Identifying infrequent genetic changes in monozygotic twins afflicted with hypospadias via targeted panel sequencing.

PURPOSE: We aimed to identify the genetic causes of hypospadias in children using targeted gene panel sequencing for disorders of sex development (DSD). MATERIALS AND METHODS: This study included 18 twin boys with hypospadias: seven and two pairs were monozygotic and dizygotic twins, respectively, and six were discordant and three were concordant twins. Targeted gene panel sequencing for 67 known DSD genes was performed. Sequence variants were classified into five different categories, pathogenic, likely pathogenic, variants of uncertain significance, likely benign, and benign, following the American College of Medical Genetics and Genomics Standards and Guidelines. RESULTS: The mean gestational age and birth weight were 35.3±2.0 weeks and 1.96±0.61 kg, respectively, with seven patients being small for gestational age. Hypospadias was present in 12 patients, with posterior type in 33.3% and anterior type in 66.7%. In three families with twins, both siblings had hypospadias. In addition, cryptorchidism was observed in one subject. Surgical correction of hypospadias was performed at a mean age of 22.1 months. Molecular analysis identified 12 different genetic variants, including two pathogenic mutations in the AMH (p.E389*) and SRD5A2 (p.R246Q) genes, found in subjects with hypospadias, respectively. However, only heterozygous mutations were detected. CONCLUSIONS: This study did not identify a definitive genetic component contributing to the development of hypospadias; however, the findings suggest that intrauterine growth retardation may play a significant role.

Choroiditis following severe acute respiratory syndrome coronavirus 2 infection in unvaccinated identical twins.

Unvaccinated identical twins developed bilateral anterior uveitis soon after the onset of coronavirus disease 2019 symptoms. During follow-up, both patients developed choroiditis, and one twine developed posterior scleritis and serous retinal detachment. Prompt treatment with oral prednisone ameliorated the lesions, and no recurrence was observed at the 18-month follow-up. Choroiditis may rarely be associated with severe acute respiratory syndrome coronavirus 2 infection, and it responds well to corticosteroid therapy. Although the exact mechanism is unknown, we hypothesize that the virus may act as an immunological trigger for choroiditis.

Monozygotic twins discordant for depression: An extended network comparison of depressive symptoms, cognitive functions and daily activities.

Monozygotic twins share the same genotype; however, they can be phenotypically discordant on various traits. Studying discordant monozygotic twins allows the investigation of differences in associations between symptoms and psychopathological risk factors, controlled for shared genetic liability. The network approach to psychopathology suggests that depressive symptoms, along with risk and protective factors (e.g., cognition, daily activities), form a complex system of mutually interacting components. We compared monozygotic twins discordant for lifetime depression on their respective extended networks of depressive symptoms, cognitive functions and daily activities (intellectual, physical, social), and evaluated if these networks differ in their associations between variables and in the role of each variable within the network. Regularized partial correlations investigated the networks' composition in 147 monozygotic twin pairs discordant for depression from the Danish Twin Registry. Affected twins had stronger overall associations within their network of depressive symptoms, cognitive functions and daily activities than their unaffected co-twins, while the importance of the network components' associations did not differ between the co-twins. In affected twins, decreased frequency in experiencing happiness had the strongest association with remaining variables (i.e., the most influence in activating other network elements). Also, variables from different groups were significantly associated (e.g., loneliness with delayed memory, pessimism with low social activities, verbal learning with intellectual activities). In unaffected twins, both mood symptoms and cognitive functions were important, but between-groups associations were quasi-absent. These results suggest that external events affecting the ability to feel happiness likely trigger the psychopathological process (depression network activation), independently from the genetic predisposition to depression.

Rare Pathogenic Variants Identified in Whole Exome Sequencing of Monozygotic Twins With Autism Spectrum Disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a childhood-onset complex neurodevelopmental disorder characterized by problems with communication and social interaction and restricted, repetitive, stereotyped behavior. The prevalence of ASD is one in 36 children. The genetic architecture of ASD is complex in spite of its high heritability. To identify the potential candidate genes of ASD, we carried out a comprehensive genetic study of monozygotic (MZ) twins concordant or discordant for ASD. METHODS: Five MZ twins and their parents were recruited for the study. Four of the twins were concordant, whereas one was discordant for ASD. Whole exome sequencing was conducted for the twins and their parents. The exome DNA was enriched using Twist Human Customized Core Exome Kit, and paired-end sequencing was performed on HiSeq system. RESULTS: We identified several rare and pathogenic variants (homozygous recessive, compound heterozygous, de novo) in ASD-affected individuals. CONCLUSION: We report novel variants in individuals diagnosed with ASD. Several of these genes are involved in brain-related functions and not previously reported in ASD. Intriguingly, some of the variants were observed in the genes involved in sensory perception (auditory [MYO15A, PLEC, CDH23, UBR3, GPSM2], olfactory [OR9K2], gustatory [TAS2R31], and visual [CDH23, UBR3]). This is the first comprehensive genetic study of MZ twins in an Indian population. Further validation is required to determine whether these variants are associated with ASD.

