Family Genetic Studies Research Articles

Commentary: The best-laid plans: the problems and pitfalls of assessing mild cognitive impairment

bility and the environment determines change in cognitive ability during 35 years of adulthood. Psychol Sci 2009; 20:1146–52. 36 Ganguli M, Snitz BE, Saxton JA et al. Outcomes of mild cognitive impairment by definition: A population study. Arch Neurol 2011;68:761–67. 37 R Development Core Team. R: A Language and Environment for Statistical Computing. Vienna: R Foundation for Statistical Computing, 2011. 38 van Buuren S, Groothuis-Oudshoorn K. MICE: Multivariate imputation by chained equations in R. J Stat Soft 2011;45:1–67. 39 Boker S, Neale MC, Maes H et al. OpenMx: An open source extended structural equation modeling framework. Psychometrika 2011;76:306–17. 40 Eaves LJ, Last KA, Young PA, Martin NG. Model-fitting approaches to the analysis of human behavior. Heredity 1978;41:249–320. 41 Neale MC, Cardon LR. Methodology for Genetic Studies of Twins and Families. Dordrecht, The Netherlands: Kluwer, 1992. 42 Akaike H. Factor analysis and AIC. Psychometrika 1987;52: 317–32. 43 Manly JJ, Tang MX, Schupf N, Stern Y, Vonsattel JP, Mayeux R. Frequency and course of mild cognitive impairment in a multiethnic community. Ann Neurol 2008;63:494–506. 44 Stern Y. What is cognitive reserve? Theory and research application of the reserve concept. J Int Neuropsychol Soc 2002;8:448–60. 45 Brainerd CJ, Reyna VF, Petersen RC, Smith GE, Taub ES. Is the apolipoprotein e genotype a biomarker for mild cognitive impairment? Findings from a nationally representative study. Neuropsychology 2011;25:679–89. 46 Flory JD, Manuck SB, Ferrell RE, Ryan CM, Muldoon MF. Memory performance and the apolipoprotein E polymorphism in a community sample of middleaged adults. Am J Med Genet 2000;96:707–11. 47 Jorm AF, Butterworth P, Anstey KJ et al. Memory complaints in a community sample aged 60–64 years: Associations with cognitive functioning, psychiatric symptoms, medical conditions, APOE genotype, hippocampus and amygdala volumes, and white-matter hyperintensities. Psychol Med 2004;34:1495–506. 48 Petersen RC. Mild cognitive impairment as a diagnostic entity. J IintMed 2004;256:183–94. 49 Dolcos S, MacDonald SW, Braslavsky A, Camicioli R, Dixon RA. Mild cognitive impairment is associated with selected functional markers: Integrating concurrent, longitudinal, and stability effects. Neuropsychology 2012;26: 209–23.

Generalized and Specific Neurocognitive Deficits in Psychotic Disorders: Utility for Evaluating Pharmacological Treatment Effects and as Intermediate Phenotypes for Gene Discovery

A growing body of research suggests that schizophrenia and bipolar disorder share overlapping clinical, neurobiological, and genetic features, raising important questions about the boundaries and distinctiveness of these 2 major psychiatric disorders. A generalized cognitive impairment has long been understood to be a core feature of schizophrenia. More recently, it has become apparent that cognitive impairment also occurs in bipolar disorder, particularly in those patients with a history of psychotic symptoms. Whether a generalized deficit exists across a spectrum of psychotic disorders is less clearly established. Additionally, in the context of a broad impairment, it remains a significant challenge to identify deficits in specific cognitive processes that may have distinct neurochemical or regional brain substrates and linkages to particular risk-associated genetic factors. In this article, we review the findings from neuropsychological studies across a spectrum that includes schizophrenia, schizoaffective and bipolar disorders, and conclude the available evidence strongly supports that a generalized deficit is present across psychotic disorders that differs in severity more so than form. We then consider the implications of generalized and specific deficits in psychosis for 2 areas of research--the evaluation of pharmacological treatments targeting cognitive deficits, and the investigation of cognitive intermediate phenotypes in family genetic studies. Examples from the literature that touch on the relevance of the generalized deficit in these contexts are provided, as well as consideration for the continued need to identify specific impairments that are separable from the generalized deficit in order to advance drug and gene discovery.

