Discordant congenital heart defects in monochorionic twins: Risk factors and proposed pathophysiology.

A six-fold increase in congenital heart defects (CHD) exists among monochorionic (MC) twins compared to singleton or dichorionic twin pregnancies. Though MC twins share an identical genotype, discordant phenotypes related to CHD and other malformations have been described, with reported rates of concordance for various congenital anomalies at less than 20%. Our objective was to characterize the frequency and spectrum of CHD in a contemporary cohort of MC twins, coupled with genetic and clinical variables to provide insight into risk factors and pathophysiology of discordant CHD in MC twins. Retrospective analysis of all twins receiving prenatal fetal echocardiography at a single institution from January 2010 -March 2020 (N = 163) yielded 23 MC twin pairs (46 neonates) with CHD (n = 5 concordant CHD, n = 18 discordant CHD). The most common lesions were septal defects (60% and 45.5% in concordant and discordant cohorts, respectively) and right heart lesions (40% and 18.2% in concordant and discordant cohorts, respectively). Diagnostic genetic testing was abnormal for 20% of the concordant and 5.6% of the discordant pairs, with no difference in rate of abnormal genetic results between the groups (p = 0.395). No significant association was found between clinical risk factors and development of discordant CHD (p>0.05). This data demonstrates the possibility of environmental and epigenetic influences versus genotypic factors in the development of discordant CHD in monochorionic twins.

Association between intrauterine growth restriction and patent ductus arteriosus: Use of a dichorionic twin pregnancy model.

OBJECTIVE: To evaluate the association between intrauterine growth restriction (IUGR) and the incidence of fetuses with patent ductus arteriosus (PDA) and Hemodynamically significant PDA (Hs-PDA) in dichorionic twins (DC) with selective IUGR. MATERIALS AND METHODS: This is an observational cohort study and retrospective case assessment, involved twins born at Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan between 2013 and 2018. DC twins with selective IUGR (sIUGR) were defined as the presence of a birth weight discordance of >25% and a smaller twin with a birth weight below the tenth percentile. PDA was diagnosed using echocardiography between postnatal day 3 and 7. Hs-PDA was defined as PDA plus increased pulmonary circulation, poor systemic perfusion, cardiomegaly, pulmonary edema, or hypotension requiring pharmacotherapeutic intervention. RESULT: A total of 1187 twins were delivered during the study period, and 53 DC twins with selective IUGR were included in this study. DC twins with PDA have higher rate of preterm birth, lower gestational age of delivery, and lower mean birth weight of both twins compared with DC twins without PDA. In a comparison of the sIUGR twin with the appropriate for gestational age co-twin, both the incidences of PDA (28.30% vs. 7.55%, respectively; P = 0.003) and Hs-PDA (24.53% vs. 5.66%, respectively; P = 0.002) were higher in sIUGR fetuses than in the appropriate for gestational age co-twins. Small gestational age of delivery was the only variable to predict PDA and Hs-PDA [p = 0.002, Odds ratio = 0.57 (0.39-0.82), p = 0.009, Odds ratio = 0.71 (0.55-0.92), respectively]. CONCLUSION: An analysis of dichorionic twins with sIUGR indicated that IUGR increased the risk of PDA and hemodynamically significant PDA.

The association between ADHD and physical health: a co-twin control study.

Attention-deficit/hyperactivity disorder (ADHD) has been associated with increased risk for physical comorbidity. This study used a twin cohort to investigate the association between physical diseases and phenotypic variations of ADHD. A twin cohort enriched for ADHD and other neurodevelopmental conditions were analysed. The Attention Problems subscale of the Child Behavior Checklist/Adult Behavior Checklist (CBCL/ABCL-AP) was used to measure the participants' severity of ADHD symptoms. Physical health issues were obtained with a validated questionnaire and were tested in relation to ADHD symptom severity in a co-twin control model. Neurological problems were significantly associated with a diagnosis of ADHD. A conditional model for the analysis of within-twin pair effects revealed an inverse association between digestive problems and the severity of ADHD symptoms, after adjusting for co-existing autism spectrum disorder and ADHD medications. Our findings suggest that individuals with ADHD are susceptible to neurological problems, why a thorough neurological check-up is indicated in clinical practice for this population. In addition, health conditions of digestive system could be considered as a non-shared environmental factor for behavioral phenotypes in ADHD. It supports the possible role of gut-brain axis in the underpinnings of ADHD symptoms, at least for a subgroup of individuals with certain genetic predisposition.

