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Identification of RELN variation p.Thr3192Ser in a Chinese family with schizophrenia.

Zhou Z, Hu Z, Zhang L, Hu Z, Liu H, Liu Z, Du J, Zhao J, Zhou L, Xia K, Tang B, Shen L - Sci Rep (2016)

Bottom Line: A missense variation c.9575 C > G (p.Thr3192Ser) was identified in RELN, which is known as a risk gene for SCZ, located on chromosome 7q22, in the pedigree.This rare variant, as a highly penetrant risk variant, co-segregated with the phenotype.Our results provide genetic evidence that RELN may be one of pathogenic gene in SCZ.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China.

ABSTRACT
Schizophrenia (SCZ) is a serious psychiatric disease with strong heritability. Its complexity is reflected by extensive genetic heterogeneity and much of the genetic liability remains unaccounted for. We applied a combined strategy involving detection of copy number variants (CNVs), whole-genome mapping, and exome sequencing to identify the genetic basis of autosomal-dominant SCZ in a Chinese family. To rule out pathogenic CNVs, we first performed Illumina single nucleotide polymorphism (SNP) array analysis on samples from two patients and one psychiatrically healthy family member, but no pathogenic CNVs were detected. In order to further narrow down the susceptible region, we conducted genome-wide linkage analysis and mapped the disease locus to chromosome 7q21.13-22.3, with a maximum multipoint logarithm of odds score of 2.144. Whole-exome sequencing was then carried out with samples from three affected individuals and one unaffected individual in the family. A missense variation c.9575 C > G (p.Thr3192Ser) was identified in RELN, which is known as a risk gene for SCZ, located on chromosome 7q22, in the pedigree. This rare variant, as a highly penetrant risk variant, co-segregated with the phenotype. Our results provide genetic evidence that RELN may be one of pathogenic gene in SCZ.

No MeSH data available.


Related in: MedlinePlus

Heterozygous missense mutation of RELN in SCZ family and genomic organization of the human RELN.(A) Sequence analysis of exon 59 of RELN in a normal control and the affected proband of this family is shown. The DNA sequence chromatogram shows a heterozygous C > G nucleotide change (black arrow) in exon 59 of RELN (c.9575C > G), which leads to the replacement of threonine (ACC) with serine (AGC) at codon 3192 (p.Thr3192Ser). (B) Protein sequence alignment of RELN orthologs shows the region surrounding the mutated T3192S. Homo = Homo sapiens; Mus = Mus musculus; Rattus = Rattus norvegicus; Pan = Pan troglodytes; Macaca = Macaca mulatta; Canis = Canis lupus; Bos = Bos taurus; Gallus = Gallus domesticu.
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f2: Heterozygous missense mutation of RELN in SCZ family and genomic organization of the human RELN.(A) Sequence analysis of exon 59 of RELN in a normal control and the affected proband of this family is shown. The DNA sequence chromatogram shows a heterozygous C > G nucleotide change (black arrow) in exon 59 of RELN (c.9575C > G), which leads to the replacement of threonine (ACC) with serine (AGC) at codon 3192 (p.Thr3192Ser). (B) Protein sequence alignment of RELN orthologs shows the region surrounding the mutated T3192S. Homo = Homo sapiens; Mus = Mus musculus; Rattus = Rattus norvegicus; Pan = Pan troglodytes; Macaca = Macaca mulatta; Canis = Canis lupus; Bos = Bos taurus; Gallus = Gallus domesticu.

Mentions: Assuming that these three patients have the same genetic cause of disease reduced the number of variants to 6,106 common to all affected individuals. As the hereditary mode in the family is autosomal-dominant, the candidate variants were expected to be heterozygous in the three patients. To distinguish potentially pathogenic mutations from other variants, we focused only on functional variants (non-synonymous, nonsense, located in the canonical splice sites, or coding indels), anticipating that synonymous variants were far less likely to be pathogenic. On the basis of the genotypes of available public data-sets, additional polymorphisms were excluded, leaving 33 novel variants. Considering that most pathogenic variants either affected highly conserved sequences and/or were predicted to be deleterious, we used the ANNOVAR package, which contains 23 types of software to assess the remaining variants for a likely functional impact. As a result of the filtering steps above, the candidate pool was reduced to 19 variants (19 genes). To identify rare variants co-segregating with SCZ for the kindred, we have performed variant detection in all available members of the pedigree. The missense variant (c.9575C > G, p.Thr3192Ser) in RELN (chr7:103131145, RefSeq NM_005045/ NM_173054) was the only co-segregating mutation among these candidate variants tested by Sanger sequencing (Fig. 2A). The variant status of all tested individuals was depicted in Fig. 1A. Additionally, this variant was not found in the NHLBI Exome Sequencing Project (ESP6500), the 1000 Genomes Project, and the Single Nucleotide Polymorphism Database (dbSNP137), while the allele frequency of this variant was 8.24 × 10−6 in the ExAC database. Moreover, the missense substitute was also not detected in the 500 unaffected control individuals, indicating the rarity of the variation in the same geographic population. Thr3192 was found at a highly conserved position, indicating an important role for this residue. (Fig. 2B). Apart from these, the mutation we identified using exome sequencing is located in the same chromosomal region (7q21.13-q22.3) as that identified by linkage analysis, which cross-validated RELN as the potentially causative SCZ gene in this family (Fig. 1B).


