Genetic in long QT syndromes

The long QT syndrome (LQTS) is a genetic disorder characterized by prolongation of the QT interval in the electrocardiogram (ECG) and a propensity to "torsades de pointes" ventricular tachycardia frequently leading to syncope, cardiac arrest, or sudden death usually in young otherwise healthy individuals. LQTS caused by mutations of predominantly potassium and sodium ion channel genes or channel-interacting proteins leading to positive overcharge of myocardial cell with consequent heterogeneous prolongation of repolarization in various layers and regions of myocardium. These conditions facilitate the early after-depolarization and reentry phenomena underlying development of polymorphic ventricular tachycardia observed in patients with LQTS. Obtaining detailed patient history regarding cardiac events in the patient and his/her family members combined with careful interpretation of standard 12-lead ECG (with precise measurement of QT interval in all available ECGs and evaluation of T-wave morphology) usually is sufficient to diagnose the syndrome. The LQTS show great genetic heterogeneity and has been identified more than 500 mutations distributed in 10 genes: KCNQ1, HERG, SCN5A, KCNE1, KCNE2, ANKB, KCNJ2, CACNA1A, CAV3 and SCN4B. Despite advances in the field, 25-30% of patients remain undiagnosed genetic. Genetic testing plays an important role and is particularly useful in cases with nondiagnostic or borderline ECG findings.

Towards an Earlier Diagnosis of Primary Ciliary Dyskinesia: Which Patients Should Undergo Detailed Diagnostic Testing?

Primary ciliary dyskinesia is a rare heterogeneous recessive genetic disorder of motile cilia, leading to chronic upper and lower respiratory symptoms. Prevalence is estimated at around 1:10,000, but many patients remain undiagnosed, while others receive the label incorrectly. Proper diagnosis is complicated by the fact that the key symptoms such as wet cough, chronic rhinitis and recurrent upper and lower respiratory infection, are common and nonspecific. There is no single gold standard test to diagnose PCD. Presently, the diagnosis is made by augmenting the medical history and physical examination with in patients with a compatible medical history following a demanding combination of tests including nasal nitric oxide, high- speed video microscopy, transmission electron microscopy, genetics, and ciliary culture. These tests are costly and need sophisticated equipment and experienced staff, restricting use to highly specialised centers. Therefore, it would be desirable to have a screening test for identifying those patients who should undergo detailed diagnostic testing. Three recent studies focused on potential screening tools: one paper assessed the validity of nasal nitric oxide for screening, and two studies developed new symptom-based screening tools. These simple tools are welcome, and hopefully remind physicians whom to refer for definitive testing. However, they have been developed in tertiary care settings, where 10 to 50% of tested patients have PCD. Sensitivity and specificity of the tools are reasonable, but positive and negative predictive values may be poor in primary or secondary care settings. While these studies take an important step forward towards an earlier diagnosis of PCD, more remains to be done before we have tools tailored to different health care settings.

Mutations affecting disulphide bonds contribute to a fairly common prevalence of F13B gene defects: results of a genetic study in 14 families with factor XIII B deficiency

Severe factor XIII (FXIII) deficiency is a rare autosomal recessive coagulation disorder affecting one in two million individuals. The aim of the present study was to screen for and analyse F13B gene defects in the German population. A total of 150 patients presenting with suspected FXIII deficiency and one patient with severe (homozygous) FXIII deficiency were screened for mutations in F13A and F13B genes. Twenty-five individuals presented with detectable heterozygous mutations, 12 of them in the F13A gene and 13 of them in the F13B gene. We report on the genotype-phenotype correlations of the individuals showing defects in the F13B gene. Direct sequencing revealed 12 unique mutations including seven missense mutations (Cys5Arg, Ile81Asn, Leu116Phe, Val217Ile, Cys316Phe, Val401Glu, Pro428Ser), two splice site mutations (IVS2-1G>C, IVS3-1G>C), two insertions (c.1155_1158dupACTT, c.1959insT) and one in-frame deletion (c.471-473delATT). Two of the missense mutations (Cys5Arg, Cys316Phe) eliminated disulphide bonds (Cys5-Cys56, Cys316-Cys358). Another three missense mutations, (Leu116Phe, Val401Glu, Pro428Ser) were located proximal to other cysteine disulphide bonds, therefore indicating that the region in and around these disulphide bonds is prone to functionally relevant mutations in the FXIII-B subunit. The present study reports on a fairly common prevalence of F13B gene defects in the German population. The regions in and around the cysteine disulphide bonds in the FXIII-B protein may be regions prone to frequent mutations.

