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

Abstract

Exome sequencing is a powerful tool for discovery of the Mendelian disease genes. Previously, we reported a novel locus for autosomal recessive non-syndromic mental retardation (NSMR) in a consanguineous family [Nolan, D.K., Chen, P., Das, S., Ober, C. and Waggoner, D. (2008) Fine mapping of a locus for nonsyndromic mental retardation on chromosome 19p13. Am. J. Med. Genet. A, 146A, 1414-1422]. Using linkage and homozygosity mapping, we previously localized the gene to chromosome 19p13. The parents of this sibship were recently included in an exome sequencing project. Using a series of filters, we narrowed the putative causal mutation to a single variant site that segregated with NSMR: the mutation was homozygous in five affected siblings but in none of eight unaffected siblings. This mutation causes a substitution of a leucine for a highly conserved proline at amino acid 182 in TECR (trans-2,3-enoyl-CoA reductase), a synaptic glycoprotein. Our results reveal the value of massively parallel sequencing for identification of novel disease genes that could not be found using traditional approaches and identifies only the seventh causal mutation for autosomal recessive NSMR.

Figure 1.

(A) Pedigree of the Family G. DNA was available for the individuals marked with a filled red arrow. The kinship coefficient, θ, for the parents is 0.059. The 545C → T mutation in the TECR gene (Pro182Leu) was homozygous in the five affected siblings and was heterozygous in the parents and seven of eight unaffected siblings. One deceased son (affection status unknown) and one unaffected daughter were not included in this study. (B) Four of the siblings with NSMR are shown. Photographs reprinted with permission.

Figure 2.

(A) Schematic representation of the TECR primary transcript, exons and processed transcript. The location of the mutation affecting Pro182 in exon 8 of the TECR gene is indicated with a red line. (B) Results of sequencing studies. The nucleotide sequences corresponding to amino acids 180–184 in an affected, a carrier and a non-carrier sibling. (C) Cross-species sequence alignment of this segment of the TECR protein. The red line indicates the location of the highly conserved proline at amino acid 182 that is mutated to leucine in NSMR. Sequences were obtained from NCBI. Hs, Homo sapiens; Bt, Bos taurus; Mm, Mus musculus; Rn, Rattus norvegicus; Xt, Xenopus tropicalis; Xl, X. laevis; Dr, Danio rerio.

Figure 3.

Haplotype analysis of the Pro182Leu mutation; the arrowhead shows the position of the mutation. The x-axis shows the 141 SNPs that define the 2.2 Mb homozygous segment in the affected siblings; individuals representing each genotype are shown in each row, grouped by the three Pro182Leu genotypes. All Pro/Leu carriers shared at least one allele (orange) with the affected individuals at every SNP within a 1.6 Mb interval surrounding the TECR mutation; blue shows SNP genotypes that do not share either allele with the homozygous segment in the affected siblings.