We report the results of two studies examining the genetic overlap between schizophrenia and velocardiofacial syndrome. In study A, we characterize two interstitial deletions identified on chromosome 22qll in a sample of schizophrenic patients. The size of the deletions was estimated to be between 1.5 and 2 megabases. In study B, we examine whether variations in deletion size are associated with the schizophrenic phenotype in velocardiofacial syndrome patients. Our results show that a region of the genome that has been previously implicated by genetic linkage analysis can harbor genetic lesions that increase the susceptibility to schizophrenia. Our findings should facilitate identification and cloning of the schizophrenia susceptibility gene(s) in this region and identification of more homogeneous subgroups of patients.

Although schizophrenia is strongly hereditary, there are limited data regarding biological risk factors and pathophysiological processes. In this longitudinal study of adolescents with 22q11.2 deletion syndrome, we identified the catechol-O-methyltransferase low-activity allele (COMT(L)) as a risk factor for decline in prefrontal cortical volume and cognition, as well as for the consequent development of psychotic symptoms during adolescence. The 22q11.2 deletion syndrome is a promising model for identifying biomarkers related to the development of schizophrenia.

Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1; MIM 254800) is an autosomal recessive disorder with onset between 6 and 13 years followed by variable progression to mental deterioration and cerebellar ataxia. It is a rare disorder but more common in Finland (1 in 20,000) and the western Mediterranean. Two point mutations in the cysteine proteinase inhibitor gene cystatin B (CSTB), proved that this gene is responsible for EPM1 (ref. 3). An extensive search in the CSTB gene revealed mutations accounting only for 14% of the 58 unrelated EPM1 alleles studied. Here we report that the majority of EPM1 alleles contain expansions of a dodecamer (12-mer) repeat located about 70 nucleotides upstream of the transcription start site nearest to the 5' end of the CSTB gene. Normal alleles contain 2 or 3 copies of this repeat whereas mutant alleles contain more than 60 such repeats and have reduced levels of CSTB messenger RNA in blood but not in cell lines. 'Premutation' CSTB alleles with 12-17 repeats show marked instability when transmitted to offspring.

Approximately 1.1 billion people currently live in countries where consanguineous marriages are customary, and among them one in every three marriages is between cousins. Opinions diverge between those warning of the possible health risks to offspring and others who highlight the social benefits of consanguineous marriages. A consanguinity study group of international experts and counselors met at the Geneva International ConsanguinityWorkshop from 3 rd to 7 th May 2010 to discuss the known and presumptive risks and benefits of close kin marriages, and to identify important future areas for research on consanguinity.The group highlighted the importance of evidence-based counselling recommendations for consanguineous marriages, and of undertaking both genomic and social research in defining the various influences and outcomes of consanguinity. Technological advances infor rapid high-throughput genome sequencing (HTS), and for the identification of copy number variants by comparative genomic hybridization (aCGH) offer a significantn unprecedented opportunity to identify genotype-phenotype correlations focusing on autozygosity, the hallmark of consanguinity. The ongoing strong preferential culture of close kin marriages in many societies, and among migrant communities in Western countries, merits an equivalently detailed assessment of the social and genetic benefits of consanguinity in future studies.

The increasing number of laboratories offering molecular genetic analysis of the CFTR gene and the growing use of commercial kits strengthen the need for an update of previous best practice guidelines (published in 2000). The importance of organizing regional or national laboratory networks, to provide both primary and comprehensive CFTR mutation screening, is stressed. Current guidelines focus on strategies for dealing with increasingly complex situations of CFTR testing. Diagnostic flow charts now include testing in CFTR-related disorders and in fetal bowel anomalies. Emphasis is also placed on the need to consider ethnic or geographic origins of patients and individuals, on basic principles of risk calculation and on the importance of providing accurate laboratory reports. Finally, classification of CFTR mutations is reviewed, with regard to their relevance to pathogenicity and to genetic counselling.

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The validation and verification of laboratory methods and procedures before their use in clinical testing is essential for providing a safe and useful service to clinicians and patients. This paper outlines the principles of validation and verification in the context of clinical human molecular genetic testing. We describe implementation processes, types of tests and their key validation components, and suggest some relevant statistical approaches that can be used by individual laboratories to ensure that tests are conducted to defined standards.

Using a systematically ascertained sample of 57 families, each having 2 or more members with a consensus diagnosis of schizophrenia (DSM-III-R criteria), we have carried out linkage studies of 520 loci, covering approximately 70% of the genome for susceptibility loci for schizophrenia. A two-stage strategy based on lod score thresholds from simulation studies of our sample identified regions for further exploration. In each region, a dense map of highly informative dinucleotide repeat polymorphisms (heterozygosity greater than .70) was analyzed using dominant, recessive, and "affected only" models and nonparametric sib pair identity-by-descent methods. For one region, 8p22-p21, affected sib-pair analyses gave a P value = .0001, corresponding to a lod score approximately equal to 3.00. For 8p22-p21, the maximum two-point lod score occurred using the "affected only" recessive model (ZMAX = 2.35; theta M = theta F); allowing for a constant sex difference in recombination fractions found in reference pedigrees, ZMAX = 2.78 (theta M/theta F = 3). For a second region, 3p26-p24, the maximum two-point lod score was 2.34 ("affected only" dominant model), and the affected sib-pair P value was .01. These two regions are worthy of further exploration as potential sites of susceptibility genes for schizophrenia.