TY - JOUR
T1 - Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy
AU - Deciphering Developmental Disorders (DDD) Study
AU - O'Donnell-Luria, Anne H.
AU - Pais, Lynn S.
AU - Faundes, V. ctor
AU - Wood, Jordan C.
AU - Sveden, Abigail
AU - Luria, Victor
AU - Abou Jamra, Rami
AU - Accogli, Andrea
AU - Amburgey, Kimberly
AU - Anderlid, Britt Marie
AU - Azzarello-Burri, Silvia
AU - Basinger, Alice A.
AU - Bianchini, Claudia
AU - Bird, Lynne M.
AU - Buchert, Rebecca
AU - Carre, Wilfrid
AU - Ceulemans, Sophia
AU - Charles, Perrine
AU - Cox, Helen
AU - Culliton, Lisa
AU - Currò, Aurora
AU - McRae, Jeremy F.
AU - Clayton, Stephen
AU - Fitzgerald, Tomas W.
AU - Kaplanis, Joanna
AU - Prigmore, Elena
AU - Rajan, Diana
AU - Sifrim, Alejandro
AU - Aitken, Stuart
AU - Akawi, Nadia
AU - Alvi, Mohsan
AU - Ambridge, Kirsty
AU - Barrett, Daniel M.
AU - Bayzetinova, Tanya
AU - Jones, Philip
AU - Jones, Wendy D.
AU - King, Daniel
AU - Krishnappa, Netravathi
AU - Mason, Laura E.
AU - Singh, Tarjinder
AU - Tivey, Adrian R.
AU - Ahmed, Munaza
AU - Anjum, Uruj
AU - Archer, Hayley
AU - Armstrong, Ruth
AU - Awada, Jana
AU - Balasubramanian, Meena
AU - Banka, Siddharth
AU - Maas, Saskia M.
AU - van Koningsbruggen, Silvana
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85066447016&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31079897
U2 - https://doi.org/10.1016/j.ajhg.2019.03.021
DO - https://doi.org/10.1016/j.ajhg.2019.03.021
M3 - Article
C2 - 31079897
SN - 0002-9297
VL - 104
SP - 1210
EP - 1222
JO - American journal of human genetics
JF - American journal of human genetics
IS - 6
ER -