A Novel LINS1 Truncating Mutation in Autosomal Recessive Nonsyndromic Intellectual Disability.

Babylakshmi Muthusamy,Satish Chandra Girimaji,Anikha Bellad,Akhilesh Pandey,Pramada Prasad,R M Kiragasur,G Bhuvanalakshmi,Aravind K Bandari

doi:10.3389/fpsyt.2020.00354

Abstract

The large majority of cases with intellectual disability are syndromic (i.e. occur with other well-defined clinical phenotypes) and have been studied extensively. Autosomal recessive nonsyndromic intellectual disability is a group of genetically heterogeneous disorders for which a number of potentially causative genes have been identified although the molecular basis of most of them remains unexplored. Here, we report the clinical characteristics and genetic findings of a family with two male siblings affected with autosomal recessive nonsyndromic intellectual disability. Whole exome sequencing was carried out on two affected male siblings and unaffected parents. A potentially pathogenic variant identified in this study was confirmed by Sanger sequencing to be inherited in an autosomal recessive fashion. We identified a novel nonsense mutation (p.Gln368Ter) in the LINS1 gene which leads to loss of 389 amino acids in the C-terminus of the encoded protein. The truncation mutation causes a complete loss of LINES_C domain along with loss of three known phosphorylation sites and a known ubiquitylation site in addition to other evolutionarily conserved regions of LINS1. LINS1 has been reported to cause MRT27 (mental retardation, autosomal recessive 27), a rare autosomal recessive nonsyndromic intellectual disability, with limited characterization of the phenotype. Identification of a potentially pathogenic truncating mutation in LINS1 in two profoundly intellectually impaired patients also confirms its role in cognition.

Highlights

Intellectual disability (ID) is a neurodevelopmental disorder characterized by significant limitations in intellectual functioning and adaptive behavior, which include conceptual, social, and practical skills
Five affected members including a female patient were described with the clinical characteristics of including normal motor development, delayed speech, moderate ID and epilepsy [27]
LINS1 gene as the molecular cause for MRT27 was first described by Najmabadi et al using homozygosity mapping and generation sequencing in a consanguineous family comprising of four affected individuals with moderate ID and microcephaly [28]

Summary

Introduction

Intellectual disability (ID) is a neurodevelopmental disorder characterized by significant limitations in intellectual functioning and adaptive behavior, which include conceptual, social, and practical skills. A meta-analysis of ID estimated its prevalence as ~10 in 1,000 population with differences based on age and income [1]. LINS1 Truncating Mutation in MRT27 low-middle income countries are reported to be affected with ID [1]. ID is classified into syndromic ID and nonsyndromic ID based on the clinical presentation of patients. In syndromic ID, patients exhibit one or more distinct clinical features or comorbidities in addition to ID. Nonsyndromic ID is generally a pure form of ID which is defined by the presence of ID as the sole clinical feature. The distinction between syndromic and nonsyndromic ID is often blurred owing to overlap and subclinical presentation [2]. More than 200 candidate genes have been associated with nonsyndromic ID far [3]

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