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

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.

Emerging Paradigms in Cancer Genetics: Some Important Findings from High-Density Single Nucleotide Polymorphism Array Studies

“…The idea that long homozygous by descent regions may harbor disease-causing genes (particularly recessive alleles) has been explored in several studies, including patients with autism (18), Alzheimer’s disease (17), Parkinson’s disease (19), schizophrenia (20), and bipolar affective disorder (21). When our group examined the germ-line SNP array data of 74 colorectal cancer patients, we found that the percentage of those having autozygous segments greater or equal to 4 Mb is at least twice as high as control groups (22).…”

Modulation of AMPA receptor function by auxiliary subunits

“…Detailed behavioral analyses for other auxiliary subunits have not been performed yet. In this context, it is worth mentioning that genetic analyses (linkage analyses) suggested that TARP γ-2 and 3 might be implicated in diseases of the central nervous system such as familial epilepsy, schizophrenia, and bipolar disorders [97][98][99][100][101]. …”

Regulation of the actin cytoskeleton by the Ndel1-Tara complex is critical for cell migration

“…It has also been widely hypothesized that the disturbances in auditory processing occur frequently in schizophrenic patients compared with normal subjects5859. Although controversy exists in the association between sensory inputs and schizophrenia, there are a number of clinical and genetic studies reporting a contribution of hearing impairment to psychiatric disorders596061, implying the significant influence of auditory stimuli in neurodevelopmental processes. Given that mutations in the Tara locus are associated with deafness4243, it is noteworthy that there is a high comorbidity between hearing defects and psychiatric disorders such as schizophrenia in the general population58596061.…”