Identification of RELN variation p.Thr3192Ser in a Chinese family with schizophrenia.

Zhou Z, Hu Z, Zhang L, Hu Z, Liu H, Liu Z, Du J, Zhao J, Zhou L, Xia K, Tang B, Shen L - Sci Rep (2016)

Heterozygous missense mutation of RELN in SCZ family and genomic organization of the human RELN.(A) Sequence analysis of exon 59 of RELN in a normal control and the affected proband of this family is shown. The DNA sequence chromatogram shows a heterozygous C > G nucleotide change (black arrow) in exon 59 of RELN (c.9575C > G), which leads to the replacement of threonine (ACC) with serine (AGC) at codon 3192 (p.Thr3192Ser). (B) Protein sequence alignment of RELN orthologs shows the region surrounding the mutated T3192S. Homo = Homo sapiens; Mus = Mus musculus; Rattus = Rattus norvegicus; Pan = Pan troglodytes; Macaca = Macaca mulatta; Canis = Canis lupus; Bos = Bos taurus; Gallus = Gallus domesticu.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4829830&req=5

f2: Heterozygous missense mutation of RELN in SCZ family and genomic organization of the human RELN.(A) Sequence analysis of exon 59 of RELN in a normal control and the affected proband of this family is shown. The DNA sequence chromatogram shows a heterozygous C > G nucleotide change (black arrow) in exon 59 of RELN (c.9575C > G), which leads to the replacement of threonine (ACC) with serine (AGC) at codon 3192 (p.Thr3192Ser). (B) Protein sequence alignment of RELN orthologs shows the region surrounding the mutated T3192S. Homo = Homo sapiens; Mus = Mus musculus; Rattus = Rattus norvegicus; Pan = Pan troglodytes; Macaca = Macaca mulatta; Canis = Canis lupus; Bos = Bos taurus; Gallus = Gallus domesticu.
Mentions: Assuming that these three patients have the same genetic cause of disease reduced the number of variants to 6,106 common to all affected individuals. As the hereditary mode in the family is autosomal-dominant, the candidate variants were expected to be heterozygous in the three patients. To distinguish potentially pathogenic mutations from other variants, we focused only on functional variants (non-synonymous, nonsense, located in the canonical splice sites, or coding indels), anticipating that synonymous variants were far less likely to be pathogenic. On the basis of the genotypes of available public data-sets, additional polymorphisms were excluded, leaving 33 novel variants. Considering that most pathogenic variants either affected highly conserved sequences and/or were predicted to be deleterious, we used the ANNOVAR package, which contains 23 types of software to assess the remaining variants for a likely functional impact. As a result of the filtering steps above, the candidate pool was reduced to 19 variants (19 genes). To identify rare variants co-segregating with SCZ for the kindred, we have performed variant detection in all available members of the pedigree. The missense variant (c.9575C > G, p.Thr3192Ser) in RELN (chr7:103131145, RefSeq NM_005045/ NM_173054) was the only co-segregating mutation among these candidate variants tested by Sanger sequencing (Fig. 2A). The variant status of all tested individuals was depicted in Fig. 1A. Additionally, this variant was not found in the NHLBI Exome Sequencing Project (ESP6500), the 1000 Genomes Project, and the Single Nucleotide Polymorphism Database (dbSNP137), while the allele frequency of this variant was 8.24 × 10−6 in the ExAC database. Moreover, the missense substitute was also not detected in the 500 unaffected control individuals, indicating the rarity of the variation in the same geographic population. Thr3192 was found at a highly conserved position, indicating an important role for this residue. (Fig. 2B). Apart from these, the mutation we identified using exome sequencing is located in the same chromosomal region (7q21.13-q22.3) as that identified by linkage analysis, which cross-validated RELN as the potentially causative SCZ gene in this family (Fig. 1B).

Bottom Line: A missense variation c.9575 C > G (p.Thr3192Ser) was identified in RELN, which is known as a risk gene for SCZ, located on chromosome 7q22, in the pedigree.This rare variant, as a highly penetrant risk variant, co-segregated with the phenotype.Our results provide genetic evidence that RELN may be one of pathogenic gene in SCZ.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China.

ABSTRACT
Schizophrenia (SCZ) is a serious psychiatric disease with strong heritability. Its complexity is reflected by extensive genetic heterogeneity and much of the genetic liability remains unaccounted for. We applied a combined strategy involving detection of copy number variants (CNVs), whole-genome mapping, and exome sequencing to identify the genetic basis of autosomal-dominant SCZ in a Chinese family. To rule out pathogenic CNVs, we first performed Illumina single nucleotide polymorphism (SNP) array analysis on samples from two patients and one psychiatrically healthy family member, but no pathogenic CNVs were detected. In order to further narrow down the susceptible region, we conducted genome-wide linkage analysis and mapped the disease locus to chromosome 7q21.13-22.3, with a maximum multipoint logarithm of odds score of 2.144. Whole-exome sequencing was then carried out with samples from three affected individuals and one unaffected individual in the family. A missense variation c.9575 C > G (p.Thr3192Ser) was identified in RELN, which is known as a risk gene for SCZ, located on chromosome 7q22, in the pedigree. This rare variant, as a highly penetrant risk variant, co-segregated with the phenotype. Our results provide genetic evidence that RELN may be one of pathogenic gene in SCZ.

No MeSH data available.


Related in: MedlinePlus