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

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

Resposta hemática de tilápias-do-nilo alimentadas com dietas suplementadas com colina e submetidas a estímulo por baixa temperatura Hematic response of Nile tilapia fed diets supplemented with choline and submitted to stimulus by low temperature

Esta pesquisa foi realizada com o objetivo de avaliar a resposta hemática de tilápias-do-nilo (Oreochromis niloticus) arraçoadas com dietas suplementadas com colina e submetidas a estímulo por baixa temperatura. O período experimental foi realizado em duas etapas: a primeira, de 109 dias, e a segunda, de 7 dias. Durante a primeira etapa, foram utilizados 192 alevinos com peso médio inicial de 4 g, distribuídos em 32 tanques-rede de 200 L instalados em aquários de mil litros. As rações foram formuladas de modo a apresentar 28,0% de proteína digestível e 3.100,0 kcal ED/kg e mesma concentração de aminoácidos. O delineamento experimental foi inteiramente casualizado com oito tratamentos e quatro repetições. As rações foram suplementadas com colina (cloreto de colina 60,0%), de modo a apresentar 100,0; 200,0; 400,0; 600,0; 800,0; 1.000,0 e 1.200,0 mg/kg de ração, e avaliadas em comparação a uma ração sem suplementação. Após o período de 109 dias, foram efetuadas as análises hematológicas dos peixes. Após as análises, os peixes foram transferidos para a sala de desafio e distribuídos em 24 aquários, onde foram mantidos a 17ºC durante sete dias. Após esse período, foram feitas as mesmas análises do período anterior ao desafio. A suplementação de colina não influenciou a eritropoiese ao estímulo pelo frio. A suplementa��ão dietética de colina não interfere na síntese de eritrócitos e leucócitos e a temperatura de 17,0ºC determina linfopenia e neutrofilia.<br>The aim of this study was to evaluate the hematic response of Nile tilapia (Oreochromis niloticus) fed diets supplemented with choline and submitted to temperature stress. The experimental period was realized in two phases: the first, during 109 days, and the second, for seven days. During the first stage, 192 fingerlings with average initial weight of 4 g were distributed in 32 net cages (200 L) allocated in 1,000-L aquaria. The diets were formulated to present 28% of digestible protein and 3,100 kcal DE/kg and the same concentration of amino acids. It was used a complete random experimental design with eight treatments and four replicates. The diets were choline supplemented (60% choline chloride) in order to present 100.0; 200.0; 400.0; 600.0; 800.0; 1,000.0 and 1,200.0 mg/kg of diet and evaluated by comparing to a non-supplemented diet. After the 109-day period, the hematological analyses of the fish were performed. After these analyzes, fish were transferred to the challenge room, distributed in 24 aquaria, and kept at 17ºC during seven days. After this period, the same analyzes of the period previous to the challenge were done. Choline supplementation did not affected erythropoiesis to stimulus by the cold temperature. Dietary choline supplementation does not affect erythrocyte and leukocyte synthesis and the 17ºC temperature determines lymphopenia and neutrophilia