Is Mental Retardation Genetic?

The study of the genetic basis of mental retardation has grown enormously since its humble beginnings in the 1930s, with a survey of individuals confined to long-stay psychiatric settings.

The World Health Organization (WHO) defines mental retardation (MR) as having an IQ below 70 together with significant delays in developing two or more important areas of competence before the age of 18. The intelligence quotient (IQ) is a measure of cognitive ability. The term "developmental delay" is typically applied to children younger than five years old who show delays in the attainment of developmental milestones at the predicted age. Another aspect of developmental delay is that it is applied before the age of 5, when IQ testing is accurate and valid, and that it takes into account learning and adaptive deficiencies that predict eventual intellectual disability.

There are a wide variety of causes of mental retardation, some of which are chromosomal, some genetic, some metabolic, and some of which are attributable to prenatal illnesses that occur during pregnancy. Poor prenatal and postpartum care. Numerous perinatal deaths may be caused by birth hypoxia and other complications. Congenital phenylketonuria is one of many metabolic abnormalities that can cause mental impairment in children, yet it is entirely avoidable.

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What factors contribute to mental retardation?

Fetal alcohol syndrome, foetal alcohol effect, drug use during pregnancy (legal and illicit), brain injury, brain disease, and genetic diseases including Down syndrome and fragile X all contribute to the development of a child with intellectual disabilities.

Mental retardation can result from a number of factors, including as genetic diseases, maternal illnesses, adverse social environments, drug use, and exposure to toxic chemicals in the environment. Among the known causes of MR are:

• Various genetic disorders (e.g. Down's Syndrome, phenylketonuria)
• Certain maternal infections during pregnancy (e.g. rubella)
• Mother who abuses substances such as alcohol during pregnancy
• Certain psychosocial conditions (e.g. problems with caregiving, low socioeconomic status, low parental education)
• Maternal exposure to various drugs (e.g. thalidomide, valproic acid)
• Maternal exposure to environmental chemicals (discussed in detail later)

The growing body of scientific evidence has disproven the once-popular theory that retardation may be traced back to either "organic" or "environmental" factors. The mutual influences of genetics and early experiences are increasingly being acknowledged as crucial to every child's growth and development.

Gene Families that Cause Mental Retardation

LARGE CHROMOSOME ABNORMALITIES

Since the 1970s, researchers have known that mental retardation had a hereditary basis. Since Down syndrome was discovered to be the result of a chromosome defect, researchers have been trying to pin down ever-tinier chromosomal aberrations as the cause of mental retardation. The goal is to learn the molecular causes of intellectual disability so that better care can be given to those who suffer from it and their loved ones. In the past, when a karyotype was essentially a visual inspection of the full genome at the resolution of 5-10 Mb, the detection of gain or loss of genetic material on regular chromosome analysis at a 500 G banding resolution was usually clinically relevant. Embryonic abnormalities are usually always the result of a gain or loss of 5-10 Mb of DNA, which reflects a substantial footprint of genes wherever the aberration is found in the genome. Cognitive impairment is the most common symptom of a chromosomal mutation, but heart formation problems and dysmorphic characteristics are also common consequences. Rare mutations are described on occasion, however they often have minimal clinical importance and are linked to differences in euchromatic material.

MICRODELETIONS

It wasn't until the early 1990s that researchers found a link between specific diseases and recurrent, light-microscopically invisible deletions of DNA. Among these were the common microdeletion syndromes of Wolf-Hirshhorn, Prader-Willi, Cri du Chat, Williams, Miller-Dieker lissencephaly, Angelman, Rubinstein-Taybi, Smith-Magenis, Alagille, DiGeorge, and 22q11. These could only be detected through fluorescence in situ hybridization (FISH) or a similar technique. Each syndrome is unique in its own way, but they all share a common link to intellectual disability of varied degrees and, in some circumstances, a focus on a particular domain of knowledge.

A strategy for screening for the aberrant inheritance of subtelomeric DNA polymorphisms in people with mental retardation and dysmorphic traits was developed by Flint et al. in 1995, expanding on this technique. Since this discovery, screening telomeres for deletions, with a diagnostic yield of 2.5-15%, has become standard clinical practise for appropriately selected patients. Recently, numerous new microdeletion syndromes, including 3q29 microdeletion syndrome, have been delineated as a result of screening people with modest dysmorphic characteristics but mental retardation as the primary trait. These disorders are not easily grouped clinically, but the discovery of a shared microdeletion provides the foundation for the classification. This is indicative of a larger movement towards molecular similarities (recurrent comparable deletions or duplications) as a basis for grouping clinical dysmorphology features in the classification of mental retardation syndromes linked with fine chromosomal abnormalities.

