Expanding the genetic and phenotypic spectrum of TRAPPC9 and MID2-related neurodevelopmental disabilities: report of two novel mutations, 3D-modelling, and molecular docking studies

IF 2.6 3区 生物学 Q2 GENETICS & HEREDITY Journal of Human Genetics Pub Date : 2024-03-11 DOI:10.1038/s10038-024-01242-9
Marwa Kharrat, Chahnez Triki, Abir ben isaa, Wafa Bouchaala, Olfa Alila, Jihen Chouchen, Yosra Ghouliya, Fatma Kamoun, Abdelaziz Tlili, Faiza Fakhfakh
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Abstract

Intellectual disabilities (ID) and autism spectrum disorders (ASD) have a variety of etiologies, including environmental and genetic factors. Our study reports a psychiatric clinical investigation and a molecular analysis using whole exome sequencing (WES) of two siblings with ID and ASD from a consanguineous family. Bioinformatic prediction and molecular docking analysis were also carried out. The two patients were diagnosed with profound intellectual disability, brain malformations such as cortical atrophy, acquired microcephaly, and autism level III. The neurological and neuropsychiatric examination revealed that P2 was more severely affected than P1, as he was unable to walk, presented with dysmorphic feature and exhibited self and hetero aggressive behaviors. The molecular investigations revealed a novel TRAPPC9 biallelic nonsense mutation (c.2920 C > T, p.R974X) in the two siblings. The more severely affected patient (P2) presented, along with the TRAPPC9 variant, a new missense mutation c.166 C > T (p.R56C) in the MID2 gene at hemizygous state, while his sister P1 was merely a carrier. The 3D modelling and molecular docking analysis revealed that c.166 C > T variant could affect the ability of MID2 binding to Astrin, leading to dysregulation of microtubule dynamics and causing morphological abnormalities in the brain. As our knowledge, the MID2 mutation (p.R56C) is the first one to be detected in Tunisia and causing phenotypic variability between the siblings. We extend the genetic and clinical spectrum of TRAPPC9 and MID2 mutations and highlights the possible concomitant presence of X-linked as well as autosomal recessive inheritance to causing ID, microcephaly, and autism.

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扩展 TRAPPC9 和 MID2 相关神经发育障碍的遗传和表型谱:报告两种新型突变、三维建模和分子对接研究。
智障(ID)和自闭症谱系障碍(ASD)的病因多种多样,包括环境和遗传因素。我们的研究报告采用全外显子组测序(WES)技术,对一个近亲家庭中患有智障和自闭症谱系障碍的两个兄弟姐妹进行了精神科临床调查和分子分析。研究还进行了生物信息学预测和分子对接分析。这两名患者被诊断为深度智障、大脑皮质萎缩等脑部畸形、后天性小头畸形和自闭症三级。神经和神经精神检查显示,P2 的病情比 P1 更为严重,因为他无法行走,表现出畸形特征,并有自我和异性攻击行为。分子研究发现,这对兄妹中存在一种新型 TRAPPC9 双重无义突变(c.2920 C > T, p.R974X)。病情较重的患者(P2)在出现 TRAPPC9 变异的同时,还出现了 MID2 基因中的一个新的错义突变 c.166 C > T (p.R56C),且为半合子状态,而他的姐姐 P1 只是携带者。三维建模和分子对接分析表明,c.166 C > T 变异可能影响 MID2 与 Astrin 的结合能力,导致微管动力学失调,引起大脑形态异常。据我们所知,MID2 基因突变(p.R56C)是首次在突尼斯检测到的基因突变,它导致了兄弟姐妹之间的表型差异。我们扩展了 TRAPPC9 和 MID2 突变的遗传和临床谱系,并强调了 X 连锁遗传和常染色体隐性遗传可能同时存在,从而导致 ID、小头畸形和自闭症。
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来源期刊
Journal of Human Genetics
Journal of Human Genetics 生物-遗传学
CiteScore
7.20
自引率
0.00%
发文量
101
审稿时长
4-8 weeks
期刊介绍: The Journal of Human Genetics is an international journal publishing articles on human genetics, including medical genetics and human genome analysis. It covers all aspects of human genetics, including molecular genetics, clinical genetics, behavioral genetics, immunogenetics, pharmacogenomics, population genetics, functional genomics, epigenetics, genetic counseling and gene therapy. Articles on the following areas are especially welcome: genetic factors of monogenic and complex disorders, genome-wide association studies, genetic epidemiology, cancer genetics, personal genomics, genotype-phenotype relationships and genome diversity.
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