Dizygotic Twins Research Articles

Differences in the heritability of craniofacial skeletal and dental characteristics between twin pairs with skeletal Class I and II malocclusions.

ObjectiveTo investigate differences in the heritability of skeletodental characteristics between twin pairs with skeletal Class I and Class II malocclusions.MethodsForty Korean adult twin pairs were divided into Class I (C-I) group (0° ≤ angle between point A, nasion, and point B [ANB]) ≤ 4°; mean age, 40.7 years) and Class II (C-II) group (ANB > 4°; mean age, 43.0 years). Each group comprised 14 monozygotic and 6 dizygotic twin pairs. Thirty-three cephalometric variables were measured using lateral cephalograms and were categorized as the anteroposterior, vertical, dental, mandible, and cranial base characteristics. The ACE model was used to calculate heritability (A > 0.7, high heritability). Thereafter, principal component analysis (PCA) was performed.ResultsTwin pairs in C-I group exhibited high heritability values in the facial anteroposterior characteristics, inclination of the maxillary and mandibular incisors, mandibular body length, and cranial base angles. Twin pairs in C-II group showed high heritability values in vertical facial height, ramus height, effective mandibular length, and cranial base length. PCA extracted eight components with 88.3% in the C-I group and seven components with 91.0% cumulative explanation in the C-II group.ConclusionsDifferences in the heritability of skeletodental characteristics between twin pairs with skeletal Class I and II malocclusions might provide valuable information for growth prediction and treatment planning.

Pitfalls in Diagnosing Heterotopic Pregnancy in Sub-Saharan Africa: A Case Report at the Yaounde University Teaching Hospital (Cameroon)

Heterotopic pregnancy (HP) is a dizygotic twin pregnancy in which one gestational sac is intrauterine and the other is extrauterine. The prevalence of HP is unknown in Cameroon where the diagnosis is difficult and usually fortuitous like in other resource-poor settings. We herein depict pitfalls and delays in the diagnosis and management of a ruptured heterotopic pregnancy at the Yaounde University Teaching Hospital. After a wrong diagnosis and inadequate treatment, our patient presented at our emergency unit with severe pelvic pain and clinical signs of hemoperitoneum with shock. She underwent a total left salpingectomy through laparotomy. She had a complete spontaneous abortion five days after the surgery. Given that sonography is not routinely available in emergency departments in resource-poor settings, it may be relevant for practitioners to always bear HP in mind when facing ruptured ectopic pregnancies.

Lack of GNAS Remethylation During Oogenesis May Be a Cause of Sporadic Pseudohypoparathyroidism Type Ib.

Pseudohypoparathyroidism type Ib (PHP1B) is characterized by hypocalcemia and hyperphosphatemia due to parathyroid hormone resistance in the proximal renal tubules. Maternal pathogenic STX16/GNAS variants leading to maternal epigenetic GNAS changes impair expression of the stimulatory G protein alpha-subunit (Gsα) thereby causing autosomal dominant PHP1B. In contrast, genetic defects responsible for sporadic PHP1B (sporPHP1B) remain mostly unknown. Determine whether PHP1B encountered after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) causes GNAS remethylation defects similar to those in sporPHP1B. Retrospective analysis. Nine among 36 sporPHP1B patients investigated since 2000, all with loss of methylation (LOM) at the 3 maternal GNAS differentially methylated regions (DMRs) and gain of methylation at the paternal NESP DMR, had been conceived through IVF or ICSI. Besides abnormal GNAS methylation, IVF/ICSI PHP1B cases revealed no additional imprinting defects. Three of these PHP1B patients have dizygotic twins, and 4 have IVF/ICSI-conceived siblings, all with normal GNAS methylation; 2 unaffected younger siblings were conceived naturally. Sporadic and IVF/ICSI-conceived PHP1B patients revealed indistinguishable epigenetic changes at all 4 GNAS DMRs, thus suggesting a similar underlying disease mechanism. Given that remethylation at the 3 maternal DMRs occurs during oogenesis, male factors are unlikely to cause LOM postfertilization. Instead, at least some of the sporPHP1B variants could be caused by a defect or defects in an oocyte-expressed gene that is required for fertility and for re-establishing maternal GNAS methylation imprints. It remains uncertain, however, whether the lack of GNAS remethylation alone and the resulting reduction in Gsα expression is sufficient to impair oocyte maturation.