Rare tiny family polymorphic deletions or duplications were seen after extensive screening of telomeres in people with mental retardation, making it often challenging to determine the clinical implications of a loss in an individual with mental retardation. They were still unusual at this point in time.

The link between microdeletions and mental retardation has been well-established, and recent advances in technology have made it possible to detect microdeletions and microduplications across the entire genome with just a single or a small number of tests. Using probes spaced at least 1 Mb apart on the genome allows the simultaneous usage of numerous probes. It has been demonstrated in recent papers that 10% of people with mental retardation possess deletions or duplications. Patients with severe mental impairment and dysmorphia were first chosen for this study. The observed deletions are typically sizable, affecting many genes.

COPY NUMBER CHANGES

The detection of single gene defects that cause mental retardation has been made possible by the continued development and refining of array CGH technology, which has resulted in more wide coverage of the genome. Because of its accessibility and the high number of X-linked mental retardation genes that map to this chromosome, X chromosome development has been prioritised at the outset (16). In a study of 100 patients, the use of an unique BAC tiling resolution genome-wide microarray found that 10% had de novo anomalies in a group of developmentally challenged persons, suggesting that further progress in this area is warranted. However, 97% of patients in this study had a copy number change that could be replicated, and on average, each patient had three mutations found across their genome. Many of these variations were either inherited and so assumed to be polymorphisms, or they could not be definitively pinned down because neither parent was available for testing. Though this tiling approach improves genome coverage significantly over the 1 Mb array, determining whether or not a rare variation is pathogenic has become a significant challenge. Copy number changes that are pathological or polymorphic can be resolved relatively easily in cases where the phenotype is unusual in the population and likely to be due to a single gene or a small number of single genes within the genome, but this is more difficult in cases where the phenotype is less distinct, such as mental retardation, and the number of single genes that cause this phenotype is at least 100 and probably very many more.

The human genome is shown to be extremely polymorphic, with large-scale copy number duplications or deletions occuring often between individuals. In addition, inversions and complicated rearrangements are significantly more common than was previously found, and their potential to predispose to disease is currently being investigation.

COPY NUMBER CHANGES IN SINGLE GENES

Many Mendelian disorders map to regions of the genome where copy number alterations are rare, however in the case of many single-gene disorders, such as Duchenne muscular dystrophy, Pelizeaus Merzbacher disease, and Charcot-Marie-Tooth disease, deletions and duplications are common causes of disease.

Males with severe mental impairment and increasing neurological symptoms have recently been linked to a pathological duplication of MECP2 and L1CAM. Still, further X chromosomal duplications at Xp22.3, Xq22.3, and Xq26.3 have been identified without any obvious pathology. This designation of duplication in Xq28 to clinical significance would not have been conceivable without the prior detection of point mutations in L1CAM and MECP2, and other duplications of genes in Xq28 have not necessarily been related with the disease.

Whether or not a gene is pathogenic is determined by whether or not anomalies in its coding sequence are absent from adequate control populations. It is important to distinguish between traits caused by haploinsufficiency of a single gene and those caused by a substantial loss when dealing with microdeletions linked to dysmorphic features and mental retardation. It has yet to be fully determined for several microdeletion disorders, such as Williams and 22q11 deletion syndrome, which gene in the shared deleted area causes which of the phenotypic traits. Patients with progressively smaller deletions were collected, and a balanced translocation was associated with the phenotype of the previously found 9q34 deletion syndrome. This allowed for the identification of the single gene within the often deleted area that caused the disease. Since minor gain or loss of genetic material in patients with translocations and no phenotype has been described, showing only the disruption of a gene at a balanced translocation breakpoint is still insufficient to be convinced that a particular gene causes disease. This trait has been linked to a unique disease-causing gene thanks to the identification of a point mutation in a single gene near 9q34 in euchromatic histone methyltransferase 1 (EHMT1). In addition to other clinical or dysmorphic traits, mental retardation is now known to be caused by a mutation in this gene.

