Bolat Hilmi, Genç Akdağ Dilan, Ünsel-Bolat Gül
Department of Medical Genetics, Faculty of Medicine, Balıkesir University, Balıkesir, Türkiye.
Department of Child and Adolescent Psychiatry, Faculty of Medicine, Balıkesir University, Balıkesir, Türkiye.
Dev Neurobiol. 2025 Oct;85(4):e22994. doi: 10.1002/dneu.22994.
The EMC10 gene on chromosome 19 encodes one of the highly conserved endoplasmic reticulum membrane complexes (EMC). Specific mutations in EMC10 cause a disorder known as neurodevelopmental disorder with dysmorphic facies and variable seizures (NEDDFAS) (OMIM #619264), characterized by global developmental delay and dysmorphic facial features, which become apparent in early childhood. This study aims to present the clinical data associated with a novel variant of a patient diagnosed with NEDDFAS (OMIM #619264), a condition rarely reported in the literature. By examining the phenotypic implications and molecular mechanisms of pathogenic variants in the EMC10 gene, this study seeks to contribute to a better understanding of the genetic and clinical spectrum of the disease. Our case was followed up in the Child and Adolescent Psychiatry clinic with the diagnosis of intellectual disability. Initial genetic testing included karyotype analysis, FMR1 CGG repeat analysis, and chromosomal microarray analysis. Subsequently, whole-exome sequencing (WES) was performed, and Sanger sequencing was used to confirm the identified variant and conduct familial segregation analysis. We identified a novel homozygous frameshift variant in the EMC10 gene, NM_206538.4:c.431del, resulting in NP_996261.1:p.Asp144AlafsTer3 using WES. This variant was classified as pathogenic (P) according to ACMG criteria, which was clinically relevant to the patient's condition. Segregation analysis revealed that both the mother and the father were heterozygous carriers of this variant. To date, the phenotype associated with this variant has been reported in 31 individuals from 16 different families. To our knowledge, our case is the first reported patient in the Turkish population carrying an EMC10 gene variant. Among reported cases, variations in symptom distribution and severity have been observed. We propose that EMC10 gene variants may exhibit dual molecular effects. There are two types of neurodevelopmental clinical presentations: (1) a classic disease pattern with mild-to-moderate intellectual disability (ID) and no neurological findings and (2) a progressive disease pattern with severe ID, hypotonia, and abnormalities in gait.
位于19号染色体上的EMC10基因编码一种高度保守的内质网膜复合物（EMC）。EMC10基因的特定突变会导致一种名为“伴有畸形面容和可变癫痫的神经发育障碍”（NEDDFAS）（OMIM编号#619264）的疾病，其特征为全面发育迟缓及畸形面容，这些症状在幼儿期就会显现。本研究旨在呈现与一名被诊断为NEDDFAS（OMIM编号#619264）的患者的新型变异相关的临床数据，该疾病在文献中鲜有报道。通过研究EMC10基因中致病变异的表型影响和分子机制，本研究旨在促进对该疾病的遗传和临床谱系的更好理解。我们的病例在儿童和青少年精神病诊所进行随访，诊断为智力残疾。初始基因检测包括核型分析、FMR1 CGG重复序列分析和染色体微阵列分析。随后进行了全外显子测序（WES），并使用桑格测序法确认所鉴定的变异并进行家系分离分析。我们通过WES在EMC10基因（NM_206538.4）中鉴定出一个新型纯合移码变异，即c.431del，导致NP_996261.1:p.Asp144AlafsTer3。根据美国医学遗传学与基因组学学会（ACMG）标准，该变异被归类为致病性变异（P），这与患者的病情在临床上相关。分离分析显示，母亲和父亲都是该变异的杂合携带者。迄今为止，来自16个不同家庭的31名个体报告了与该变异相关的表型。据我们所知，我们的病例是土耳其人群中首例报告携带EMC10基因变异的患者。在已报告的病例中，观察到了症状分布和严重程度的差异。我们提出EMC10基因变异可能表现出双重分子效应。存在两种类型的神经发育临床表现：（1）一种典型的疾病模式，伴有轻度至中度智力残疾（ID）且无神经学表现；（2）一种进行性疾病模式，伴有严重ID、肌张力减退和步态异常。