A Genome Scan for Loci Shared by Autism Spectrum Disorder and Language Impairment

The authors conducted a genetic linkage study of families that have both autism spectrum disorder (ASD) and language-impaired probands to find common communication impairment loci. The hypothesis was that these families have a high genetic loading for impairments in language ability, thus influencing the language and communication deficits of the family members with ASD. Comprehensive behavioral phenotyping of the families also enabled linkage analysis of quantitative measures, including normal, subclinical, and disordered variation in all family members for the three general autism symptom domains: social, communication, and compulsive behaviors. The primary linkage analysis coded persons with either ASD or specific language impairment as "affected." The secondary linkage analysis consisted of quantitative metrics of autism-associated behaviors capturing normal to clinically severe variation, measured in all family members. Linkage to language phenotypes was established at two novel chromosomal loci, 15q23-26 and 16p12. The secondary analysis of normal and disordered quantitative variation in social and compulsive behaviors established linkage to two loci for social behaviors (at 14q and 15q) and one locus for repetitive behaviors (at 13q). These data indicate shared etiology of ASD and specific language impairment at two novel loci. Additionally, nonlanguage phenotypes based on social aloofness and rigid personality traits showed compelling evidence for linkage in this study group. Further genetic mapping is warranted at these loci.

Perceptions of nature, nurture and behaviour

Trying to separate out nature and nurture as explanations for behaviour, as in classic genetic studies of twins and families, is now said to be both impossible and unproductive. In practice the nature-nurture model persists as a way of framing discussion on the causes of behaviour in genetic research papers, as well as in the media and lay debate. Social and environmental theories of crime have been dominant in criminology and in public policy while biological theories have been seen as outdated and discredited. Recently, research into genetic variations associated with aggressive and antisocial behaviour has received more attention in the media. This paper explores ideas on the role of nature and nurture in violent and antisocial behaviour through interviews and open-ended questionnaires among lay publics. There was general agreement that everybody’s behaviour is influenced to varying degrees by both genetic and environmental factors but deterministic accounts of causation, except in exceptional circumstances, were rejected. Only an emphasis on nature was seen as dangerous in its consequences, for society and for individuals themselves. Whereas academic researchers approach the debate from their disciplinary perspectives which may or may not engage with practical and policy issues, the key issue for the public was what sort of explanations of behaviour will lead to the best outcomes for all concerned.

Increased decidual mRNA expression levels of candidate maternal pre-eclampsia susceptibility genes are associated with clinical severity

IntroductionPre-eclampsia (PE) has a familial association, with daughters of women who had PE during pregnancy having more than twice the risk of developing PE themselves. Through genome-wide linkage and genetic association studies in PE-affected families and large population samples, we previously identified the following as positional candidate maternal susceptibility genes for PE; ACVR1, INHA, INHBB, ERAP1, ERAP2, LNPEP, COL4A1 and COL4A2. The aims of this study were to determine mRNA expression levels of previously identified candidate maternal pre-eclampsia susceptibility genes from normotensive and severe PE (SPE) pregnancies and correlate mRNA expression levels with the clinical severity of SPE. MethodsThird trimester decidual tissues were collected from both normotensive (n = 21) and SPE pregnancies (n = 24) and mRNA expression levels were determined by real-time PCR. Gene expression was then correlated with several parameters of clinical severity in SPE. Statistical significance was determined by Mann–Whitney U test and Spearman's Correlation. ResultsThe data demonstrate significantly increased decidual mRNA expression levels of ACVR1, INHBB, ERAP1, ERAP2, LNPEP, COL4A1 and COL4A2 in SPE (p < 0.05). Increased mRNA expression levels of several genes – INHA, INHBB, COL4A1 and COL4A2 were correlated with earlier onset of PE and earlier delivery of the fetus (p < 0.05). ConclusionThese results suggest altered expression of maternal susceptibility genes may play roles in PE development and the course of disease severity.

Transcription factors and atrial fibrillation

Atrial fibrillation (AF) is a prevalent cardiac arrhythmia with a significant genetic component. In recent years, familial and population-based genetic studies in AF have led to the emergence of transcription factors as potentially important contributors to arrhythmia susceptibility. Further evidence to implicate transcription factors in AF has come from studies in animal models, which demonstrate that these proteins play critical roles during AF-related atrial remodelling. Transcription factors have the potential to create a pro-arrhythmogenic substrate in the pulmonary veins and the atrium. However, further research is necessary to fully characterize the mechanistic links between these proteins and AF pathogenesis. In the future, such studies could potentially lead to the development of novel therapies for the arrhythmia. This review focuses on the association between transcription factors and AF.

