Abstract
Over the past five years, the MYCBP2 has emerged as a potential candidate gene associated with neurodevelopmental disorders (NDDs). In 2023, a newly characterized condition, termed MYCBP2-related developmental delay with corpus callosum defects (MDCD), has been reported in eight individuals presenting corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy and autistic features. To date, all reported cases have been associated with distinct de novo variants. Here, we describe the first family with three affected members carrying a novel pathogenic MYCBP2 variant. A mother and her two sons were referred to our laboratory for genetic testing. The phenotypic characteristics of our three patients included intellectual disability, speech impairment, facial dysmorphism, microcephaly and seizures (presented only in the mother). We performed WES on the three affected family members using Twist Human Core+RefSeq+Mitochondrial Panel on Illumina Nova Seq 6000. We have identified a novel loss of function variant in MYCBP2 [NM_015057.5 c.7311del, p.(Leu2438Trpfs*3)] in heterozygous state in the mother and her two sons. The variant causes a frameshift, leading to NMD and C-terminal truncation, eliminating key domains (RING and TC) essential for ubiquitin ligase activity and interactions with other cellular components, particularly in processes related to synaptic regulation. Here, we present the clinical manifestation of MYCBP2-related developmental delay in three patients of a same family. Our study further supports the critical role of MYCBP2 in the pathogenesis of NDDs and contributes to the phenotype of a recently recognized MDCD syndrome.