Migraine heritability and beyond: A scoping review of twin studies.

OBJECTIVE: This scoping review aimed to summarize current knowledge from twin studies on migraine. Migraine heritability, genetic correlations with migraine comorbid disorders, and the use of discordant twin pairs in migraine research are described. Further, the review considers the unused potential of twin studies in migraine research and reflects on future directions. BACKGROUND: Twin studies can be used to understand how heritable and environmental factors influence human traits and disorders. The classical twin design compares the resemblance of a trait in monozygotic twins to that in dizygotic twins. The classical twin design can be extended to estimate the genetic correlation between disorders, model causality, and describe differences within discordant twin pairs. METHODS: Studies focusing on migraine and using a twin study design were included. The search was performed on the PubMed-MEDLINE database using the search terms "migraine" AND "twin" OR "twins." It was done in May 2023, rerun in November 2023, and managed with the Covidence software. RESULTS: The search identified 52 twin studies on migraine. In 24 papers, the heritability of migraine was estimated with a classical twin design. Heritability estimates ranged from 0.36 to 0.48 for studies with adults, both men and women, and unspecified migraine. Migraine heritability was predominantly estimated with twin cohorts of North European ancestry, and only two studies examined migraine subtypes. A multilevel classical twin design was used in 11 studies to examine the co-occurrence between migraine and comorbid disorders. The differences within migraine discordant twin pairs were examined in nine studies. CONCLUSION: The heritability of migraine was estimated with a classical twin design in twin cohorts from seven different countries, with remarkably similar results across studies. Future studies should include migraine subtypes and twin cohorts of non-North European ancestry to better reflect the global population. Beyond heritability estimations, the twin method is a valuable tool for understanding causality and describing differences within discordant twin pairs. Despite more than 80 years of twin studies in migraine research, the twin design has a large unused potential to advance our understanding of migraine.

[Examination of breast density in breast cancer discordant twin pairs]. / Emlodenzitás vizsgálata emlorákdiszkordáns ikerpárok esetében.

Previous twin studies show that genetic factors are responsible for 63% of the variability in breast density. We analyzed the mammographic images of 9 discordant twin pairs for breast cancer from the population-based Hungarian Twin Registry. We measured breast density using 3D Slicer software. Genetic variants predisposing to breast cancer were also examined. One of the examined twin pairs had a BRCA2 mutation in both members. There was no significant difference between the mean values of breast density in the tumor and non-tumor groups (p=0.323). In terms of parity and the presence of menopause, we found mostly no significant difference between the members of the twin pair. In our cohort of identical twins discordant for breast cancer, the average breast density showed no significant difference, which can be explained by the common genetic basis of breast cancer and breast density.

Whole genome sequencing study of identical twins discordant for psychosis.

Monozygotic (MZ) twins are often thought to have identical genomes, but recent work has shown that early post-zygotic events can result in a spectrum of DNA variants that are different between MZ twins. Such variants may explain phenotypic discordance and contribute to disease etiology. Here we performed whole genome sequencing in 17 pairs of MZ twins discordant for a psychotic disorder (schizophrenia, schizoaffective disorder or bipolar disorder). We examined various classes of rare variants that are discordant within a twin pair. We identified four genes harboring rare, predicted deleterious missense variants that were private to an affected individual in the cohort. Variants in FOXN1 and FLOT2 would have been categorized as damaging from recent schizophrenia and bipolar exome sequencing studies. Additionally, we identified four rare genic copy number variants (CNVs) private to an affected sample, two of which overlapped genes that have shown evidence for association with schizophrenia or bipolar disorder. One such CNV was a 3q29 duplication previously implicated in autism and developmental delay. We have performed the largest MZ twin study for discordant psychotic phenotypes to date. These findings warrant further investigation using other analytical approaches.

Testing Quantitative and Qualitative Sex Effects in a National Swedish Twin-Sibling Study of Posttraumatic Stress Disorder.