Developmental origins of cardiometabolic health outcomes in twins: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Studies of twins can reduce confounding and provide additional evidence about the causes of disease, due to within-pair matching for measured and unmeasured factors. Although findings from twin studies are typically applicable to the general population, few studies have taken full advantage of the twin design to explore the developmental origins of cardiometabolic health outcomes. We aimed to systematically review the evidence from twin studies and generate pooled estimates for the effects of early-life risk factors on later-life cardiometabolic health. METHODS AND RESULTS: An initial search was conducted in March 2018, with 55 studies of twins included in the review. Risk of bias was assessed using the Newcastle-Ottawa Scale, and eligible studies were included in a meta-analysis, where pooled estimates were calculated. Twenty-six studies analysed twins as individuals, and found that higher birthweight was associated with lower SBP (ß = -2.02 mmHg, 95%CI: -3.07, -0.97), higher BMI (ß = 0.52 kg/m2, 95%CI: 0.20, 0.84) and lower total cholesterol (ß = -0.07 mmol/L, 95%CI: -0.11, -0.04). However, no associations were reported in studies which adjusted for gestational age. Few of the included studies separated their analyses into within-pair and between-pair associations. CONCLUSIONS: Early-life risk factors were associated with cardiometabolic health outcomes in twin studies. However, many estimates from studies in this review were likely to have been confounded by gestational age, and few fully exploited the twin design to assess the developmental origins of cardiometabolic health outcomes.

Biliary atresia in twins: a systematic review and meta-analysis.

PURPOSE: Biliary atresia (BA) in twins is extremely rare reported in the literature, but twin studies are useful methods of examining the associated factors of a complex disease. The objective of this study was to analyze the characteristics and patterns of biliary atresia in twins from reviewing available articles. METHODS: PubMed and EMBASE databases were reviewed for related articles using the keywords ''biliary atresia'', ''twins'', ''monozygotic (MZ)'', and ''dizygotic (DZ)'', including relevant papers in the reference lists. RESULTS: This analysis was extracted from 12 articles, with a total of 35 twin pairs included. BA was found in 36 out of 70 twin subjects (51.4%), of which had an even gender split. 97.1% twins were discordant, among 55.9% of which were monozygotic twin sets, indicating that BA may be related to genetic phenotype or penetrance. Isolated BA was the largest group with 27 (75%) affected twins. Only one pair of dizygotic twins (2.9%) demonstrate concordance for BA, and have one affected family member. CONCLUSION: BA was found in nearly half of twin subjects with an even gender split. Isolated BA was the largest group, in which the number of monozygotic twins was similar with dizygotic twins, so the onset of the disease may not associate with the zygosity of twins. Most of twin sets had discordant disease presentation, especially monozygotic twins therein, emphasizing the role of epigenetic factor in the pathogenesis of BA. Future studies should take genetic testing among any twin sets in BA, especially the disease-associated mutations, thus be useful to investigate the etiology of disease.

Volitional eye movement control and ADHD traits: a twin study.

BACKGROUND: Top-down volitional command of eye movements may serve as a candidate endophenotype of ADHD, an important function underlying goal-directed action in everyday life. In this twin study, we examined the relation between performance on a response inhibition eye-tracking paradigm and parent-rated ADHD traits in a population-based twin sample. We hypothesized that altered eye movement control is associated with the severity of ADHD traits and that this association is attributable to genetic factors. METHODS: A total of 640 twins (320 pairs, 50% monozygotic) aged 9-14 years) from the Child and Adolescent Twin Study in Sweden (CATSS) participated. Twins performed the antisaccade task indexing inhibitory alterations as either direction errors (following exogenous cues rather than instructions) or premature anticipatory eye movements (failure to wait for cues). We calculated the associations of eye movement control and ADHD traits using linear regression mixed-effects models and genetic and environmental influences with multivariate twin models. RESULTS: Premature anticipatory eye movements were positively associated with inattentive traits (ß = .17; 95% CI: 0.04, 0.31), while controlling for hyperactive behaviors and other covariates. Both premature anticipatory eye movements and inattention were heritable (h2  = 0.40, 95% CI: 0.22, 0.56; h2  = 0.55; 95% CI: 0.42, 0.65; respectively), and their genetic correlation was small but statistically significant (r = .19, 95% CI: 0.02, 0.36). However, the genetic correlation did not remain significant after adjusting for covariates (age, sex, hyperactivity traits, IQ). No link was found between direction errors and ADHD traits. CONCLUSIONS: This study indicates that there is a specific, genetically influenced, relation between top-down eye movement control and the inattentive traits typical of ADHD.