Bipolar disorder susceptibility region on chromosome 3q29 not confirmed in a case-control association study

We identified a bipolar disorder (BPD) susceptibility region on chromosome 3q29 in a genome-wide linkage scan (Bailer et al. 2002 (Biol Psychiatry 52: 40), NPL-score 4.09) and follow-up linkage analysis (Schosser et al. 2004 (J Psychiatr Res 38(3): 357), NPL-scores >3 with five markers). These findings were supported by further fine-mapping of this region (Schosser et al. 2007 (Eur Neuropsychopharmacol 17(6-7): 501)), finding NPL-scores >3.9 with SNPs (single nucleotide polymorphisms) spanning a region of 3.46 Mbp in BPD families. Since genetic association studies are more powerful than linkage studies for detecting susceptibility genes of small effect size, we aimed to replicate these findings in an independent case-control sample collected in London (UK) and Vienna (Austria).

Common obesity risk alleles in childhood attention-deficit/hyperactivity disorder

Children with attention-deficit/hyperactivity disorder (ADHD) have a higher rate of obesity than children without ADHD. Obesity risk alleles may overlap with those relevant for ADHD. We examined whether risk alleles for an increased body mass index (BMI) are associated with ADHD and related quantitative traits (inattention and hyperactivity/impulsivity). We screened 32 obesity risk alleles of single nucleotide polymorphisms (SNPs) in a genome-wide association study (GWAS) for ADHD based on 495 patients and 1,300 population-based controls and performed in silico analyses of the SNPs in an ADHD meta-analysis comprising 2,064 trios, 896 independent cases, and 2,455 controls. In the German sample rs206936 in the NUDT3 gene (nudix; nucleoside diphosphate linked moiety X-type motif 3) was associated with ADHD risk (OR: 1.39; P = 3.4 × 10(-4) ; Pcorr  = 0.01). In the meta-analysis data we found rs6497416 in the intronic region of the GPRC5B gene (G protein-coupled receptor, family C, group 5, member B; P = 7.2 × 10(-4) ; Pcorr  = 0.02) as a risk allele for ADHD. GPRC5B belongs to the metabotropic glutamate receptor family, which has been implicated in the etiology of ADHD. In the German sample rs206936 (NUDT3) and rs10938397 in the glucosamine-6-phosphate deaminase 2 gene (GNPDA2) were associated with inattention, whereas markers in the mitogen-activated protein kinase 5 gene (MAP2K5) and in the cell adhesion molecule 2 gene (CADM2) were associated with hyperactivity. In the meta-analysis data, MAP2K5 was associated with inattention, GPRC5B with hyperactivity/impulsivity and inattention and CADM2 with hyperactivity/impulsivity. Our results justify further research on the elucidation of the common genetic background of ADHD and obesity.

Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency 1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.Molecular Psychiatry advance online publication, 20 November 2012; doi:10.1038/mp.2012.161.

DCLK1 variants are associated across schizophrenia and attention deficit/hyperactivity disorder

Doublecortin and calmodulin like kinase 1 (DCLK1) is implicated in synaptic plasticity and neurodevelopment. Genetic variants in DCLK1 are associated with cognitive traits, specifically verbal memory and general cognition. We investigated the role of DCLK1 variants in three psychiatric disorders that have neuro-cognitive dysfunctions: schizophrenia (SCZ), bipolar affective disorder (BP) and attention deficit/hyperactivity disorder (ADHD). We mined six genome wide association studies (GWASs) that were available publically or through collaboration; three for BP, two for SCZ and one for ADHD. We also genotyped the DCLK1 region in additional samples of cases with SCZ, BP or ADHD and controls that had not been whole-genome typed. In total, 9895 subjects were analysed, including 5308 normal controls and 4,587 patients (1,125 with SCZ, 2,496 with BP and 966 with ADHD). Several DCLK1 variants were associated with disease phenotypes in the different samples. The main effect was observed for rs7989807 in intron 3, which was strongly associated with SCZ alone and even more so when cases with SCZ and ADHD were combined (P-value = 4 × 10(-5) and 4 × 10(-6), respectively). Associations were also observed with additional markers in intron 3 (combination of SCZ, ADHD and BP), intron 19 (SCZ+BP) and the 3'UTR (SCZ+BP). Our results suggest that genetic variants in DCLK1 are associated with SCZ and, to a lesser extent, with ADHD and BP. Interestingly the association is strongest when SCZ and ADHD are considered together, suggesting common genetic susceptibility. Given that DCLK1 variants were previously found to be associated with cognitive traits, these results are consistent with the role of DCLK1 in neurodevelopment and synaptic plasticity.