OBJECTIVE: Twin studies have demonstrated that posttraumatic stress disorder (PTSD) is moderately heritable, and the pattern of findings across studies suggests higher heritability in females compared with males. Formal testing of sex differences has yet to be done in twin studies of PTSD. The authors sought to estimate the genetic and environmental contributions to PTSD, and to formally test for sex differences, in the largest sample to date of both sexes, among twins and siblings. METHODS: Using the Swedish National Registries, the authors performed structural equation modeling to decompose genetic and environmental variance for PTSD and to formally test for quantitative and qualitative sex differences in twins (16,242 pairs) and in full siblings within 2 years of age of each other (376,093 pairs), using diagnostic codes from medical registries. RESULTS: The best-fit model suggested that additive genetic and unique environmental effects contributed to PTSD. Evidence for a quantitative sex effect was found, such that heritability was significantly greater in females (35.4%) than males (28.6%). Evidence of a qualitative sex effect was found, such that the genetic correlation was high but less than complete (rg=0.81, 95% CI=0.73-0.89). No evidence of shared environment or special twin environment was found. CONCLUSIONS: This is the first demonstration of quantitative and qualitative sex effects for PTSD. The results suggest that unique environmental effects, but not the shared environment, contributed to PTSD and that genetic influences for the disorder are stronger in females compared with males. Although the heritability is highly correlated, it is not at unity between the sexes.

Posttraumatic Stress Disorder and Obstructive Sleep Apnea in Twins.

Importance: Obstructive sleep apnea (OSA) is a common condition in older adult (aged >65 years) populations, but more mechanistic research is needed to individualize treatments. Previous evidence has suggested an association between OSA and posttraumatic stress disorder (PTSD) but is limited by possible selection bias. High-quality research on this association with a careful evaluation of possible confounders may yield important mechanistic insight into both conditions and improve treatment efforts. Objective: To investigate the association of current PTSD symptoms and PTSD diagnosis with OSA. Design, Setting, and Participants: This cross-sectional study of twin pairs discordant for PTSD, which allows for adjustment for familial factors, was conducted using in-laboratory polysomnography from March 20, 2017, to June 3, 2019. The study sample comprised male veteran twins recruited from the Vietnam Era Twin Registry. The data analysis was performed between June 11, 2022, and January 30, 2023. Exposure: Symptoms of PTSD in twins who served in the Vietnam War. Diagnosis of PTSD was a secondary exposure. Main Outcomes and Measures: Obstructive sleep apnea was assessed using the apnea-hypopnea index (AHI) (≥4% oxygen saturation criterion as measured by events per hour) with overnight polysomnography. Symptoms of PTSD were assessed using the PTSD Checklist (PCL) and structured clinical interview for PTSD diagnosis. Results: A total of 181 male twins (mean [SD] age, 68.4 [2.0] years) including 66 pairs discordant for PTSD symptoms and 15 pairs discordant for a current PTSD diagnosis were evaluated. In models examining the PCL and OSA within pairs and adjusted for body mass index (BMI) and other sociodemographic, cardiovascular, and psychiatric risk factors (including depression), each 15-point increase in PCL was associated with a 4.6 (95% CI, 0.1-9.1) events-per-hour higher AHI. Current PTSD diagnosis was associated with an adjusted 10.5 (95% CI, 5.7-15.3) events-per-hour higher AHI per sleep-hour. Comparable standardized estimates of the association of PTSD symptoms and BMI with AHI per SD increase (1.9 events per hour; 95% CI, 0.5-3.3 events per hour) were found. Conclusions and Relevance: This cross-sectional study found an association between PTSD and sleep-disordered breathing. The findings have important public health implications and may also enhance understanding of the many factors that potentially affect OSA pathophysiology.

Necrotizing enterocolitis in monochorionic twins: Insights from an identical twin model.

Necrotizing enterocolitis (NEC) is a major cause of neonatal morbidity and mortality in preterm neonates, yet its pathophysiology remains unclear. The aim of this study is to evaluate risk factors for NEC using an identical twin model. In this case-control study, all monochorionic twin pairs born in our center in 2002-2020 were retrospectively reviewed for NEC. Potential risk factors for NEC were studied. For within-pair comparison, outcomes were compared between affected and unaffected twins. Within-pair analyses showed that the twin with NEC had a lower birth weight compared to its unaffected co-twin (1100 (913-1364) vs. 1339 (1093-1755) grams). Median gestational age at birth and birth weight were lower in twin pairs in the NEC-group compared to the no-NEC group, 29.1 weeks (27.8-30.8) versus 33.6 (30.7-36.0) and 1221 g (1010-1488) versus 1865 (1356-2355) respectively. Twin pregnancies in the NEC-group were more often complicated by twin-to-twin transfusion syndrome compared to the no-NEC-group (70 % (14/20) vs. 49 % (472/962)), particularly when treated with amnioreduction. This unique population of identical twins confirms that preterm neonates with a relatively lower birth weight are more prone to develop NEC compared to their co-twin, regardless of other genetic, maternal and obstetrical factors.

