Homozygous Missense Variant in the N-Terminal Region of ANK3 Gene Is Associated with Developmental Delay, Seizures, Speech Abnormality, and Aggressive Behavior

Molecular syndromology

article

Younus, Muhammad¹  Rasheed, Memoona²  Lin, Zhaohan¹  Asiri, Saeed A.³  Almazni, Ibrahim A.³  Alshehri, Mohammed Ali³  Shafiq, Sarfraz⁴  Iqbal, Imran⁵  Khan, Amjad⁶  Ullah, Hanif⁷  Umair, Muhammad⁸  Waqas, Ahmed⁹ 

[1] State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University;Department of Pathology, Islamabad Medical and Dental College;Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Najran University;Department of Anatomy and Cell Biology, University of Western Ontario;Department of PLR, Institute of Active Polymers;Faculty of Science, Department of Biological Sciences ,(Zoology), University of Lakki Marwat;Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine;Medical Genomics Research Department, King Abdullah International Medical Research Center ,(KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs;Department of Zoology, Division of Science and Technology, University of Education Lahore

关键词: Autosomal recessive;    Homozygous;    Missense variant;    ANK3;    Intellectual disability;    Whole exome sequencing;   

DOI  :  10.1159/000526381

学科分类：基础医学

来源: S Karger AG

【 摘 要 】

Introduction: Intellectual disability (ID) is a lifelong disability that affects an individual’s learning capacity and adaptive behavior. Such individuals depend on their families for day-to-day survival and pose a significant challenge to the healthcare system, especially in developing countries. ID is a heterogeneous condition, and genetic studies are essential to unravel the underlying cellular pathway for brain development and functioning. Methods: Here we studied a female index patient, born to a consanguineous Pakistani couple, showing clinical symptoms of ID, ataxia, hypotonia, developmental delay, seizures, speech abnormality, and aggressive behavior. Whole exome sequencing (WES) coupled with Sanger sequencing was performed for molecular diagnosis. Further, 3D protein modeling was performed to see the effect of variant on protein structure. Results:C; p.Tyr60His) in the ANK3 gene. In silico analysis and 3-dimensional (3D) protein modeling supports the deleterious impact of this variant on the encoding protein, which compromises the protein’s overall structure and function. Conclusion: Our finding supports the clinical and genetic diversity of the ANK3 gene as a plausible candidate gene for ID syndrome. Intelligence is a complex polygenic human trait, and understanding molecular and biological pathways involved in learning and memory can solve the complex puzzle of how cognition develops. Intellectual disability (ID) is defined as a deficit in an individual’s learning and adaptive behavior at an early age of onset [American Psychiatric Association, 2013]. It is one of the major medical, and cognitive disorders with a prevalence of 1–3% in the population worldwide [Leonard and Wen, 2002]. ID often exists with other disabling mental conditions such as autism, attention deficit hyperactivity disorder, epilepsy, schizophrenia, bipolar disorder, or depression. Almost half of the cases appear to have a genetic explanation that ranges from cytogenetically visible abnormalities to monogenic defects [Flint, 2001; Ropers, 2010; Tucker-Drob et al., 2013]. Intellectual disability is a genetically heterogeneous condition, and more than 700 genes have been identified to cause ID alone or as a part of the syndrome. Research in X-linked ID has identified more than 100 disease-causing genes on the X chromosome that play a role in cognition; however, research into autosomal causes of ID is still ongoing [Vissers et al., 2016].

【 授权许可】

CC BY