Boeri Silvia, Scala Marcello, Madia Francesca, Perucco Francesca, Vozzi Diego, Capra Valeria, Zara Federico, Nobili Lino, Mancardi Maria Margherita
Unit of Child Neuropsychiatry, IRCCS Istituto Giannina Gaslini, Epicare Network for Rare Disease, Genoa, Italy.
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.
Epileptic Disord. 2023 Dec;25(6):874-879. doi: 10.1002/epd2.20141. Epub 2023 Aug 8.
The MYT1L gene plays a critical role in brain development, promoting the differentiation and proliferation of cells, important for the formation of brain connections. MYT1L is also involved in regulating the development of the hypothalamus, which is a crucial actor in weight regulation. Genetic variants in the MYT1L are associated with a range of developmental disorders, including intellectual disability, autism spectrum disorder, facial dysmorphisms, and epilepsy. The specific role of MYT1L in epilepsy remains elusive and no patients with developmental and epileptic encephalopathy (DEE) have been described so far. In this study, we report a patient with DEE presenting with severe refractory epilepsy, obesity, and behavioral abnormalities. Exome sequencing led to the identification of the heterozygous variant NM_001303052.2: c.1717G>A, p.(Gly573Arg) (chr2-1910340-C-T; GRCh38.p14) in the MYT1L gene. This variant was found to be inherited by the father, who was a mosaic and did not suffer from any neuropsychiatric disorders. Our observations expand the molecular and phenotype spectrum of MYT1L-related disorders, suggesting that affected individuals may present with severe epileptic phenotype leading to neurocognitive deterioration. Furthermore, we show that mosaic parents may not display the disease phenotype, with relevant implications for genetic counseling.
MYT1L基因在大脑发育中起着关键作用，促进细胞的分化和增殖，这对脑连接的形成很重要。MYT1L还参与调节下丘脑的发育，而下丘脑是体重调节中的关键因素。MYT1L基因的遗传变异与一系列发育障碍有关，包括智力残疾、自闭症谱系障碍、面部畸形和癫痫。MYT1L在癫痫中的具体作用仍不清楚，迄今为止尚未描述过患有发育性和癫痫性脑病（DEE）的患者。在本研究中，我们报告了一名患有DEE的患者，其表现为严重难治性癫痫、肥胖和行为异常。外显子组测序导致在MYT1L基因中鉴定出杂合变异NM_001303052.2：c.1717G>A，p.（Gly573Arg）（chr2-1910340-C-T；GRCh38.p14）。发现该变异由父亲遗传，父亲是嵌合体，未患任何神经精神疾病。我们的观察结果扩展了MYT1L相关疾病的分子和表型谱，表明受影响个体可能表现出严重的癫痫表型，导致神经认知恶化。此外，我们表明嵌合型父母可能不表现出疾病表型，这对遗传咨询具有重要意义。
