Abstract
In the last few years, next-generation sequencing has led to enormous progress in deciphering monogenic forms of intellectual disability. Autosomal dominant intellectual disability (ADID) and X chromosomal intellectual disability (XLID) have been the focus of research. Apart from metabolic disorders, autosomal recessive intellectual disability (ARID) is still behind, probably because it is more heterogeneous and less prevalent in industrial populations. The prevalence of ARID in a cohort of affected children of an outbred population is estimated to be about 10%, with an upward tendency in still unclarified cases. The risk for ARID in children of first cousins or closer is a magnitude higher than for children of unrelated parents. Taken together, it seems that children of related parents are at a 2 to 3 times higher risk for ID. There are no prevalent ARID genes, pathways, or protein complexes and the functions of the affected proteins are very diverse and limited not only to neurological aspects. Thus, in a regular case, there is no reasoning for picking a few genes for a first diagnostic step, and a genetic diagnosis of ID in general, and ARID specifically, is better made using large panels or exome sequencing. In addition, in the last few months, evidence has been growing that many ARID genes are pleiotropic and that the resulting phenotypes may have a broad spectrum. For an exhaustive deciphering of the genetics of ARID, we suggest research at the level of single genes rather than large meta-analyses.
Highlights
Genetics of autosomal recessive intellectual disabilityThe term intellectual disability (ID) includes alternative terms such as low functioning autism spectrum disorders, mental retardation, and neurodevelopmental disorders (NDD)
The DDD study of 7448 ID cases revealed that autosomal recessive defects accounted for 11.7% of all cases with a clear molecular diagnosis, but that an over-proportionate fraction of autosomal recessive intellectual disability (ARID) was in consanguineous families [1]
As the DDD study [1] reports that ID due to a de novo variant is 1:295, diagnosable autosomal recessive forms of intellectual disability in a community with consanguineous mating would be roughly estimated to be about 2% (8 × 1:295, as the prevalence of diagnosable ARID [47%] is almost 8 times higher than that of a diagnosable de novo variant 6%), a risk that adds to the basic risk for non-consanguineous mating, making the prevalence of diagnosable monogenic ID in the children of first cousins or closer two timers higher
Summary
The term intellectual disability (ID) includes alternative terms such as low functioning autism spectrum disorders, mental retardation, and neurodevelopmental disorders (NDD). Genetic causes of ID are highly heterogeneous, including large chromosomal abnormalities, submicroscopic copy number variants, and monogenic forms due to pathogenic variants in single genes [1, 15, 16]. The monogenic forms are classified based on inheritance mode to X linked (XLID), autosomal dominant (ADID), and, the subject of this review, autosomal recessive intellectual disability (ARID)
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