Pathogenic variants in NUBPL result in failure to assemble the matrix arm of complex I and cause a complex leukoencephalopathy with thalamic involvement.

Disorders of the white matter are genetically very heterogeneous including several genes involved in mitochondrial bioenergetics. Diagnosis of the underlying cause is aided by pattern recognition on neuroimaging and by next-generation sequencing. Recently, genetic changes in the complex I assembly factor NUBPL have been characterized by a consistent recognizable pattern of leukoencephalopathy affecting deep white matter including the corpus callosum and cerebellum. Here, we report twin boys with biallelic variants in NUBPL, an unreported c.351 G > A; p.(Met117Ile) and a previously reported pathological variant c. 693 + 1 G > A. Brain magnetic resonance imaging showed abnormal T2 hyperintense signal involving the periventricular white matter, external capsule, corpus callosum, and, prominently, the bilateral thalami. The neuroimaging pattern evolved over 18 months with marked diffuse white matter signal abnormality, volume loss, and new areas of signal abnormality in the cerebellar folia and vermis. Magnetic resonance spectroscopy showed elevated lactate. Functional studies in cultured fibroblasts confirmed pathogenicity of the genetic variants. Complex I activity of the respiratory chain was deficient spectrophotometrically and on blue native gel with in-gel activity staining. There was absent assembly and loss of proteins of the matrix arm of complex I when traced with an antibody to NDUFS2, and incomplete assembly of the membrane arm when traced with an NDUFB6 antibody. There was decreased NUBPL protein on Western blot in patient fibroblasts compared to controls. Compromised NUBPL activity impairs assembly of the matrix arm of complex I and produces a severe, rapidly-progressive leukoencephalopathy with thalamic involvement on MRI, further expanding the neuroimaging phenotype.

DNA methylation fingerprint of monozygotic twins and their singleton sibling with intellectual disability carrying a novel KDM5C mutation.

Mutations in KDM5C (lysine (K)-specific demethylase 5C) were causally associated with up to 3% of X-linked intellectual disability (ID) in males. By exome and Sanger sequencing, a novel frameshift KDM5C variant, predicted to eliminate the JmjC catalytic domain from the protein, was identified in two monozygotic twins and their older brother, which was inherited from their clinically normal mother, who had completely skewed X-inactivation. DNA methylation (DNAm) data were evaluated using the Illumina 450 K Methylation Beadchip arrays. Comparison of methylation levels between the three patients and male controls identified 399 differentially methylated CpG sites, which were enriched among those CpG sites modulated during brain development. Most of them were hypomethylated (72%), and located mainly in shores, whereas the hypermethylated CpGs were more represented in open sea regions. The DNAm changes did not differ between the monozygotic twins nor between them and their older sibling, all presenting a global hypomethylation, similar to other studies that associated DNA methylation changes to different KDM5C mutations. The 38 differentially methylated regions (DMRs) were enriched for H3K4me3 marks identified in developing brains. The remarkable similarity between the methylation changes in the monozygotic twins and their older brother is indicative that these epigenetic changes were mostly driven by the KDM5C mutation.

A modern approach to identifying and characterizing child asthma and wheeze phenotypes based on clinical data.

