Molecular Genetics of Mental Retardation
Authors: Basel‐Vanagaite Lina 
Published: December 2008

Mental retardation (MR) affects 1–3% of the population. It can be subdivided into syndromic and nonsyndromic forms. The empiric recurrence risk for siblings in families with a mentally retarded child is 8–10%. Gross chromosomal imbalances are implicated in the aetiology in 10–24% of cases and cryptic chromosomal imbalances in about 10%. In families with X‐linked MR (XLMR) a disease‐causing mutation can be identified in 42%; in families with autosomal recessive MR a causative mutation can be identified only rarely since only five genes have been discovered. The function of many of the proteins involved in MR is related to signal transduction, regulation of transcription, core metabolism, DNA (
deoxyribonucleic acid
) and RNA (
ribonucleic acid
) processing, protein synthesis, regulation of cell cycle or ubiquitination. Establishing a molecular diagnosis in mentally retarded individuals can have a major impact on reproductive counselling, prevention of mental handicap and on further understanding of molecular mechanisms involved in human cognitive processes.

Key concepts

Mental retardation can be subdivided into syndromic forms, characterized by cognitive impairment accompanied by dysmorphic features, malformations or neurological abnormalities, and nonsyndromic forms, characterized by MR without additional features.

Gross chromosomal imbalances can be identified in 10–24% of the patients with MR and are more frequently found in patients with syndromic MR.

Pathogenic cryptic copy number changes are implicated in the aetiology of ∼10% of cases of all types of MR; the frequency of cryptic chromosomal imbalances is unknown in nonsyndromic MR.

Culturo‐familial MR is believed to be caused by a combination of genetic and environmental factors and is usually nonsyndromic; possible quantitative trait loci that play a role in the predisposition to MR have been identified.

More than 80 genes are known to be involved in nonsyndromic and syndromic XLMR. After exclusion of Fragile X syndrome, mutations in these genes can be identified in 42% of individuals with XLMR.

Only five genes and eight loci are known to be involved in autosomal recessive nonsyndromic MR, and most of the causative genes still have to be discovered.

The functions of proteins involved in cognitive impairment are diverse and are related to signal transduction, regulation of transcription, core metabolism, DNA and RNA processing, protein synthesis, regulation of the cell cycle, ubiquitination and other cellular processes.

Diagnostic workup of patients with MR should include all or some of the following: careful dysmorphological and neurological examination, karyotyping, fragile X analysis, investigations aimed at detection of microdeletions/microduplications and resequencing of mental retardation‐causing genes. Mutations in some of the genes can be suspected due to the existence of specific metabolic or endocrine abnormalities.

Empiric recurrence risks for siblings in families with a mentally retarded child are 8–10%. Recurrence risks for MR caused by single gene mutations depend on the mode of inheritance.

A large‐scale programme for the prevention of MR based on carrier screening is rarely possible in specific populations except for Fragile X syndrome. Prenatal diagnostic options in most of the at‐risk families are not available since the chances of identifying a mutation in a proband with unexplained MR are still low.