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The prevalence of the 22q11.2 duplication is unknown in children with cardiovascular malformations (CVMs). As most individuals with the duplication are detected in the search for other conditions, especially the 22q11.2 deletion, CVMs associated with the duplication are subject to referral bias. We circumvented this bias by investigating the prevalence of the 22q11.2 duplication in a population-based cohort of children with CVMs. The study population was defined as children born in 2000-2008, who were registered in the Danish National Patient Registry with a diagnosis of CVM from one of the two national university departments of pediatric cardiology. Sensitive multiplex ligation-dependent probe amplification was performed on dried blood spot samples from each individual's neonatal screening test. The study population consisted of 2,952 children with CVMs, 2,424 of whom were eligible for genetic testing; 13 individuals (0.5% [0.3-0.9%]) carried the duplication. Nine individuals (69%) had not previously been tested for a copy number variation on chromosome 22q11.2 in the clinical setting for children with CVMs. We conclude that 22q11.2 duplication is rare in children with CVMs, and is primarily found in malformations that are also associated with the 22q11.2 deletion. © 2012 Wiley Periodicals, Inc.

The American Heart Association (AHA) recommends family screening for hypertrophic cardiomyopathy (HCM). We assessed the outcome of family screening combining clinical evaluation and screening for sarcomere gene mutations in a cohort of 90 Danish HCM patients and their close relatives, in all 451 persons. Index patients were screened for mutations in all coding regions of 10 sarcomere genes (MYH7, MYL3, MYBPC3, TNNI3, TNNT2, TPM1, ACTC, CSRP3, TCAP, and TNNC1) and five exons of TTN. Relatives were screened for presence of minor or major diagnostic criteria for HCM and tracking of DNA variants was performed. In total, 297 adult relatives (>18 years) (51.2%) fulfilled one or more criteria for HCM. A total of 38 HCM-causing mutations were detected in 32 index patients. Six patients carried two disease-associated mutations. Twenty-two mutations have only been identified in the present cohort. The genetic diagnostic yield was almost twice as high in familial HCM (53%) vs. HCM of sporadic or unclear inheritance (19%). The yield was highest in families with an additional history of HCM-related clinical events. In relatives, 29.9% of mutation carriers did not fulfil any clinical diagnostic criterion, and in 37.5% of relatives without a mutation, one or more criteria was fulfilled. A total of 60% of family members had no mutation and could be reassured and further follow-up ceased. Genetic diagnosis may be established in approximately 40% of families with the highest yield in familial HCM with clinical events. Mutation-screening was superior to clinical investigation in identification of individuals not at increased risk, where follow-up is redundant, but should be offered in all families with relatives at risk for developing HCM. Hum Mutat 0,1–8, 2008. © 2008 Wiley-Liss, Inc.

As the number of single-nucleotide polymorphism (SNP) screening and other mutation scanning studies have increased explosively, following the development of high-throughput instrumentation, it becomes even more important to have sufficient template DNA. The source of DNA is often limited, especially in epidemiological studies, which require many samples as well as enough DNA to perform numerous SNP screenings or mutation scannings. Therefore, the aim is to solve the problem of stock DNA limitation. This need has been an important reason for the development of whole genome amplification (WGA) methods. Several systems are based on Phi29 polymerase multiple displacement amplification (MDA) or on DNA fragmentation (OmniPlex). Using TaqMan SNP genotyping assays, we have tested four WGA systems -- AmpliQ Genomic Amplifier Kit, GenomiPhi, Repli-g, and GenomePlex -- on DNA extracted from Guthrie cards to evaluate the amplification bias, concordance- and call rates, cost efficiency, and flexibility. All systems successfully amplified picograms of DNA from Guthrie cards to micrograms of product without loss of heterozygosity and with minimal allelic bias. A modified AmpliQ set up was chosen for further evaluation. In all, 2,000 SNP genotyping results from amplified and nonamplified samples were compared and the concordance rates between the samples were 99.7%. The call rate using the TaqMan system was 99.8%. DNA extracted from Guthrie cards and amplified with one of the four evaluated WGA systems is applicable in epidemiological genetic screenings. System choice should be based on requirements for system flexibility, product yield, and use in subsequent analysis.

BACKGROUND: Long QT syndrome (LQTS) is a cardiac ion channelopathy which presents clinically with palpitations, syncope or sudden death. More than 700 LQTS-causing mutations have been identified in 13 genes, all of which encode proteins involved in the execution of the cardiac action potential. The most frequently affected genes, covering > 90% of cases, are KCNQ1, KCNH2 and SCN5A.METHODS: We describe 64 different mutations in 70 unrelated Danish families using a routine five-gene screen, comprising KCNQ1, KCNH2 and SCN5A as well as KCNE1 and KCNE2.RESULTS: Twenty-two mutations were found in KCNQ1, 28 in KCNH2, 9 in SCN5A, 3 in KCNE1 and 2 in KCNE2. Twenty-six of these have only been described in the Danish population and 18 are novel. One double heterozygote (1.4% of families) was found. A founder mutation, p.F29L in KCNH2, was identified in 5 "unrelated" families. Disease association, in 31.2% of cases, was based on the type of mutation identified (nonsense, insertion/deletion, frameshift or splice-site). Functional data was available for 22.7% of the missense mutations. None of the mutations were found in 364 Danish alleles and only three, all functionally characterised, were recorded in the Exome Variation Server, albeit at a frequency of < 1:1000.CONCLUSION: The genetic etiology of LQTS in Denmark is similar to that found in other populations. A large founder family with p.F29L in KCNH2 was identified. In 48.4% of the mutations disease causation was based on mutation type or functional analysis.