A Novel Mutation in SCN9A in a Child With Congenital Insensitivity to Pain

BackroundCongenital insensitivity to pain (CIP) is a rare condition in which patients have no pain perception and anosmia but are otherwise essentially normal (OMIM 243000). The recent discovery of the genetic defects underlying 3 monogenic pain disorders has provided additional and important insights about some components of human pain. Genetic studies in families demonstrating recessively inherited channelopathy-associated insensitivity to pain have identified nonsense mutations that result in truncation of the voltage-gated sodium channel type IX subunit (SCN9A), a 113.5-kb gene comprising coding 26 exons. Here we describe a patient with CIP with a new mutation in SCN9A not described yet. MethodsAll exons were sequenced. ResultAll 26 coding exons were sequenced and two changes were identified in homozygosity in exon 10: c.1126 A > C causing K376Q and c.1124delG causing p.G375Afs* frame shift. ConclusionWe report a novel, loss-of-function mutation in homozygosity that causes congenital insensitivity to pain and provide a comprehensive clinical description of the patient. This contributes to the clinical and neurophysiological characteristic of the sodium channel Nav1.7 channelopathy and expand our genetic knowledge which might provide more accurate and comprehensive clinical electrophysiological and genetic information.

Association of genetic risk severity with ADHD clinical characteristics

This study sought to examine the association between the cumulative risk severity conferred by the total number of attention-deficit/hyperactivity disorder (ADHD) risk alleles of the DAT1 3'UTR variable number tandem repeat (VNTR), DRD4 Exon 3 VNTR, and 5-HTTLPR with ADHD characteristics, clinical correlates, and functional outcomes in a pediatric sample. Participants were derived from case-control family studies of boys and girls diagnosed with ADHD, a genetic linkage study of families with children with ADHD, and a family genetic study of pediatric bipolar disorder. Caucasian children 18 and younger with and without ADHD and with available genetic data were included in this analysis (N = 591). The association of genetic risk severity with sociodemographic, clinical characteristics, neuropsychological, emotional, and behavioral correlates was examined in the entire sample, in the sample with ADHD, and in the sample without ADHD, respectively. Greater genetic risk severity was significantly associated with the presence of disruptive behavior disorders in the entire sample and oppositional defiant disorder in participants with ADHD. Greater genetic risk severity was also associated with the absence of anxiety disorders, specifically with the absence of agoraphobia in the context of ADHD. Additionally, one ADHD symptom was significantly associated with greater genetic risk severity. Genetic risk severity is significantly associated with ADHD clinical characteristics and co-morbid disorders, and the nature of these associations may vary on the type (externalizing vs. internalizing) of the disorder.

Maternal anxiety disorders prior to conception, psychopathology during pregnancy and early infants’ development: a prospective-longitudinal study

Family-genetic studies suggest that anxiety disorders run in families and that mechanisms of familial transmission might act as early as during pregnancy. The aims of the Maternal Anxiety in Relation to Infant Development (MARI) Study are to prospectively investigate the course of pregnancy in women with and without anxiety disorders prior to conception from early pregnancy to postpartum focussing on (a) maternal psychopathology, (b) maternal perinatal health, and (c) offspring outcomes that are supposed to be early indicators/ antecendents for later anxiety disorders. The MARI Study is a prospective-longitudinal study program with seven waves of assessment: T1 (baseline: week10 to 12 of gestation), T2 (week22 to 24 of gestation), T3 (week35 to 37 of gestation), T4 (10days postpartum), T5 (2months postpartum), T6 (4months postpartum), and T7 (16months postpartum). Overall, N = 306 pregnant women were enrolled during early pregnancy (T1) and allocated to one of the following initial diagnostic groups: no AD: no anxiety nor depressive disorder prior to pregnancy (N = 109), pure D: pure depressive disorder(s) prior to pregnancy (N = 48), pure A: pure anxiety disorder(s) prior to pregnancy (N = 84), and comorbid AD: comorbid anxiety and depressive disorders prior to pregnancy (N = 65). Overall, N = 284 mothers could be retained until T6 (retention rate: 92.8%) and N = 274 until T7 (retention rate: 89.5%). Clinical and psychosocial measures were used including a standardized diagnostic interview (CIDI-V) with dimensional scales and standardized observation paradigms (mother-infant-relationship, infant temperament and neuropsychological development). Dimensional anxiety and depression liability indices were developed to reflect the severity of anxiety and depressive disorders prior to pregnancy and to ease longitudinal modelling. Findings from this study will contribute to improved knowledge about the natural course of anxiety disorders during transition to parenthood and associated outcomes that are assumed to be early indicators of later psychopathology in the offspring. Results are expected to provide new insights into mechanisms of familial transmission and clues for targeted prevention and early intervention.

