The Molecular Genetics of Autosomal Recessive Nonsyndromic Intellectual Disability: a Mutational Continuum and Future Recommendations

Abstract

Intellectual disability (ID) is a clinical manifestation of the central nervous system without any major dysmorphologies of the brain. Biologically it affects learning capabilities, memory, and cognitive functioning. The basic defining features of ID are characterized by IQ<70, age of onset before 18 years, and impairment of at least two of the adaptive skills. Clinically it is classified in a syndromic (with additional abnormalities) and a nonsyndromic form (with only cognitive impairment). The study of nonsyndromic intellectual disability (NSID) can best explain the pathophysiology of cognition, intelligence and memory. Genetic analysis in autosomal recessive nonsyndrmic ID (ARNSID) has mapped 51 disease loci, 34 of which have revealed their defective genes. These genes play diverse physiological roles in various molecular processes, including methylation, proteolysis, glycosylation, signal transduction, transcription regulation, lipid metabolism, ion homeostasis, tRNA modification, ubiquitination and neuromorphogenesis. High-density SNP array and whole exome sequencing has increased the pace of gene discoveries and many new mutations are being published every month. The lack of uniform criteria has assigned multiple identifiers (or accession numbers) to the same MRT locus (e.g. MRT7 and MRT22). Here in this review we describe the molecular genetics of ARNSID, prioritize the candidate genes in uncharacterized loci, and propose a new nomenclature to reorganize the mutation data that will avoid the confusion of assigning duplicate accession numbers to the same ID locus and to make the data manageable in the future as well.

Leber’s hereditary optic neuropathy, intellectual disability and epilepsy presenting with variable penetrance associated to the m.3460G >A mutation and a heteroplasmic expansion of the microsatellite in MTRNR1 gene – case report

“…Typically, intellectual disability may be part of a more complex syndromic condition and, to our knowledge, it has never been associated with mtDNA alterations. Though we cannot exclude that there might be a coincidence of an LHON mutation with a mutation in nuclear genes associated with intellectual disability [ 43 ] and epilepsy [ 44 ], we noticed that the neurologic and psychiatric signs manifested as a strong maternal inherited trait. The peculiar pattern of MTRNR1 mutation as well as the presence of the longest species of mtMS segregating with intellectual disability is suggestive of their association although the size of the family does not allow to make a statistically significant link between the presence of the 961Tdel + C(n)ins variant and the non-LHON clinical features detected in the family.…”

A recurrent missense variant inSLC9A7causes nonsyndromic X-linked intellectual disability with alteration of Golgi acidification and aberrant glycosylation

“…>100 genes) located on the X-chromosome (7)(8)(9)(10)(11). These genes cover the gamut of biological processes, ranging from events in the nucleus such as genome replication, chromatin remodelling and transcription to extra-nuclear activities involving signal transduction, cytoskeletal dynamics, metabolism, vesicular trafficking, glycosylation and membrane excitability (12)(13)(14)(15)(16)(17)(18)(19). It is not unexpected that mutations that impact on these critical cellular functions can profoundly affect central nervous system development and cognitive functioning (20,21).…”

Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability

“…With a prevalence between 1% and 3%, intellectual disability (ID) is among the most important problems in healthcare. Particularly, hereditary autosomal‐recessive forms of the disorder (autosomal recessive intellectual disability [ARID]) have a very heterogeneous molecular basis, and genes with an increased number of disease‐causing mutations are not common (for review see, e.g., Khan et al., ; Musante & Ropers, ). Interestingly, apart from genes specifically expressed in synapses or in the nervous system, many ubiquitously expressed housekeeping genes have been implicated in ARID and neurological disorders (Najmabadi et al., ).…”