CODING ABNORMALITIES IN SINGLE GENES

Disease-causing genes have traditionally been located through the analysis of familial instances. Extreme mental retardation in the family is usually a lethal reproductive mutation, hence autosomal dominant pedigrees are rare. The rate at which new mutations occur is crucial to the spread of disease genes in autosomal dominant conditions. Clinically identifying people with a shared phenotype, such as mental retardation without syndromic characteristics, can be challenging. Therefore, there are very few identified autosomal dominant genes that cause mental retardation. Collecting people with mental impairment and distinguishable dysmorphic traits for analysis and grouping has been essential to the discovery of novel genes. Systematic deletion mapping and point mutation analyses have been used to identify the single genes necessary to cause the phenotype in conditions like Smith-Magenis syndrome and Rubinstein-Taybi.

Homozygosity mapping in very consanguineous families with affected siblings can be very useful for identifying autosomal recessive causes of mental retardation. Autosomal genes for mental retardation are undoubtedly numerous, but progress in identifying them has been sluggish. Autozygosity mapping of very consanguineous families has been used to identify three genes: PRSS12 (on chromosome 4q26), CRBN (on chromosome 3p26), and most recently CC2D1A (on chromosome 19p13.12). Identifying uncommon families affected by the ailment and enriching a population with a founder mutation that will have occurred by chance are necessary steps in this strategy, yet it is highly effective at detecting autosomal recessive disease genes. In the next 5–10 years, several novel genes are expected to arise utilising this approach. But because it does not offer a systematic way of surveying the genome, it is not likely to discover all autosomal recessive genes.

X-LINKED MENTAL RETARDATION

Many single genes for mental retardation have been found, and they are almost all located on X. There is a male preponderance of affected individuals relative to females (ratio1: 1.3), which has been attributed to X-linked inheritance. This is thought to be the result of both the high density of causative genes on the X chromosome and the fact that females are better equipped to keep these genes alive through reproductive fitness maintenance. Fragile X syndrome gene FMR1 was the first gene discovered, and it is still the most frequent single-gene aberration. Positional cloning and translocation breakpoint mapping have both been used to discover several genes since 1990. Some are linked exclusively to intellectual disability and not to dysmorphic features or other neurological symptoms. Some of the genes have non-syndromic phenotypes identified for them, while others have syndromic traits. The genes IL1RAPL1, TM4SF2, ZNF41, FTSJ1, DLG3, FACL4, PAK3, ARHGEF6, FMR2, GDI, ZNF81, and ZNF674 are currently classed as non-syndromic mental retardation genes, while the genes NLGN4, RPS6KA3 (RSK2), OPHN1, ATRX, SLC6A8, ARX, SYN1, AGTR2, MECP2, PQBP1, F

The number of newly identified genes has not increased exponentially over the past 18 months, despite technological advancements that would indicate either that almost all the genes on the X chromosome have been found or that the remaining number of genes to be found are becoming increasingly difficult to identify due to their rarity. The latter theory is bolstered by the fact that, despite exhaustive screening of the known genes, the causative mutation for moderate to severe mental retardation in families with three or four generations of affected members and a clear X-linked inheritance pattern has not been located. Approximately fifty genes in the Xp11 region were searched for brain expression, and only three were found. The sequence homology and functional similarity of 70 candidate genes to those already identified in a panel of 300 X-linked families led to the discovery of only one unique gene, in which three missense variations were found (Raymond et al., unpublished). In order to find the remaining X-linked genes for mental retardation, a fresh methodical approach is required. At an effort to discover new genes that contribute to X-linked mental retardation, the authors of this paper launched the Genetics of Learning Disability (GOLD) study in Cambridge, UK. In a cohort of 200 families with X-linked mental retardation, the team is employing high throughput genomic DNA sequencing to examine all coding exons of all X-chromosomal genes. It is estimated that 854 genes will need to be tested, and that 7,200 primer pairs would be needed to adequately cover the genes. The family was chosen for sequencing because there were at least two males in the family who showed symptoms, the karyotype was normal, and the cause of the disease was unknown. Due to the high likelihood that a disease in such a large family is caused by a single gene flaw, attention is first focused on such families. While the final results of this massive study have not been released to the public, it is becoming clear that many novel, rare variations on the X chromosome are being discovered in the cohort of 200 families, and not all of them are likely to be disease-causing. Truncating mutations are not uncommonly polymorphic and are not always linked to the illness phenotype, as shown by the available data. This has significant repercussions for the field of molecular genetics and highlights the importance of using samples from close relatives to track mutations and being mindful that de novo sequence variants are not always dangerous. However, it is hoped that the discovery of many more genes responsible with X-linked mental retardation will make a major contribution to the research.