Differences Between Children With Dyslexia Who Are and Are Not Gifted in Verbal Reasoning

New findings are presented for children in grades 1 to 9 who qualified their families for a multi-generational family genetics study of dyslexia (impaired word decoding/spelling) who had either superior verbal reasoning (n=33 at or above 1 2/3 standard deviation, superior or better range; 19% of these children) or average verbal reasoning (n=31 below population mean, but above - 2/3 standard deviation, average range; 18% of these children). Evidence-based rationale and results supporting the tested hypotheses are provided: (a) twice exceptional students with superior verbal reasoning and dyslexia significantly outperformed those with average verbal reasoning and dyslexia on reading, spelling, morphological, and syntactic skills, (b) but not on verbal working-memory behavioral markers of genetically based dyslexia related to impaired phonological and orthographic word-form storage and processing, naming orthographic symbols (phonological loop), writing orthographic symbols (orthographic loop), and supervisory attention (focus, switch, sustain, or monitor attention). Superior verbal reasoning may mask dyslexia if only very low achievement is used to identify this disorder of oral word reading and written spelling. Instruction for twice exceptional students who have dyslexia, but are also verbally gifted, should focus not only on oral word reading and written spelling but also the impaired working memory components within intellectually engaging lesson sets. These findings for gifted students with dyslexia are situated within the broader context of the many kinds of twice exceptionalities related to specific learning disabilities that exist in school-age children and youth.

O.22 Autosomal dominant Core Congenital Myopathy caused by a mutation in the MYH7 gene

Autosomal dominant (AD) Central core disease (CCD) named currently congenital myopathy with core is an inherited disorder characterised by the presence of cores which are well-limited rounded areas devoid of any oxidative staining. The cores extend almost along the full length of the fibres; these areas correspond to sarcomeric disorganisation, Z line streaming and absence of mitochondria. Genetic studies of AD-CCD families demonstrated the presence of heterozygous mutations in the RYR1 gene in the large majority of families. However, this gene was excluded in some families, suggesting a genetic heterogeneity of AD-Core myopathies (Romero et al., 2005). To enlarge the genetic spectrum of autosomal dominant congenital myopathies with cores demonstrating mutations in a second gene. AD-CCD family with three affected members: the mother and two of three siblings. The symptoms began during the early childhood with delayed motor development. Later they develop proximal weakness, hypertrophy of calves, scapular winging and significant weakness (amyotrophic) of quadriceps and tibialis anterior. No cardiac or ocular involvement was noted. The muscle biopsies sections showed a particular pattern: relatively large and eccentric cores (placed near the subsarcolemmal regions) associated with type 1 predominance and fibre type disproportion in a patient. The large majority of the cores have abrupt borders. Electron microscopy confirmed the presence of multiple large disorganised sarcomeric areas as characteristic unstructured and structured cores. Moreover, some fibres contain focal disorganised areas. Exome sequencing analysis identified a heterozygous missense mutation L1723P in MYH7 segregating with the disease and affecting a conserved residue in the tail domain. With this study we describe MYH7 as a second causative gene for AD-CCD in addition to RYR1 . Our study enlarges the genetic spectrum of AD-CCD myopathies.