'Asthma' is a complex disease that encapsulates a heterogeneous group of phenotypes and endotypes. Research to understand these phenotypes has previously been based on longitudinal wheeze patterns or hypothesis-driven observational criteria. The aim of this study was to use data-driven machine learning to identify asthma and wheeze phenotypes in children based on symptom and symptom history data, and, to further characterize these phenotypes. The study population included an asthma-rich population of twins in Sweden aged 9-15 years (n = 752). Latent class analysis using current and historical clinical symptom data generated asthma and wheeze phenotypes. Characterization was then performed with regression analyses using diagnostic data: lung function and immunological biomarkers, parent-reported medication use and risk-factors. The latent class analysis identified four asthma/wheeze phenotypes: early transient wheeze (15%); current wheeze/asthma (5%); mild asthma (9%), moderate asthma (10%) and a healthy phenotype (61%). All wheeze and asthma phenotypes were associated with reduced lung function and risk of hayfever compared to healthy. Children with mild and moderate asthma phenotypes were also more likely to have eczema, allergic sensitization and a family history of asthma. Furthermore, those with moderate asthma phenotype had a higher eosinophil concentration (ß 0.21, 95%CI 0.12, 0.30) compared to healthy and used short-term relievers at a higher rate than children with mild asthma phenotype (RR 2.4, 95%CI 1.2-4.9). In conclusion, using a data driven approach we identified four wheeze/asthma phenotypes which were validated with further characterization as unique from one another and which can be adapted for use by the clinician or researcher.

The Italian Twin Registry: An Update at 18 Years From Its Inception.

The Italian Twin Registry (ITR), established in 2001, is a population-based registry of voluntary twins. To date, it consists of approximately 29,000 twins who gave their consent to participate in the studies proposed by the ITR research group. The database comprises 11,500 monozygotic and 16,700 dizygotic twins resident throughout the country and belonging to a wide age range (from 0 to 95 years, mean 36.8 years). This article provides an overview of the recruitment strategies along with the major phenotypes investigated during an 18 years' research period. Over the years, several self-reported questionnaire data were collected, together with saliva/blood samples and measurements taken during in-person interviews or outpatient clinical examinations. Mental and behavioral phenotypes as well as atherosclerotic traits were studied in depth across different age groups. A birth cohort of twins was established and followed up. Novel research hypotheses are also being tested in ongoing projects. The ITR is involved in international studies in collaboration with other twin registries and represents a valuable resource for national and international research initiatives regarding a broad spectrum of health-related characteristics.

Co-Twin Control Studies: Natural Events, Experimental Interventions and Rare Happenings/Twin Research: Cancer Risk in Overweight Twins; Prognosis After Fetal Loss of One Twin; Twin Concordance for Parkinson's Disease; Neuroanatomy of Musically Discordant MZ Twins/News Articles: Twin Birth with Two Wombs; Twins' Prenatal Interactions; Switched-at-Birth Twins; Fetus-in-Fetu; Unsolved Paternity.

Co-twin control is a well-known methodological twin research design, but its variations and complexities are less well known. Various issues and illustrations are presented with reference to studies involving natural events, experimental interventions and rare happenings that underlie monozygotic (MZ) twins' environmental differences. This discussion is followed by summaries of recent twin research pertaining to cancer risk in overweight twins, the physical risk to surviving twins after fetal loss of a co-twin, a 20-year update of twin concordance for Parkinson's disease, and neuroanatomical differences in musically discordant MZ twin pairs. Several twin-related items that have attracted attention in the news are also summarized.

Shared Genetic Etiology of Hwabyung (Anger Syndrome) and Somatization Symptoms in South Korean Adolescent and Young Adult Twins.

