Autosomal recessive mental retardation: homozygosity mapping identifies 27 single linkage intervals, at least 14 novel loci and several mutation hotspots

Abstract

Mental retardation (MR) has a worldwide prevalence of around 2% and is a frequent cause of severe disability. Significant excess of MR in the progeny of consanguineous matings as well as functional considerations suggest that autosomal recessive forms of MR (ARMR) must be relatively common. To shed more light on the causes of autosomal recessive MR (ARMR), we have set out in 2003 to perform systematic clinical studies and autozygosity mapping in large consanguineous Iranian families with non-syndromic ARMR (NS-ARMR). As previously reported (Najmabadi et al. in Hum Genet 121:43-48, 2007), this led us to the identification of 12 novel ARMR loci, 8 of which had a significant LOD score (OMIM: MRT5-12). In the meantime, we and others have found causative gene defects in two of these intervals. Moreover, as reported here, tripling the size of our cohort has enabled us to identify 27 additional unrelated families with NS-ARMR and single-linkage intervals; 14 of these define novel loci for non-syndromic ARMR. Altogether, 13 out of 39 single linkage intervals observed in our cohort were found to cluster at 6 different loci on chromosomes, i.e., 1p34, 4q27, 5p15, 9q34, 11p11-q13 and 19q13, respectively. Five of these clusters consist of two significantly overlapping linkage intervals, and on chr 1p34, three single linkage intervals coincide, including the previously described MRT12 locus. The probability for this distribution to be due to chance is only 1.14 × 10(-5), as shown by Monte Carlo simulation. Thus, in contrast to our previous conclusions, these novel data indicate that common molecular causes of NS-ARMR do exist, and in the Iranian population, the most frequent ones may well account for several percent of the patients. These findings will be instrumental in the identification of the underlying genes.

Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration

“…[8][9][10][11][12] In affected children from consanguineous families, autosomal recessive (AR) inheritance is common; 13 however, congenital disorders with ID constitute an important medical problem because they represent a challenge in diagnosis, high prevalence and life-long care that most of these patients need. 14 A recent review suggests that ARID is not rare, and in outbred populations as many as 13-24% of ID may be due to AR genes, 13 and identifying the underlying genetic cause is an important issue in clinical genetics.…”

Homozygosity mapping in 64 Syrian consanguineous families with non-specific intellectual disability reveals 11 novel loci and high heterogeneity

“…Although functional considerations and empirical data from mouse models suggest that most gene defects are inherited as recessive disorders, 1,4,5 a recent study suggests that autosomal dominant de novo mutations are most prevalent. 6 Until now, 26 significantly linked non-specific intellectual disability of autosomal recessive inheritance (NS-ARID) loci were described, [7][8][9][10] and only 10 genes (six of them located in described regions) were identified: PRSS12 (OMIM#606709, on 4q26, former MRT1), CRBN (OMIM#609262, on 3p26, former MRT2), CC2D1A (OMIM#610055, on 19p13.12, former MRT3), ST3GAL3 (OMIM#606494, on 1p34.3), GRIK2 (OMIM#138277, on 6q16, former MRT6), TUSC3 (OMIM#601385, on 8p22, former MRT7), ZNF26 (no OMIM#, on 19q13.2), TRAPPC9 (OMIM#613192, on 8q24, former MRT13), ZCH14 (OMIM# 613279, on 14q31.3), and TECR (MIM*610057 on 19p13.12) (Figure 1). 1,[11][12][13][14][15][16][17][18][19] Taking into account that over 90 genes are responsible for only about 40% of X-chromosomal recessive ID cases, and that about half of the estimated 22 000 human genes are expressed in the brain, the total number of ARID genes may run into the hundreds.…”

“…1 Considering the heterogeneity observed in previous linkage studies, and the fact that the so far identified genes do not account for a significant fraction of NS-ARID cases, systematic approaches are the most promising strategy to identify further genes. 7,8,10 Large consanguineous families provide enough information to map loci, based on analysis in a single family and thus represent the best starting point. We present here the results of the homozygosity mapping in a series of 64 Syrian multiplex consanguineous families with NS-ARID.…”

A defect in the CLIP1 gene (CLIP-170) can cause autosomal recessive intellectual disability

“…2,4 Although the homozygous regions of some reported ARID genes (MED13L, COQ5, ZCCHC8) overlap with this locus, 3 to the best of our knowledge, the present locus has not been previously linked to ID. Up to now, 40 loci for ARID (MRT1-40) have been registered in the OMIM database.…”

“…Up to now, we have reported several novel MRT loci (mental retardation loci) and genes for recessive cognitive disorders. [2][3][4] Here, we present a single homozygous interval on chromosome 12q24, with LOD score 43, which is a new MRT locus for ARID. Targeted exome sequencing within this interval revealed a nonsense variant in the CLIP1 gene (MIM 179838), which encodes a member of the microtubule (MT) plus-end tracking proteins.…”