R1933X mutation in the MYH9 gene in May-Hegglin anomaly mimicking idiopathic thrombocytopenic purpura

May-Hegglin anomaly (MHA) is a rare autosomal dominant disorder characterized by the triad of thrombocytopenia, giant platelets, and inclusion bodies in leukocytes. Recent evidence links MHA to mutations in the MYH9 gene. MHA has not been reported in Taiwan before. We report a 25-year-old Taiwanese man who presented with prolonged bleeding after dental extraction. Examination of peripheral blood smear revealed thrombocytopenia (platelet = 35,000/μL), giant platelets, and Döhle-like cytoplasmic inclusions in neutrophils. A strong family history of thrombocytopenia favored hereditary macrothrombocytopenia over idiopathic thrombocytopenic purpura (ITP). Electron microscopy revealed a spindle shape and parallel order of filaments in the inclusions, consistent with the diagnosis of MHA. We performed mutational analysis using polymerase chain reaction followed by direct sequence of the MYH9 gene for the patient, his maternal uncle and cousin, and all showed the same heterozygous R1933X mutation in exon 40. MHA should be considered when a young patient has thrombocytopenia, frequently misdiagnosed as ITP. Morphological examination of peripheral blood smear, family history tracing and genetic studies are required to make an accurate diagnosis and avoid unnecessary and even harmful therapies such as corticosteroids and splenectomy.

Detection of Carrier Status and Mutations in Family Members of a Child with Complete Deletion of the DAX1 Gene using Multiplex Ligation-Dependent Probe Amplification

To the Editor:We have previously reported a case of adrenal crisis [1]. Real-time SYBR Green DNA PCR and gel electrophoresis showed lack of amplification of exons of NRB01/DAX1 (dosage-sensitive sex reversal) gene on Xp21 locus, suggesting a complete deletion. We demonstrated that molecular techniques may prove useful in making a diagnosis and for genetic counselling in adrenal hypoplasia congenital (AHC); information in this letter is supplementary to the article already published [1]. AHC is a rare congenital adrenal disorder where there is primary adrenal failure in early life and hypogonadotropic hypogonadism during adolescence. X-linked AHC is caused by deletions/mutations in DAX1 gene AHC critical region on X chromosome. We performed genetic analysis using Multiplex Ligation-Dependent Probe Amplification (MLPA) on family members of proband, so as to further understand genetic factors involved in inheritance and presentation of this child with AHC, and to detect affected or carrier status in relatives. MLPA, an extension of PCR, allows highly multiplexed detection of relative copy number variations of target sequences in a fast, reliable, and cost-effective manner [2]. Genetic studies in families of patients with affected members have been previously reported [3]. Six family members were tested by MLPA: child’s parents, sister, maternal aunt and her children (Fig. 1). MLPA analysis was performed using SALSA MLPA P185 Intersex probemix (MRC-Holland, Netherlands). Each probe generates an amplification product of unique length that can be detected by capillary electrophoresis. Comparison of relative sizes of the fluorescent peaks from the target probes with reference probes coamplified during the reaction, using analysis software, allows quantification of relative abundance of target regions. N. D. Phadke :K. A. Khatod GenePath Dx (Causeway Healthcare Pvt Ltd), J.M. Road, Shivajinagar, Pune, India

Association Between TPH2 Gene Polymorphisms and Attention Deficit Hyperactivity Disorder in Korean Children

Attention deficit hyperactivity disorder (ADHD) is a common disorder of the school-age population. ADHD is a familial disorder and genetic studies estimate heritability at 80%-90%. The aim of the present study was to investigate the association between the genetic type and alleles for the TPH2 gene in Korean children with ADHD. The sample consisted of 142 ADHD children and 139 control children. We diagnosed ADHD according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). ADHD symptoms were evaluated with Conners' Parent Rating Scales and Dupaul Parent ADHD Rating Scales. Blood samples were taken from the 281 subjects, DNA was extracted from blood lymphocytes, and polymerase chain reaction was performed for TPH2 polymorphism. Alleles and genotype frequencies were compared using the chi-square test. We compared the allele and genotype frequencies of TPH2 gene polymorphism in the ADHD and control groups. This study showed that there was a significant correlation among the frequencies of the rs11179027 (odd ratio [OR]=2.12, 95% confidence interval [CI]=1.13-3.97, p=0.020) and rs1843809 (OR=0.48, 95% CI=0.24-0.97, p=0.040) of alleles of TPH2, but the final conclusions are not definite. Follow-up studies with larger patient or pure subgroups are expected. These results suggested that TPH2 might be related to ADHD symptoms.

