Xin X Maas Saskia M SM Maegawa Gustavo H B GHB Marcelis Carlo L M CLM Mark Paul R PR Masruha Marcelo R MR McLaughlin Heather M HM McWalter Kirsty K Melchinger Esther U EU Mercimek-Andrews Saadet S Nava Caroline C Pendziwiat Manuela M Person Richard R Ramelli Gian Paolo GP Ramos Luiza L P LLP Rauch Anita A Reavey Caitlin C Renieri Alessandra A Rieß Angelika A Sanchez-Valle Amarilis A Sattar Shifteh S Saunders Carol C Schwarz Niklas N Smol Thomas T Srour Myriam M Steindl Katharina K Syrbe Steffen S Taylor Jenny C JC Telegrafi Aida A Thiffault Isabelle I Trauner Doris A DA van der Linden Helio H van Koningsbruggen Silvana S Villard Laurent L Vogel Ida I Vogt Julie J Weber Yvonne G YG Wentzensen Ingrid M IM Widjaja Elysa E Zak Jaroslav J Baxter Samantha S Banka Siddharth S Rodan Lance H LH

American journal of human genetics 20190509 6

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intell ...[more]

PMID: 31079897

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Project description:The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism. OGDHL expression is restricted mainly to the brain in humans. Here, we report nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum. The variants include three homozygous missense variants (p.Pro852Ala, p.Arg244Trp, and p.Arg299Gly), three compound heterozygous single-nucleotide variants (p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, and p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant (p.Cys553Leufs∗16), and one homozygous stop-gain variant (p.Arg440Ter). To support the pathogenicity of the variants, we developed a novel CRISPR-Cas9-mediated tissue-specific knockout with cDNA rescue system for dOgdh, the Drosophila ortholog of human OGDHL. Pan-neuronal knockout of dOgdh led to developmental lethality as well as defects in Krebs cycle metabolism, which was fully rescued by expression of wild-type dOgdh. Studies using the Drosophila system indicate that p.Arg673Gln, p.Phe734Ser, and p.Arg299Gly are severe loss-of-function alleles, leading to developmental lethality, whereas p.Pro852Ala, p.Ala327Val, p.Trp220Cys, p.Asp491Val, and p.Arg244Trp are hypomorphic alleles, causing behavioral defects. Transcript analysis from fibroblasts obtained from the individual carrying the synonymous variant (c.1464T>C [p.Val488Val]) in family 2 showed that the synonymous variant affects splicing of exon 11 in OGDHL. Human neuronal cells with OGDHL knockout exhibited defects in mitochondrial respiration, indicating the essential role of OGDHL in mitochondrial metabolism in humans. Together, our data establish that the bi-allelic variants in OGDHL are pathogenic, leading to a Mendelian neurodevelopmental disease in humans.

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Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

Publications

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

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