Homozygosity mapping in consanguineous families reveals extreme heterogeneity of non-syndromic autosomal recessive mental retardation and identifies 8 novel gene loci

Abstract

Autosomal recessive gene defects are arguably the most important, but least studied genetic causes of severe cognitive dysfunction. Homozygosity mapping in 78 consanguineous Iranian families with nonsyndromic autosomal recessive mental retardation (NS-ARMR) has enabled us to determine the chromosomal localization of at least 8 novel gene loci for this condition. Our data suggest that in the Iranian population NS-ARMR is very heterogeneous, and they argue against the existence of frequent gene defects that account for more than a few percent of the cases.

Intelligence: shared genetic basis between Mendelian disorders and a polygenic trait

“…At present, the causal variants for a large number of monogenic disorders have been identified (over 3000 disorders; Online Mendelian Inheritance in Man (OMIM): http:// www.ncbi.nlm.nih.gov/omim), and recent developments in sequencing technologies have made it possible to employ exome sequencing or whole-genome sequencing, possibly in combination with homozygosity mapping, as an efficient approach to identifying novel causal variants underlying Mendelian disorders. [48][49][50] The National Human Genome Research Institute has opened Centers for Mendelian Genomics (NHGRI Genome Sequencing Program, http://www.genome.gov/), whose primary goal is the discovery of as yet unknown variation underlying Mendelian disorders. Thus, at present, the utilization of existing and impending knowledge on variants underlying Mendelian disorders to identify the variation underlying polygenic traits may prove a viable, efficient, and cost-effective complement to standard approaches such as GWAS.…”

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

“…7,8 Autosomal recessive disorders are even a greater challenge in populations with low consanguineous marriages, as those will often be compound heterozygote, and thus not due to IBD mutations. In addition, it seems certain by now that mutations in the currently known NS-ARID genes (PRSS12, CRBN, CC2D1A, GRIK2, TUSC3, TRAPPC9, ZNF526, ZC3H14, ST3GAL3, and TECR) are responsible for only a small fraction of NS-ARID cases, whereas hundreds of additional genes are likely to be identified in the near future.…”

“…An example has been shown by Najmabadi et al, 7 who identified a LOD score of only two in family M001, and later identified a mutation in TRAPPC9, which is located in this region and proved that this locus is true, though the linkage analysis was not significant. 7,16 Eight complex families MR006, MR013, MR018, MR019, MR022, MR043, MR049, and MR055, have two branches each, a, and b. Families MR022a and MR022b, and MR049a and MR049b showed no common homozygous region (Supplementary Figure 1).…”

“…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.…”