The human endogenous retrovirus HERV-K18 is located within intron 1 of CD48 on chromosome 1q and is still active in the human genome. Genetic variation in HERV-K18 single-nucleotide polymorphisms (SNPs) has previously been associated with an increased risk of schizophrenia (SZ) and with type 2 diabetes (T2D) among individuals with SZ. Here, we present a replication study of association of two SNPs in HERV-K18 and 19 tagSNPs in CD48 with (a) SZ and (b) T2D in patients with SZ in two Danish samples (total number of cases=750 and controls=1214). No association was found with SZ or with T2D among individuals with SZ for any of the investigated SNPs. However, one HERV-K18 SNP showed a tendency toward an association with T2D in younger SZ patients, in agreement with previous findings, but due to a very low sample size, this result needs to be further investigated.

Deletion of chromosome 22q11.2 is considered one of the most frequent genetic causes of cardiovascular malformations. It is frequently associated with conotruncal malformations, but may also be present among patients with nonconotruncal malformations. The aim of the present study was to establish the prevalence of the 22q11.2 deletion in an unselected population-based cohort of children with various cardiovascular malformations. The study population was defined as children born in 2000-2008 who were registered in the Danish National Patient Registry with a diagnosis of cardiovascular malformation from one of the two national departments of pediatric cardiology. Sensitive multiplex ligation-dependent probe amplification was performed on dried blood spot samples from each individual's neonatal screening test. Of 2,952 children with cardiovascular malformations, 2,478 were eligible for genetic testing. A total of 46 individuals (1.9% [1.4-2.5%]) carried the deletion, with the highest prevalence among individuals registered with interrupted aortic arch (22% [11-40]). The most frequent diagnoses among individuals carrying the deletion were tetralogy of Fallot (n = 15) and ventricular septal defect (n = 15). One in four cases had not been diagnosed in the usual clinical setting. The prevalence of 22q11.2 deletions in an unselected population-based cohort of children with cardiac malformations was 1.9% [1.4-2.5%]. Genetic testing of every individual registered with a conotruncal malformation would have achieved a diagnostic sensitivity of 70% in the present cohort. Prospective studies outlining testing recommendations in children with ventricular septal defect are warranted. © 2011 Wiley Periodicals, Inc.

Objective: An interaction between predisposing genes and environmental stressors is thought to underlie the neurodevelopmental disorder schizophrenia. In a targeted gene screening, we previously found that the minor allele of the single nucleotide polymorphism (SNP) rs6336 in the neurotrophic tyrosine kinase receptor 1 (NTRK1/TRKA) gene is associated with schizophrenia as a risk factor. Methods: We genotyped the TRKA SNP in a total of eight independent Caucasian schizophrenia casecontrol groups. Result: Remarkably, although in five of the groups a higher frequency of the risk allele was indeed found in the patients compared with the controls, in the three other groups the SNP acted as a protective factor. Conclusion: An intriguing possibility is that this dual character of the TRKA SNP is caused by its interaction with endophenotypic and/or epistatic factors.

N-methyl-D-aspartate (NMDA) receptors are very important for proper brain development and several lines of evidence support that hypofunction of the NMDA receptors are involved in the pathophysiology of schizophrenia. Gene variation and gene-environmental interactions involving the genes encoding the NMDA receptors are therefore likely to influence the risk of schizophrenia. The aim of this study was to determine (1) whether SNP variation in the genes (GRIN1, GRIN2A, GRIN2B, GRIN2C, and GRIN2D) encoding the NMDA receptor were associated with schizophrenia; (2) whether GRIN gene variation in the offspring interacted with maternal herpes simplex virus-2 (HSV-2) seropositivity during pregnancy influencing the risk of schizophrenia later in life. Individuals from three independently collected Danish case control samples were genotyped for 81 tagSNPs (in total 984 individuals diagnosed with schizophrenia and 1,500 control persons) and antibodies against maternal HSV-2 infection were measured in one of the samples (365 cases and 365 controls). Nine SNPs out of 30 in GRIN2B were significantly associated with schizophrenia. One SNP remained significant after Bonferroni correction (rs1806194, P(nominal) = 0.0008). Significant interaction between maternal HSV-2 seropositivity and GRIN2B genetic variation in the offspring were observed for seven SNPs and two remained significant after Bonferroni correction (rs1805539, P(nominal) = 0.0001 and rs1806205, P(nominal) = 0.0008). The significant associations and interactions were located at the 3' region of GRIN2B suggesting that genetic variation in this part of the gene may be involved in the pathophysiology of schizophrenia. © 2011 Wiley-Liss, Inc.

Introduction No consensus exists regarding the ability to detect the 22q11 deletion syndrome based on clinical assessment. Traditionally, diagnosis depends on clinical referral. Thus, individuals with typical manifestations are easily identified, but when manifestations are atypical or subclinical, diagnosis may be delayed or even missed. The aim of the present literature review was to evaluate the validity of clinical assessment as a method of predicting 22q11.2 deletions in individuals with congenital cardiac malformations. Methods We identified 14 studies in which clinical assessment was blinded to the result from the genetic analysis. Results Among 1458 patients, 159 (11% [9–13%]) carried the 22q11.2 deletion. The clinicians correctly identified 110 (69% [62–76%]) of them, whereas 49 (31% [24–38%]) would have remained undiagnosed if genetic screening had not been performed. Sensitivity, specificity, predictive value of positive and negative tests ranged from 0–100%, 43–100%, 7–100%, and 79–100%, respectively. Conclusions Clinical assessment identifies less than 3/4 patients with a 22q11.2 deletion, whereas more than 1/4 remain undiagnosed if genetic tests are not performed on a routine basis. In this review, we found that clinical assessment is not suited for detecting individuals to be tested for 22q11.2 deletions.