CYP21A2 p.E238 Deletion as Result of Multiple Microconversion Events

More than 90% of congenital adrenal hyperplasia (CAH) cases are associated with mutations in the 21-hydroxylase gene (CYP21A2) in the HLA class III area on the short arm of chromosome 6p21.3. The major part of disease-causing mutations in CYP21A2 alleles are CYP21A1P-derived sequence transferred to the active gene by macroconversion or microconversion events. Only around 5% of all disease-causing CYP21A2 alleles harbor rare mutations that do not originate from the pseudogene. A complete list of all reported CYP21A2 mutations can be found in the CYP21A2 database created by the Human Cytochrome P450 (CYP) Allele Nomenclature Committee (http://www.imm.Ki.se/CYPalleles/cyp21.htm). In this report, we describe clinical and genetic findings regarding an Italian woman suffering from a classic salt-wasting form of CAH due to a severe 21-hydroxylase deficiency. A complex genetic family study was performed including a prenatal diagnosis. The patient was found to be heterozygous for p.I172N (exon 4), p.E238del (exon 6), p.M239K (exon 6), and p.F306insT (exon 7) mutations and homozygous for p.I236N (exon 6) and p.V237E (exon 6) mutations. The deletion of glutamic acid 238 is a new mutation not reported before in the literature. CYP21A2 genotyping has become a valuable complement to biochemical CAH investigation. We highlight the contribution of molecular genetic advancements to the clinical management of patients with 21-hydroxylase deficiency.

Does sex moderate the clinical correlates of pediatric bipolar-I disorder? Results from a large controlled family-genetic study

BackgroundSince little is known as to whether sex differences affect the clinical presentation of pediatric BP-I disorder, it is an area of high clinical, scientific and public health relevance. MethodsSubjects are 239 BP-I probands (65 female probands, 174 male probands) and their 726 first-degree relatives, and 136 non-bipolar, non-ADHD control probands (37 female probands, 99 male probands) and their 411 first-degree relatives matched for age and sex. We modeled the psychiatric and cognitive outcomes as a function of BP-I status, sex, and the BP-I status-gender interaction. ResultsBP-I disorder was equally familial in both sexes. With the exception of duration of mania (shorter in females) and number of depressive episodes (more in females), there were no other meaningful differences between the sexes in clinical correlates of BP-I disorder. With the exception of a significant sex effect for panic disorder and a trend for substance use disorders (p=0.05) with female probands being at a higher risk than male probands, patterns of comorbidity were similar between the sexes. Despite the similarities, boys with BP-I disorder received more intensive and costly academic services than girls with the same disorder. LimitationsSince we studied children referred to a family study of bipolar disorder, our findings may not generalize to clinic settings. ConclusionsWe found more similarities than differences between the sexes in the personal and familial correlates of BP-I disorder. Clinicians should consider bipolar disorder in the differential diagnosis of both boys and girls afflicted with symptoms suggestive of this disorder.

LRP6 Enhances Glucose Metabolism by Promoting TCF7L2-Dependent Insulin Receptor Expression and IGF Receptor Stabilization in Humans

Common genetic variations in Wnt signaling genes have been associated with metabolic syndrome and diabetes by mechanisms that are poorly understood. A rare nonconservative mutation in Wnt coreceptor LRP6 (LRP6(R611C)) has been shown to underlie autosomal dominant early onset coronary artery disease, type 2 diabetes, and metabolic syndrome. We examined the interplay between Wnt and insulin signaling pathways in skeletal muscle and skin fibroblasts of healthy nondiabetic LRP6(R611C) mutation carriers. LRP6 mutation carriers exhibited hyperinsulinemia and reduced insulin sensitivity compared to noncarrier relatives in response to oral glucose ingestion, which correlated with a significant decline in tissue expression of the insulin receptor and insulin signaling activity. Further investigations showed that the LRP6(R611C) mutation diminishes TCF7L2-dependent transcription of the IR while it increases the stability of IGFR and enhances mTORC1 activity. These findings identify the Wnt/LRP6/TCF7L2 axis as a regulator of glucose metabolism and a potential therapeutic target for insulin resistance.

The genetic and molecular basis of bicuspid aortic valve associated thoracic aortopathy: a link to phenotype heterogeneity.

