Genetics and pathophysiology of mental retardation

Abstract

Mental retardation (MR) is defined as an overall intelligence quotient lower than 70, associated with functional deficit in adaptive behavior, such as daily-living skills, social skills and communication. Affecting 1-3% of the population and resulting from extraordinary heterogeneous environmental, chromosomal and monogenic causes, MR represents one of the most difficult challenges faced today by clinician and geneticists. Detailed analysis of the Online Mendelian Inheritance in Man database and literature searches revealed more than a thousand entries for MR, and more than 290 genes involved in clinical phenotypes or syndromes, metabolic or neurological disorders characterized by MR. We estimate that many more MR genes remain to be identified. The purpose of this review is to provide an overview on the remarkable progress achieved over the last decade in delineating genetic causes of MR, and to highlight the emerging biological and cellular processes and pathways underlying pathogeneses of human cognitive disorders.

Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration

“…[8][9][10][11][12] In affected children from consanguineous families, autosomal recessive (AR) inheritance is common; 13 however, congenital disorders with ID constitute an important medical problem because they represent a challenge in diagnosis, high prevalence and life-long care that most of these patients need. 14 A recent review suggests that ARID is not rare, and in outbred populations as many as 13-24% of ID may be due to AR genes, 13 and identifying the underlying genetic cause is an important issue in clinical genetics.…”

IL1-receptor accessory protein-like 1 (IL1RAPL1), a protein involved in cognitive functions, regulates N-type Ca 2+ -channel and neurite elongation

“…The underlying causes are extremely heterogeneous, including genetic causes, many of which are X-linked (XLMR) (1,2). Null mutations in the IL1-receptor accessory protein-like 1 gene (IL1RAPL1) [National Center for Biotechnology Information (NCBI) accession no.…”

Homozygosity mapping in outbred families with mental retardation

“…2,3 Genetic causes contribute significantly to MR and among these autosomal recessive inheritances may account for a substantial part of this disorder. Although no recent estimations have been made, autosomal recessive genes have previously been estimated to account for up to 25% of unexplained MR. [4][5][6][7] This is more than two times as frequent as the contribution of single X-chromosomal genes to MR, which is estimated to explain MR in 10% of affected men. [8][9][10] For practical reasons, over the last few decades, the focus in genetic MR research has been on X-linked MR, leading to the identification of 90 disease genes on the X-chromosome of which 38 (42%) lead to nonsyndromic MR. 11 In contrast, of the 348 genes contributing to autosomal recessive mental retardation (AR-MR) phenotypes, only six genes (1.6%) have been identified giving rise to nonsyndromic AR-MR (OMIM: http://www.ncbi.nlm.nih.gov/omim).…”