Fine mapping of a locus for nonsyndromic mental retardation on chromosome 19p13

Abstract

Mental retardation (MR) occurs in approximately 3% of the population and therefore significantly impacts public health. Despite this relatively high prevalence, the specific causes of MR remain unknown in most cases, although both genetic and environmental factors are known to contribute. We describe a consanguineous family with autosomal recessive (AR) nonsyndromic MR (NSMR). Because the consanguinity of this family is complex, we explore alternative approaches for generating accurate estimates of the evidence for linkage in this family, and demonstrate evidence for linkage to chromosome 19p13 (lod score ranging from 1.2 to 3.5, depending on assumptions of allele frequencies). Fine mapping of the linked region defined a critical region of 3.6 Mb, which overlaps with a previously reported gene (CC2D1A) for MR. However, no mutations in the coding region of this gene are present in the family we describe. These results suggest that another gene causing autosomal recessive nonsyndromic MR (ARNSMR) is located within this genomic region.

Exome sequencing reveals a novel mutation for autosomal recessive non-syndromic mental retardation in the TECR gene on chromosome 19p13

“…Following our initial linkage study (14), we performed wholegenome genotyping of the affected individuals and identified a shared homozygous segment that spans .2 Mb on chromosome 19p13 (Chr 19: 13 610 401-15 645 116 bp in hg Build 36.3). To facilitate the discovery of the causal mutation and gene, we included both obligate carrier parents in an exome sequencing study.…”

“…We identified 71 variants (33 missense, 37 synonymous, 1 non-protein coding) in the critical region in the parents. Given the pattern of homozygosity in the critical region in Family G, we assumed that the NSMR in this family was due to a fully penetrant autosomal recessive mutation (14). Therefore, we considered 18 of the 71 variants that were heterozygous in both parents as candidates for the NSMR mutation (Supplementary Material, Table S1).…”

“…One affected brother, who was not available for examination, was reported to also have an intention tremor. One of the sisters was not considered as affected in our earlier study (14) because her complications were attributed by the parents to a difficult delivery and fevers in the newborn period. Her developmental delay was milder than the other three affected individuals who were examined, but she had similar speech, language and fine motor skill abnormalities.…”

“…However, because she was homozygous for the same shared haplotype as her affected siblings, we thought it likely that she had the same autosomal recessive condition. Because this condition was segregating in only a single sibship and the locus mapped to one of the most gene rich regions of the human genome, we were previously unsuccessful in identifying the specific gene or mutation in this family (14).…”

Discovery and Roles of ER-Endolysosomal Contact Sites in Disease

“…A SNX13 -deficient (also called RGS-PX1) mouse was found to exhibit severe developmental defects, delayed neural tube closure, and embryonic lethality (Zheng et al 2006). Tsc13, the enoyl-CoA reductase found at the yeast NVJ, is also highly conserved in mammals as TECR, which is linked to an autosomal recessive non-syndromic intellectual disability (Nolan et al 2008). …”