Rationale and first results of developing at-risk (prodromal) criteria for bipolar disorder

Bipolar affective disorder (BD) is a severe, recurrent and disabling disorder with devastating consequences for individuals, families and society. Although these hazards and costs provide a compelling rationale for development of early detection and early intervention strategies in BD, the development of at-risk criteria for first episode mania is still in an early stage of development. In this paper we review the literature with respect to the clinical, neuroantomical and neuropsychological data, which support this goal. We also describe our recently developed bipolar at-risk criteria (BAR). This criteria comprises the peak age range of the first onset of bipolar disorder, genetic risk, presenting with sub-threshold mania, cyclothymic features or depressive symptoms. An initial pilot evaluation of the BAR criteria in 22 subjects indicated conversion rates to proxies of first-episode mania of 23% within 265 days on average, and high specificity and sensitivity of the criteria. If prospective studies confirm the validity of the BAR criteria, then the criteria would have the potential to open up new avenues of research for indicated prevention in BD and might therefore offer opportunities to ameliorate the severity of, or even prevent BD.

Bipolar disorder risk alleles in children with ADHD

Bipolar disorder (BD) and attention deficit/hyperactivity disorder (ADHD) may share common genetic risk factors as indicated by the high co-morbidity of BD and ADHD, their phenotypic overlap especially in pediatric populations, the high heritability of both disorders, and the co-occurrence in families. We therefore examined whether known polygenic BD risk alleles are associated with ADHD. We chose the eight best SNPs of the recent genome-wide association study (GWAS) of BD patients of German ancestry and the nine SNPs from international GWAS meeting a 'genome-wide significance' level of α = 5 × 10(-8). A GWAS was performed in 495 ADHD children and 1,300 population-based controls using HumanHap550v3 and Human660 W-Quadv1 BeadArrays. We found no significant association of childhood ADHD with single BD risk alleles surviving adjustment for multiple testing. Yet, risk alleles for BD and ADHD were directionally consistent at eight of nine loci with the strongest support for three SNPs in or near NCAN, BRE, and LMAN2L. The polygene analysis for the BP risk alleles at all 14 loci indicated a higher probability of being a BD risk allele carrier in the ADHD cases as compared to the controls. At a moderate power to detect association with ADHD, if true effects were close to estimates from GWAS for BD, our results suggest that the possible contribution of BD risk variants to childhood ADHD risk is considerably lower than for BD. Yet, our findings should encourage researchers to search for common genetic risk factors in BD and childhood ADHD in future studies.

Novel mutation in the ceruloplasmin gene causing a cognitive and movement disorder with diabetes mellitus

In a Chinese woman who had diabetes mellitus, undetectable ceruloplasmin, hand tremor, neck dystonia, and cognitive disturbances, genetic analyses revealed a novel homozygous mutation (848G > C or W283S) in exon 5 in the ceruloplasmin gene. Another member with a milder phenotype was also affected by this mutation. The healthy sister was heterozygous at the same position. Aceruloplasminemia has not yet been reported in China. This case suggests that increased awareness should be paid to this disorder in the presence of the typical symptoms.

[Possible genetic link between Darier's disease and depression : Review of the literature and case history.]

Darier's disease is a rare, inherited autosomal dominant skin disorder caused by a mutation in the sarcoendoplasmatic reticulum calcium transporter (SERCA)-2-gene. In a number of pedigrees, Darier's disease closely relates with affective disorder. The most likely hypothesis for this is a susceptibility gene for affective disorder near the SERCA-2-gene. A 6.5-megabase region could be identified as a susceptibility locus. This region constitutes a susceptability locus also in affective disorder without Darier's disease. The underlying gene has not yet been identified.

Mitochondrial neurogastrointestinal encephalomyopathy in three siblings: clinical, genetic and neuroradiological features

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder in which a nuclear mutation of the thymidine phosphorylase (TP) gene causes mitochondrial genomic dysfunction. Patients suffer from gastrointestinal dysmotility, cachexia, ptosis, external ophthalmoparesis, myopathy and polyneuropathy. Magnetic resonance imaging (MRI) shows leukoencephalopathy. We describe clinical, genetic and neuroradiological features of three brothers affected with MNGIE. Clinical examination, laboratory analyses, MRI and magnetic resonance spectroscopy (MRS) of the brain, and genetic analysis have been performed in all six members of the family with the three patients with MNGIE. Two of them are monozygous twins. They all suffered from gastrointestinal dysmotility, cachexia, ophthalmoplegia, muscular atrophies, and polyneuropathy. Urinary thymidine was elevated in the patients related to the severity of clinical disease, and urinary thymidine (normally not detectable) was also found in a heterozygous carrier. Brain MRI showed leukoencephalopathy in all patients; however, their cognitive functioning was normal. Brain MRS demonstrated reduced N-acetylaspartate and choline in severely affected areas. MRI of heterozygous carriers was normal. A new mutation (T92N) in the TP gene was identified. Urinary thymidine is for the first time reported to be detectable in a heterozygous carrier. MRS findings indicate loss of neurons, axons, and glial cells in patients with MNGIE, but not in heterozygous carriers.