Bicuspid aortic valve (BAV) is the most common congenital cardiac anomaly, affecting 0.5-1.4% of the general population (1-4). BAV is a clinically heterogeneous disorder with a high rate of surgically relevant aortic valve and ascending aortic complications, which occur in over 35% of those affected (5). As such, BAV confers a greater burden of disease than all other congenital heart diseases combined (3,6). Familial clustering and genetic studies have established that BAV is a heritable trait, with approximately 9% prevalence amongst firstdegree relatives, and up to 24% in families with more than one affected family member (3,7,8). Despite its importance, the etiology of BAV is largely undetermined, although it is likely to involve genetic heterogeneity, abnormal signaling pathways and aberrant neural crest cell migration (3). BAV is not only a disorder of valvular development, but also represents a complex coexistent genetic disease of the aorta and cardiac development (3,7). Thoracic aortic enlargement is common in BAV, reported in up to 50-60% of affected individuals (6,9,10). Significant phenotype heterogeneity, which may occur independently of the underlying valvular morphology and function (6,9-11), has been described, most commonly manifesting as asymmetric ascending aortic dilatation beyond the sinotubular junction with variable arch involvement and/or varying degrees of annuloaortic ectasia, predisposing to aortic dissection/ rupture, a feared complication. Indeed, BAV conveys an 8-fold increased risk of aortic dissection and over a 25-year period, the risk for aneurysm formation is 26% and for aortic surgery is 25% (2), further highlighting its health burden. Presently, ongoing controversies exist in the literature regarding the underlying pathogenesis of BAV-associated thoracic aortopathy (BAV-TA), specifically whether it is genetic or hemodynamic in origin, which have important implications for planning intervention. Intense work is currently ongoing to address this question, which has shed light on the pathogenesis of BAV-TA. Therefore, it is timely to review the current state of knowledge in this common association of BAV, focusing primarily on the interaction between genetics, molecular pathway and hemodynamic factors in influencing the heterogeneous manifestation of aortopathy seen in BAV patients.

Current and Future Therapeutic Approaches for Metastatic Pheochromocytoma and Paraganglioma: Focus on SDHB Tumors

As a result of intense genetic studies of families with specific mutations, the road to better therapeutic intervention for pheochromocytoma (PHEOs) and parangangliomas (PGLs) has more recently become populated with several promising molecular targets. Consequently a change in paradigm from a previous view on nonspecific therapy has shifted towards more selective molecular targeted therapies. In particular, malignant PHEOs/PGLs, more specifically the tumors that result from mutations in succinate dehydrogenase subunit B (SDHB), are a clear concern, and novel therapies should be developed to address this problem. Here we summarize current and future therapeutic approaches.

Genetic modifiers of the beta-haemoglobin disorders

Beta-thalassaemia and sickle cell disease (SCD) are two of the best-characterised human monogenic disorders, both resulting from mutations affecting the beta-globin gene. The central mechanism underlying the pathophysiology of β-thalassaemia is ineffective erythropoiesis arising from the redundant alpha-globin chains caused by a quantitative reduction in β-globin synthesis. In contrast, SCD is caused by the presence of a haemoglobin variant, haemoglobin S (HbS, α₂β^S₂) which results from a single nucleotide mutation (G<b>T</b>G to G<b>A</b>G) affecting codon 6 of the β-globin chain of haemoglobin (HbS, β cod 6 Glu→Val). Almost 300 mutations are now known to downregulate β-globin gene expression, while the sickle cell syndrome can arise from a combination of genotypes involving the interaction of the β^s allele with other variants of the β-globin gene (including β-thalassaemia). The causative genotypes are key determinants of disease severity. However, within each genotypic group, despite identical mutations, the frequency and severity of complications still vary considerably. Extensive biochemical and pathophysiological studies over the last 50–60 years have identified two major modifiers— inherent ability to produce fetal haemoglobin and co-inheritance of α-thalassaemia—both of which have been validated by population and family genetic studies. Elucidation of these two genetic modifiers has not been too difficult as they have a major impact on the pathophysiology of both diseases at the primary level, and the variants are common, but they do not explain the complete complex genotype/phenotype correlation. In the last 20 years, scientific research has applied several genetic approaches to dissect some of the modifiers that modulate complications at the secondary level. Genetic studies have been successful in identifying modifiers if the loci have a strong effect and if the genetic variants are common, for example influence of the <i>UGT1A1</i> promoter variants on bilirubin levels and predisposition to gallstones in both SCD and β-thalassaemia. It is possible that additional genetic modifiers could be uncovered using genetic approaches but success will depend on large sets of well-characterised patients with well-defined phenotypes. The lecture will highlight recent genetic studies and the key genetic modifiers uncovered in both disorders.