TwinsMX: Exploring the Genetic and Environmental Influences on Health Traits in the Mexican Population.

TwinsMX registry is a national research initiative in Mexico that aims to understand the complex interplay between genetics and environment in shaping physical and mental health traits among the country's population. With a multidisciplinary approach, TwinsMX aims to advance our knowledge of the genetic and environmental mechanisms underlying ethnic variations in complex traits and diseases, including behavioral, psychometric, anthropometric, metabolic, cardiovascular and mental disorders. With information gathered from over 2800 twins, this article updates the prevalence of several complex traits; and describes the advances and novel ideas we have implemented such as magnetic resonance imaging. The future expansion of the TwinsMX registry will enhance our comprehension of the intricate interplay between genetics and environment in shaping health and disease in the Mexican population. Overall, this report describes the progress in the building of a solid database that will allow the study of complex traits in the Mexican population, valuable not only for our consortium, but also for the worldwide scientific community, by providing new insights of understudied genetically admixed populations.

The Population-Based Hungarian Twin Registry: An Update.

Between 2006 and 2021, the Hungarian Twin Registry (HTR) operated a volunteer twin registry of all age groups (50% monozygotic [MZ], 50% dizygotic [DZ], 70% female, average age 34 ± 22 years), including 1044 twin pairs, 24 triplets and one quadruplet set. In 2021, the HTR transformed from a volunteer registry into a population-based one, and it was established in the Medical Imaging Centre of Semmelweis University in Budapest. Semmelweis University's innovation fund supported the development of information technology, a phone bank and voicemail infrastructure, administrative materials, and a new website was established where twins and their relatives (parent, foster parent or caregiver) can register. The HTR's biobank was also established: 157,751 individuals with a likely twin-sibling living in Hungary (77,042 twins, 1194 triplets, 20 quadruplets, and one quintuplet) were contacted between February and March of 2021 via sealed letters. Until November 20, 2022, 12,001 twin individuals and their parents or guardians (6724 adult twins, 3009 parents/guardians and 5277 minor twins) registered, mostly online. Based on simple self-reports, 37.6% of the registered adults were MZ twins and 56.8% were DZ; 1.12% were triplets and 4.5% were unidentified. Of the registered children, 22.3% were MZ, 72.7% were DZ, 1.93% were triplets, and 3.05% were unidentified. Of the registered twins, 59.9% were female (including both the adult and minor twins). The registration questionnaire consists of eight parts, including socio-demographic and anthropometric data, smoking habits and medical questions (diseases, operations, therapies). Hungary's twin registry has become the sole and largest population-based twin registry in Central Eastern Europe. This new resource will facilitate performing world-class modern genetic research.

Heritability of Clinically Diagnosed Obsessive-Compulsive Disorder Among Twins.

This cohort study estimates the heritability of clinically diagnosed obsessive-compulsive disorder in a sample of twins.

Fetus with multiple congenital anomaly syndrome caused by novel variant in ATP1A2.

We report a 32-year-old G3P1 at 35 weeks 3 days with a dichorionic, diamniotic twin gestation who presented for evaluation secondary to ventriculomegaly (VM) in one twin. Fetal ultrasound and MRI demonstrated microcephaly, severe VM, compression of the corpus callosum, scalp and nuchal thickening, elongated ears, bilateral talipes, right-sided congenital diaphragmatic hernia (CDH), and loss of normal cerebral architecture, indicative of a prior insult in the affected twin. The co-twin was grossly normal. The family pursued a palliative care pathway for the affected twin and was delivered at 37 weeks and 6 days. The affected twin passed away within the first hour of life due to respiratory compromise. Postmortem trio exome sequencing identified a homozygous likely pathogenic variant in ATP1A2 (c.2439+1G>A). Although this variant is novel, it is predicted to affect the donor split site in intron 17, resulting in a frameshift and complete loss-of-function of the gene. Biallelic loss of function variants in this gene have been reported in seven individuals with multiple anomalies similar to those in the affected twin. However, only one other individual with a possible CDH has been previously reported. Our case suggests that CDH be included in the phenotypic spectrum of this disorder and reports the first frameshift mutation causing this autosomal recessive multiple congenital anomaly syndrome.

Age-related macular degeneration discordance in monozygotic twin pairs.

