Trends in Genetics
ReviewGenetics of recessive cognitive disorders
Section snippets
ID: a major unsolved problem of healthcare
Early-onset cognitive impairment, commonly referred to as mental retardation or, more recently, ID [1], is defined as a disability ‘characterized by significant limitations both in intellectual functioning and in adaptive behavior’, and which ‘originates before the age of 18’ [2] with an IQ below 70 (= IQ 100 – 2SD) which is generally considered to be the threshold for ID. According to this definition, ID is estimated to affect 1–3% of Western populations [3] but is significantly more common
Most autosomal recessive gene defects are still unknown
Since 1991, the year when common fragile X syndrome was elucidated, more than 100 X-linked gene defects have been implicated in ID, as reported and reviewed elsewhere 6, 7. During the past decade numerous de novo and recurrent copy-number variants (CNVs) have been identified that cause or predispose to ID [8] and more recently, sequencing of affected individuals and their healthy parents has indicated that in sporadic patients, de novo basepair changes are another important cause of ID (9, 10,
Homozygosity mapping in consanguineous families
Homozygosity (or autozygosity) mapping in consanguineous families is the strategy of choice for mapping genes for recessive disorders in the human genome [12] (Box 1). Before 2002, virtually nothing was known about the molecular causes of ARID and, until 2006, no more than three genes for non-syndromic ARID had been identified, all by microsatellite-based homozygosity mapping in large consanguineous families and subsequent mutation screening of functionally plausible positional candidate genes
Next-generation sequencing (NGS): a new dimension in the elucidation of ARID
The introduction of high-throughput NGS techniques (Box 2) has revolutionized the genetic dissection of ID and the identification of gene defects underlying ARID. TECR was the first gene for which a causative homozygous variant was identified by whole-exome enrichment and sequencing (WES) of a large consanguineous family with NS-ID [19], and a missense mutation in this gene was recently found to be a common cause of NS-ID in Hutterites [20]. TECR codes for trans-2,3-enoyl-CoA reductase (also
Most novel candidates are bona fide ARID genes
Many of the recently reported novel candidate genes are very attractive candidates because of their synapse- or brain-specific function; others involve basic cellular processes which have been repeatedly implicated in ID, such as DNA transcription and translation, protein degradation, mRNA splicing, energy metabolism, or fatty-acid synthesis and turnover [22]. Conclusive proof for their indispensable role in the brain has been obtained for a growing number of these genes through the
ARID is extremely heterogeneous and clinically variable
At the time of writing, 40 genes have been implicated in NS-ID (Table 1, Table 2). In 11 of these, apparently pathogenic mutations have been detected in more than one family. A mutation in the neurotrypsin gene (PRSS12) has been found in two apparently unrelated Algerian families with NS-ID (reviewed in [4] and references therein). A mutation in the CC2D1A gene, the product of which regulates expression of the serotonin receptor 1A gene in neuronal cells, had been identified in nine nuclear
A role for recessive factors in epilepsy, autism, and other psychiatric disorders?
ID is frequently associated with psychiatric and/or neurological disorders (reviewed in [50]). Based on the International Classification of Diseases (ICD, 10th revision) it has been estimated that between 14% and 39% of individuals with ID present with comorbid psychiatric diagnoses.
Epilepsy is among the most frequently associated disorders [50], with a frequency ranging from 5.5% to 35%, which is similar to the 20–27% reported by population-based studies of children with epilepsy and some
How frequent are recessive forms of ID?
In the small families of outbred Western societies, most patients with recessive forms of ID or related disorders will be sporadic cases. If couples with offspring have two children on average, which is close to the actual situation in Europe ([84]; M. Kreyenfeld, Rostock, personal communication), only one of four patients will have an affected sibling and will be identified as a familial case. In Central Europe, between 3.3 and 6% of patients with ID referred to genetic services are familial
Implications for research and healthcare
Despite the remarkable progress in the elucidation of autosomal recessive forms of ID, it is likely that the several hundred genes already implicated in syndromic or non-syndromic ARID (see [90] and references therein) and related disorders are vastly outnumbered by the many ARID genes still waiting to be found. Considering that on the X chromosome alone, which carries 4% of all human genes, already more than 100 ID genes have been identified 6, 7, there should be at least 2500 autosomal ID
Concluding remarks
After having been disregarded for a long time, recessive gene defects are being discovered at a rapid pace as important causes of ID. Comprehensive and affordable tests to rule out all known forms of ARID will have a major effect on the diagnosis and prevention of ID, not only in developing countries where parental consanguinity is common but also elsewhere.
Acknowledgments
We thank Hossein Najmabadi and Kimia Kahrizi, Hao Hu, Masoud Garshasbi, Andreas Kuss, Wei Chen, and Thomas Wienker for their essential contributions to our past and ongoing ARID research, and Gabriele Eder for help with the preparation of the manuscript. This work was supported by the Max Planck Society and by the European Commission Framework Program 7 (FP7) project GENCODYS, grant no 241995 (coordinator: Hans van Bokhoven, Nijmegen).
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Gene Identification in Intellectual Disability
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