Somatization is known to be more prevalent in Asian than in Western populations. Using a South Korean adolescent and young adult twin sample (N = 1754; 367 monozygotic male, 173 dizygotic male, 681 monozygotic female, 274 dizygotic female and 259 opposite-sex dizygotic twins), the present study aimed to estimate heritability of somatization and to determine common genetic and environmental influences on somatization and hwabyung (HB: anger syndrome). Twins completed self-report questionnaires of the HB symptoms scale and the somatization scale via a telephone interview. The results of the general sex-limitation model showed that 43% (95% CI [36, 50]) of the total variance of somatization was attributable to additive genetic factors, with the remaining variance, 57% (95% CI [50, 64]), being due to individual-specific environmental influences, including measurement error. These estimates were not significantly different between the two sexes. The phenotypic correlation between HB and somatization was .53 (p < .001). The bivariate model-fitting analyses revealed that the genetic correlation between the two symptoms was .68 (95% CI [.59, .77]), while the individual-specific environmental correlation, including correlated measurement error, was .41 (95% CI [.34, .48]). Of the additive genetic factors of 43% that influence somatization, approximately half (20%) were associated with those related to HB, with the remainder being due to genes unique to somatization. A substantial part (48%) of individual environmental variance in somatization was unrelated to HB; only 9% of the environmental variance was shared with HB. Our findings suggest that HB and somatization have shared genetic etiology, but environmental factors that precipitate the development of HB and somatization may be largely independent from each other.

Study protocol: developing, disseminating, and implementing a core outcome set for selective fetal growth restriction in monochorionic twin pregnancies.

BACKGROUND: Selective fetal growth restriction in monochorionic twin pregnancies is associated with an increased risk of perinatal mortality and morbidity and represents a clinical dilemma. Interventions include expectant management with early preterm delivery if there are signs of fetal compromise, selective termination of the compromised twin, fetoscopic laser coagulation of the communicating placental vessels or termination of the whole pregnancy. Previous studies evaluating interventions have reported many different outcomes and outcome measures. Such variation makes comparing, contrasting, and combining results challenging, limiting ongoing research on this uncommon condition to inform clinical practice. We aim to produce, disseminate, and implement a core outcome set for selective fetal growth restriction research in monochorionic twin pregnancies. METHODS: An international steering group, including professionals, researchers, and lay experts, has been established to oversee the development of this core outcome set. The methods have been guided by the Core Outcome Measures in Effectiveness Trials Initiative Handbook. Potential core outcomes will be developed by undertaking a systematic review of studies evaluating interventions for selective fetal growth restriction in monochorionic twin pregnancies. Potential core outcomes will be entered into a three-round Delphi survey and key stakeholders including clinical professionals, researchers, and lay experts will be invited to participate. Repeated reflection and rescoring of individual outcomes should encourage group and individual stakeholder convergence towards consensus outcomes which will be entered into a modified Nominal Group Technique to finalize the core outcome set. Once core outcomes have been agreed, we will establish standardized definitions and recommend high-quality measurement instruments for each outcome. DISCUSSION: The development, dissemination, and implementation of a core outcome set for selective fetal growth restriction should ensure that future research protocols select, collect, and report outcomes and outcome measures in a standardized manner. Data synthesis will be possible on a broad level and rigorous implementation should advance the quality of research studies and their effective use in order to guide clinical practice, improve patient care, maternal, short-term perinatal outcomes, and long-term neurodevelopmental outcomes. TRIAL REGISTRATION: Core Outcome Measures in Effectiveness Trials (COMET) registration number: 998. International Prospective Register of Systematic Reviews (PROSPERO) registration number: CRD42018092697 . 18th April 2018.

Incidence of and Risk Factors for Residual Anastomoses in Twin-Twin Transfusion Syndrome Treated with Laser Surgery: A 15-Year Single-Center Experience.

OBJECTIVES: To evaluate the incidence of residual anastomoses (RA) after laser therapy for twin-twin transfusion syndrome (TTS) and investigate risk factors for incomplete laser surgery. MATERIAL AND METHODS: All available TTS placentas treated with laser at our center between 2002 and 2016 were injected with color dye to assess the presence of RA. We evaluated the incidence of RA over the past 15 years by dividing the cohort into three time periods, and studied the association with risk factors and neonatal outcome. RESULTS: Overall, RA were detected in 21.0% (78/371) of placentas. The incidence of RA decreased from 38.8% (26/67) in the initial period to 11.7% (16/137) in the most recent period (p < 0.001). On multivariate analysis, several risk factors were independently associated with the risk of RA, including Solomon laser technique (odds ratio [OR] 0.17, 95% CI 0.09-0.33) and estimation of surgical success (OR 19.28, 95% CI 8.17-45.49). Premature delivery and neonatal morbidity occurred more often in TTS cases with RA. CONCLUSIONS: The incidence of RA after laser therapy for TTS decreased significantly in the past 15 years and is now below 15% due to the use of the Solomon technique.