Isolated mediotegmental lesion causing narcolepsy and rapid eye movement sleep behaviour disorder: a case evidencing a common pathway in narcolepsy and rapid eye movement sleep behaviour disorder

Narcolepsy is usually an idiopathic disorder, often with a genetic predisposition. Symptomatic cases have been described repeatedly, often as a consequence of hypothalamic lesions. Conversely, REM (rapid eye movement) sleep behaviour disorder (RBD) is usually a secondary disorder, often due to degenerative brain stem disorders or narcolepsy. The case of a hitherto healthy man is presented, who simultaneously developed narcolepsy and RBD as the result of an acute focal inflammatory lesion in the dorsomedial pontine tegmentum in the presence of normal cerebrospinal fluid hypocretin-1 levels and in the absence of human lymphocyte antigen haplotypes typically associated with narcolepsy and RBD (DQB1*0602, DQB1*05). This first observation of symptomatic narcolepsy with RBD underlines the importance of the mediotegmental pontine area in the pathophysiology of both disorders, even in the absence of a detectable hypocretin deficiency and a genetic predisposition.

Oculopharyngeal muscular dystrophy - an under-diagnosed disorder?

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant muscle disorder, usually of late onset. OPMD is among the few triplet repeat diseases/ polyalanine (poly(A)) expansion diseases for which the function of the mutated gene is quite well established. The disease is characterised by slowly progressive bilateral ptosis, dysphagia and proximal limb weakness, appearing after the age of 40 years. Prevalence and incidence of OPMD are low, but the disease occurs all over the world. The pedigrees of two Swiss kindred have been previously reported in Switzerland. In the last 2 years, accumulation of newly diagnosed cases in North-West Switzerland have been observed, which suggests that OPMD may be more prevalent than previously thought. Primary care providers, opthalmologists and neurologists that are alert for the almost specific combination of clinical signs, together with the availability of reliable genetic testing may help to recognise currently undiagnosed patients. They can advance knowledge and the characterisation of the OPMD population in Switzerland. Since the number of disorders linked to poly(A) expansions is growing rapidly, the study of OPMD may contribute to the understanding of a large group of other developmental and degenerative diseases. On the basis of a patient with "classical" OPMD, this review summarises the clinical, therapeutic, epidemiological, pathomechanistic and genetic aspects of OPMD, provides practical information about the differential diagnosis of OPMD, and presents a survey of different investigational methods.

Exploring the genetic link between RLS and ADHD

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder of childhood onset. Clinical and biological evidence points to shared common central nervous system (CNS) pathology of ADHD and restless legs syndrome (RLS). It was hypothesized that variants previously found to be associated with RLS in two large genome-wide association studies (GWA), will also be associated with ADHD. SNPs located in MEIS1 (rs2300478), BTBD9 (rs9296249, rs3923809, rs6923737), and MAP2K5 (rs12593813, rs4489954) as well as three SNPs tagging the identified haplotype in MEIS1 (rs6710341, rs12469063, rs4544423) were genotyped in a well characterized German sample of 224 families comprising one or more affected sibs (386 children) and both parents. We found no evidence for preferential transmission of the hypothesized variants to ADHD. Subsequent analyses elicited nominal significant association with haplotypes consisting of the three SNPs in BTBD9 (chi2 = 14.8, df = 7, nominal p = 0.039). According to exploratory post hoc analyses, the major contribution to this finding came from the A-A-A-haplotype with a haplotype-wise nominal p-value of 0.009. However, this result did not withstand correction for multiple testing. In view of our results, RLS risk alleles may have a lower effect on ADHD than on RLS or may not be involved in ADHD. The negative findings may additionally result from genetic heterogeneity of ADHD, i.e. risk alleles for RLS may only be relevant for certain subtypes of ADHD. Genes relevant to RLS remain interesting candidates for ADHD; particularly BTBD9 needs further study, as it has been related to iron storage, a potential pathophysiological link between RLS and certain subtypes of ADHD.