Homozygosity mapping in a family presenting with schizophrenia, epilepsy and hearing impairment

Helen M. Knight, Alan Maclean, Muhammad Irfan, Farooq Naeem, Stephen Cass, B.S. Pickard, Walter J. Muir, D.H.R. Blackwood

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Homozygosity mapping within consanguineous families is a powerful method of localising genes for autosomal recessive disease. We investigated a family from Punjab, Pakistan, a region where consanguineous marriages are frequent. The parents have no detectable clinical disorders. However, five out of six children present with schizophrenia, epilepsy or hearing impairment either alone or in combination. This unusual phenotype in several offspring of first cousins is strongly suggestive of a rare, Mendelian recessive disorder. Two genome-wide scans initially using low-density microsatellites, and subsequently high-density SNP markers were used to map homozygous-by-descent regions in affected individuals. Candidate genes within these loci were subsequently screened for mutations. Homozygosity analysis and inbreeding coefficients were investigated to give an estimate of consanguinity. Two putative disease loci were mapped to 22q12.3-q13.3 and 2p24.3. The candidate locus on chromosome 2p24 overlaps with a deafness locus, DFNB47, linked to autosomal recessive hearing impairment, while positive findings reported for affective psychosis and schizophrenia cluster in a region of 4-5 cM on 22q13.1 within our second candidate locus. Sequence analysis of three candidate genes (KCNF1 (2p); ATF4, CACNG2 (22q)) did not reveal any exonic mutations. Inbreeding coefficients calculated for each family member support a very high degree of ancestral and recent inbreeding. The screening of other candidate genes located within these newly identified disease intervals on Chr2p24.3 and 22q12.3-q13.3 may lead to the discovery of causative variants, and consequent disrupted molecular pathways associated with this rare phenotype.
LanguageEnglish
Pages750-758
Number of pages8
JournalEuropean Journal of Human Genetics
Volume16
Issue number6
DOIs
Publication statusPublished - Jun 2008

Fingerprint

Inbreeding
Hearing Loss
Epilepsy
Schizophrenia
Psychotic Affective Disorders
Genes
Phenotype
Recessive Genes
Consanguinity
Mutation
Pakistan
Deafness
Marriage
Microsatellite Repeats
Single Nucleotide Polymorphism
Sequence Analysis
Chromosomes
Parents
Genome

Keywords

  • hearing impairment
  • epilepsy
  • schizophrenia
  • homozygosity mapping
  • chromosome 2
  • chromosome 22

Cite this

Knight, Helen M. ; Maclean, Alan ; Irfan, Muhammad ; Naeem, Farooq ; Cass, Stephen ; Pickard, B.S. ; Muir, Walter J. ; Blackwood, D.H.R. / Homozygosity mapping in a family presenting with schizophrenia, epilepsy and hearing impairment. In: European Journal of Human Genetics. 2008 ; Vol. 16, No. 6. pp. 750-758.
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Knight, HM, Maclean, A, Irfan, M, Naeem, F, Cass, S, Pickard, BS, Muir, WJ & Blackwood, DHR 2008, 'Homozygosity mapping in a family presenting with schizophrenia, epilepsy and hearing impairment' European Journal of Human Genetics, vol. 16, no. 6, pp. 750-758. https://doi.org/10.1038/ejhg.2008.11

Homozygosity mapping in a family presenting with schizophrenia, epilepsy and hearing impairment. / Knight, Helen M.; Maclean, Alan; Irfan, Muhammad; Naeem, Farooq; Cass, Stephen; Pickard, B.S.; Muir, Walter J.; Blackwood, D.H.R.

In: European Journal of Human Genetics, Vol. 16, No. 6, 06.2008, p. 750-758.

Research output: Contribution to journalArticle

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AU - Maclean, Alan

AU - Irfan, Muhammad

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AU - Cass, Stephen

AU - Pickard, B.S.

AU - Muir, Walter J.

AU - Blackwood, D.H.R.

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N2 - Homozygosity mapping within consanguineous families is a powerful method of localising genes for autosomal recessive disease. We investigated a family from Punjab, Pakistan, a region where consanguineous marriages are frequent. The parents have no detectable clinical disorders. However, five out of six children present with schizophrenia, epilepsy or hearing impairment either alone or in combination. This unusual phenotype in several offspring of first cousins is strongly suggestive of a rare, Mendelian recessive disorder. Two genome-wide scans initially using low-density microsatellites, and subsequently high-density SNP markers were used to map homozygous-by-descent regions in affected individuals. Candidate genes within these loci were subsequently screened for mutations. Homozygosity analysis and inbreeding coefficients were investigated to give an estimate of consanguinity. Two putative disease loci were mapped to 22q12.3-q13.3 and 2p24.3. The candidate locus on chromosome 2p24 overlaps with a deafness locus, DFNB47, linked to autosomal recessive hearing impairment, while positive findings reported for affective psychosis and schizophrenia cluster in a region of 4-5 cM on 22q13.1 within our second candidate locus. Sequence analysis of three candidate genes (KCNF1 (2p); ATF4, CACNG2 (22q)) did not reveal any exonic mutations. Inbreeding coefficients calculated for each family member support a very high degree of ancestral and recent inbreeding. The screening of other candidate genes located within these newly identified disease intervals on Chr2p24.3 and 22q12.3-q13.3 may lead to the discovery of causative variants, and consequent disrupted molecular pathways associated with this rare phenotype.

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KW - hearing impairment

KW - epilepsy

KW - schizophrenia

KW - homozygosity mapping

KW - chromosome 2

KW - chromosome 22

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