The idea that all cases of male mental retardation are caused by highly penetrant X-linked abnormalities is called into question by the findings of Mandel and Chelly, who found that the prevalence of mutations in ARX was high at 6.6% in X-linked pedigrees but was just 0.13% in singletons. This may account for the increased prevalence of the disease in male sib pairs quite apart from the rarer X-linked family pedigrees, suggesting that there is a general predisposition to mental retardation in males similar to that of autism, where predisposing genetic alleles need to be identified and are not necessarily located on the X chromosome. Empirical recurrence risk estimates range from 2-14% or 8.4% in a recent population-based study in Atlanta, USA, where recurrences in children born between 1981 and 1991 for isolated mental retardation were noted, and are largely based on multiple observations of sib-pair recurrence risks between 1971 and 1987.

TYPES OF GENES THAT CAUSE MENTAL RETARDATION

Increasing evidence suggests that numerous protein disorders can lead to mental impairment. Many genes involved in chromatin remodelling or signalling via the RhoGTPase pathway (GDI, PAK3, ARHGEF6) were among the first to be discovered (RPS6KA3, ATRX). Defective synaptic vesicle components or those required for their production have recently been identified (SYN1, SLC6A8, NLGN4, and DLG3), as have several unique transcription factors (ZNF41, 81, and 674). Molecular studies in rat models of learning and memory deficits have pinpointed molecules in the post-synaptic density as essential mediators of long-term potentiation and depression, thus the discovery of mutations in these genes is particularly fascinating (LDP and LTP).

Given the large number of genes implicated in the disorder, it seems unlikely that a single overarching mechanism is responsible for mental retardation. Rather, a mental retardation phenotype may arise as the last common pathway of many distinct forms of aberrant cellular processing. Humans, who like to believe their mental processing is sophisticated and complex, will find this encouraging; however, the mental retardation biologist, who naively believed that identifying the genes responsible for the disease would immediately shed light on the mechanism of the disease processes, will find this somewhat daunting.

Two recent publications have proposed that some learning and memory deficits may be treatable by therapeutic drugs, despite the complexity and number of genes already identified. Treatment with metabotropic glutamate receptors (mGluR) antagonists or lithium restores synaptic plasticity and courting behaviour in a Drosophila model of Fragile X disease, as shown by McBride et al. Lovastatin, an HMG-CoA reductase inhibitor, can also reverse memory and learning problems in a mouse model of neurofibromatosis type 1. Although these findings do not yet show therapeutic effects in humans, they do raise the prospect of delivering medication therapies for certain aspects of learning difficulty. Therefore, the initial goal of understanding the molecular basis of intellectual disability and providing an ever-improving clinical service to this group of patients and their families is rapidly being achieved, and exciting new developments are likely to arise in this field within the next 5-10 years.

The aetiology of mental retardation is mostly determined by genetic factors. In this chapter, we surveyed the spectrum of inherited mental retardation illnesses, from chromosomal abnormalities and contiguous gene syndromes to monogenic forms of the disorder and metabolic disorders that manifest as mental retardation, as well as multifactorial inheritance.

Massive efforts in research were made to identify the genetic basis and structural and functional consequences of mental impairment. First, research has been conducted with the goal of elucidating the origins and developmental course of mental retardation. Second, studies were conducted to find ways to screen newborns for treatable illnesses at an earlier age. Experience with screening for, diagnosing, and treating inborn errors of metabolism has demonstrated to have a favourable economic and societal impact (PKU, hypothyroidism, organic acidemias). Most syndromes associated with mental retardation currently have no cure and require intensive, expensive, and ongoing therapy. This means that families with children who have mental impairment need individualised professional support to prevent their children from becoming socially and even familially isolated. The availability of interventions that focus on teaching people healthy ways to deal with stressful situations, such as counselling and support groups, has lessened the toll on family life and laid the groundwork for the growth of local infrastructure.