Survival Rate without Brain Abnormalities on Postnatal Ultrasonography among Monochorionic Twins after Fetoscopic Laser Photocoagulation for Selective Intrauterine Growth Restriction with Concomitant Oligohydramnios.

INTRODUCTION: We aimed to clarify the survival rate without brain abnormalities (BA) after fetoscopic laser photoco-agulation (FLP) for monochorionic diamniotic twin gestations (MCDA) with selective intrauterine growth restriction (sIUGR) accompanied by abnormal umbilical artery (UA) Doppler waveforms and isolated oligohydramnios in the sIUGR twin. MATERIALS AND METHODS: This retrospective study included 52 cases that underwent FLP. The main outcome was survival rate without BA of the twins at age 28 days. BA was defined as severe intraventricular hemorrhage and periventricular leukomalacia on postnatal ultrasonography. RESULTS: Median gestational age at FLP was 20 (16-24) weeks. Ten cases were classified as type III based on Doppler for the UA. For all cases, including 20 cases of anterior placenta, FLP was completed without major intraoperative complications. Amnioinfusion was required in 49 cases for better fetoscopic visualization. Fetal loss occurred in 29 sIUGR twins and two larger twins, whereas one larger twin experienced neonatal death. Survival rates without BA were 44% (n = 23) for sIUGR twins and 94% (n = 49) for the larger twins. DISCUSSION: FLP for MCDA with sIUGR presenting with oligohydramnios in the sIUGR twin might be considered a prenatal treatment option.

Isfahan Twins Registry (ITR): An Invaluable Platform for Epidemiological and Epigenetic Studies: Design and Methodology of ITR.

Twin studies are one of the main tools for studying the interaction between genes and the environment in the development of complex diseases such as cancers, cardiovascular diseases and diabetes. The Isfahan Twin Registry (ITR) was launched in Isfahan in 2017 as a pilot study to establish a nationwide twin registry in Iran and aims to obtain comprehensive information about complex diseases and their risk factors from twins and multiples living in Isfahan. ITR will continue to recruit twins and multiples until all twins residing in Isfahan are registered in the registry. Twins are identified from welfare agencies, public health homes, maternity hospitals, Persian Twins Association and the local media. Demographic information, twin similarities, lifestyle, family history of diseases and past medical history are collected using validated questionnaires. Anthropometric measurements and blood pressure are measured by health professionals. Hematology panel, fasting blood sugar, total cholesterol, low-density lipoprotein, high-density lipoprotein, aspartate aminotransferase, alanine aminotransferase and quantitative C-reactive protein are measured by an automated analyzer. Extra samples are obtained for future studies. For twins aged under 6 years, parents complete the questionnaires for their children and a brief questionnaire for themselves. Currently, 998 persons (395 pairs and 67 multiples) are registered in the ITR and have provided their data. Results of preliminary data analysis are discussed in this article. We plan to carry out longitudinal assessments. ITR can play an important role in future epigenetic, biomarkers and omics studies using the biobank materials.

[Genetics of Posttraumatic Stress Disorder (PTSD)]. / Genetische Grundlagen der Posttraumatischen Belastungsstörung (PTBS).

Post-traumatic stress disorder (PTSD) is a mental disorder following a severe traumatic experience and is characterized by high rates of comorbidity with related psychiatric disorders. However, even for individuals experiencing the same trauma, there is considerable inter-individual variability in the risk of PTSD, and this is largely thought to be determined by biological processes, such as genetic predisposition and epigenetic mechanism. In this review we will summarize recent research on genetics of PTSD, primarily focusing on candidate gene-association studies, targeting on functional genetic variants in the monoaminergic system and the hypothalamic-pituitary-adrenal (HPA) axis. In addition, results from recent genome-wide association studies (GWAS) will be reported and we will highlight the interplay of genetic factors with environmental factors, based on evidence from gene-environment interaction analysis and studies on the epigenetic regulation of PTSD. Finally, we will provide a brief outlook towards the potential and perspectives of pharmaco-genetic studies.