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A Biallelic Loss-Of-Function Variant in Tmem147 Causes Profound Intellectual Disability and Spasticity Publisher Pubmed



Ghorashi T1 ; Darvish H2 ; Bakhtiari S3, 4 ; Tafakhori A5 ; Kruer MC3, 4 ; Mozdarani H1
Authors
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Authors Affiliations
  1. 1. Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
  2. 2. Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
  3. 3. Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, United States
  4. 4. Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, United States
  5. 5. Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran

Source: Neurogenetics Published:2023


Abstract

Intellectual disability (ID), occurring in syndromic or non-syndromic forms, is the most common neurodevelopmental disorder. Although many cases are caused by single gene defects, ID is highly genetically heterogeneous. Biallelic variants in the transmembrane protein TMEM147 have recently been linked to intellectual disability with dysmorphic facial features. TMEM147 is believed to localize to the endoplasmic reticulum membrane and nuclear envelope and also involved in biogenesis of multi-pass membrane proteins. Here, we report two patients born to a consanguineous family with a novel loss-of-function variant; (NM_001242597.2:c.193-197del) in TMEM147 causing intellectual disability and spasticity. Whole exome sequencing and validating Sanger sequencing were utilized to confirm the identified causal variant. Our findings were in line with the previously described patients with TMEM147 variants manifesting intellectual disability as a major clinical sign but also featured spasticity as a phenotypic expansion. This study provides additional evidence for the pathogenicity of TMEM147 mutations in intellectual disability and expands the phenotypic and variant spectrum linked to this gene. © 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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