PURPOSE: To examine age-related macular degeneration (AMD) and retinal pigment epithelium (RPE)-Bruch's membrane (BrM) complex volume associations in monozygotic twin pairs. METHODS: In this study, 106 elderly twins (53 twin pairs) from the Finnish Twin Cohort study were recruited. Each participant underwent dilated 35-degree digital colour fundus photography (CFP), and spectral domain optical coherence tomography (OCT) and replied to a structured study questionnaire. The CFPs were graded according to the Age-Related Eye Disease Study (AREDS) classification. The OCT images were segmented and volumetric data of the RPE-BrM complex volume was calculated with the Orion™ software. The worse eye according to AREDS classification was used for the analysis. RESULTS: Twenty-nine (55%) of the twin pairs were discordant with regard to AREDS classification. Fourteen (26%) pairs were discordant with one twin participant having AMD (AREDS 2-4) and the other being unaffected (AREDS 1). Four (8%) pairs had one twin participant with intermediate or late AMD (AREDS 3-4) versus the other being unaffected (AREDS 1). The within-pair polychoric correlation for AREDS was 0.605 (95% confidence interval 0.418-0.792). In multivariate analysis intermediate and late AMD as well as age associated with RPE-BrM complex volume. RPE-BrM complex volume showed a within twin pair correlation, r = 0.430 (95% confidence interval 0.172-0.688, p < 0.01). CONCLUSION: A substantial proportion of monozygotic twin pairs are discordant with regard to age-related macular degeneration phenotype. RPE-BrM complex volume associated with age and intermediate and late AMD.

Twin studies on cancer.

Studies on cancer loci by use of twin data reveal sources of variation in risk. The Nordic twin and cancer registries contain the largest cohort of population representative twins ever studied with more than median 40 years of follow-up. This article considers findings that show influences on familial risk and demonstrates the strengths of the matched case co-twin design for unraveling important risk factors of cancers. Studies using twin data will expectedly continue to provide insights into cancer epidemiology and genetics for the benefit of prevention and treatment.

Bilateral Peters' anomaly, aniridia and Wilms tumour (WAGR syndrome) in monozygotic twins.

AIM: This study reports the bilateral association of Peters' anomaly and congenital aniridia in monozygotic twins subsequently diagnosed with Wilms tumour (WAGR syndrome). METHODS: Two monozygotic female twins were referred at age 2 months with bilateral corneal opacity. A diagnosis of Peters' anomaly associated to aniridia was made in both eyes of both twins. Physical examination and ultrasonography were carried out at 12 months of age to explore the possibility of WAGR-related anomalies, specifically Wilms tumour. DNA were isolated and subjected to whole exome sequencing. RESULTS: Peters' anomaly associated to aniridia in both eyes as well as bilateral Wilms tumour in both children were diagnosed. Exome analyses showed a large heterozygous deletion encompassing 6 648 473 bp in chromosome 11p13, using Integrative Genomics Viewer and AnnotSV software. CONCLUSION: WAGR syndrome is a rare contiguous gene deletion syndrome with a greater risk of developing Wilms tumour associated with Peters' anomaly and congenital aniridia. However, co-occurrence of both anomalies was rarely reported in twins, and never in both eyes of monozygotic twins. Here, we report the bilateral association of Peters' anomaly and congenital aniridia in monozygotic twins with WAGR syndrome.

Surgically treated degenerative disk disease in twins.

PURPOSE: Previous studies have suggested that genetic factors are important in the development of degenerative disk disease (DDD). However, the concordance rates for the phenotypes requiring surgery are unknown. The purpose of this study was to determine the concordance rates for DDD requiring surgery by studying monozygotic (MZ) and dizygotic (DZ) twin pairs. METHODS: Patients, aged between 18 and 85 years, operated for DDD between 1996 and 2022 were identified in the national Swedish spine register (Swespine) and matched with the Swedish twin registry (STR) to identify MZ and DZ twins. Pairwise and probandwise concordance rates were calculated. RESULTS: We identified 11,207 patients, 53% women, operated for DDD. By matching the Swespine patients with the STR, we identified 121 twin pairs (37 MZ and 84 DZ) where one or both twins were surgically treated for DDD. The total twin incidence for operated DDD was 1.1%. For DDD requiring surgery, we found no concordant MZ pair and no concordant DZ pair where both twins were operated for DDD. When we evaluated pairs where at least one twin was operated for DDD, we found two concordant MZ pairs (the co-twins were operated for spinal stenosis) and two  concordant DZ pairs (one co-twin operated for spinal stenosis and one (co-twin operated for disk herniation). CONCLUSIONS: Our findings suggest that genetic factors are probably not a major etiologic component in most cases of DDD requiring surgery. The findings of this study can be used for counseling patients about the risk for requiring DDD surgery.