Temporary and persistent overweight and long-term labor market outcomes.

We study how the duration of being overweight earlier in life is related to subsequent long-term labor market outcomes. Our data on fraternal and identical twins born and raised in the same household contain weight measurements of the twins during their early adulthood measured in 1975, 1981, and 1990 and is linked to register-based administrative data on the earnings and employment from 1990 to 2009. When combined, these data enable an empirical strategy that controls for the family environment and genes shared by twins. We find that being persistently overweight during early adulthood is negatively associated with long-term earnings for both women and men. We find that for women, the association is driven by a decrease in labor market-attachment, whereas for men, the association is driven by lower annual earnings.

Concordance and comorbidities among monozygotic twins with tic disorders

Gilles de la Tourette Syndrome (GTS) is a multifactorial neurodevelopmental disorder characterized by tics and multiple comorbidities. The pathophysiology is not yet fully understood, but both environmental and genetic risk factors seem to be involved. Twin studies provide important knowledge on genetic factors. We assessed the concordance of GTS and chronic tic disorders (CTD) in monozygotic (MZ) twins, and examined tic severity, symptoms of obsessive-compulsive disorder (OCD), attention deficit/hyperactivity disorder and autism spectrum disorder. Twin pairs, where at least one twin was diagnosed with any tic disorder, were identified through Danish Twin Registry, Psychiatric Central Registry, Danish National Patient Registry and National Tourette Clinic, Copenhagen University Hospital, Herlev. Zygosity was tested with single-nucleotide polymorphism (SNP) genotyping and clinical assessment was done with validated tools. 14 MZ twin pairs were included: five were discordant. Seven twin pairs were concordant for GTS, and for two pairs one twin had GTS and the other CTD. Among the twins with CTD or GTS, 50% had at least one comorbidity, which is higher than in background populations. The GTS + OCD-phenotype was significantly more frequent among GTS-concordant than among discordant twins. No statistically significant differences were found between the GTS-concordant and discordant twin pairs regarding tic severity or comorbidities. Thorough clinical assessment and SNP-based genotyping are important when conducting clinical twin studies. We found high concordance of GTS and CTD, which supports the notion that both disorders have common genetic risk factors. Further studies with larger cohorts including dizygotic twins are warranted for more conclusive results.

Genetic and environmental contributions to variations on appetitive traits at 10 years of age: a twin study within the Generation XXI birth cohort

PurposeGiven the variability in adiposity despite ubiquitous exposure to obesogenic food environments, it has been suggested that individuals respond in divergent ways to the environment they live in. The food environment becomes more ‘permissive’ as children age; therefore, genetic predisposition for a more avid appetite can be better expressed, influencing dietary quality, energy intake and weight gain. Our aim was to explore the genetic and environmental contribution of variations on appetitive traits in a sample of 10-year-old Portuguese children.MethodsParticipants were twins enrolled in the Generation XXI birth cohort (n = 86 pairs). Parents reported twin’s zygosity and child appetitive traits at 10 years of age through the Children’s Eating Behavior Questionnaire. Intra-class correlations (ICCs) for all appetitive traits were calculated for monozygotic and dizygotic twins separately to examine patterns of resemblance, and structural equation modeling was conducted aiming to estimate the genetic (A), shared (C) and non-shared (E) environmental variances.ResultsModerate to strong heritability were found for child appetitive traits, with higher ICCs among monozygotic twin pairs. For all appetitive traits, with the exception of emotional undereating, genetic and non-shared environmental effects contributed to appetite variability. For emotional undereating, environmental effects seem to be more important than genetic effects (C: 0.81; 95% CI 0.71; 0.88 and E: 0.19; 95% CI 0.12; 0.29).ConclusionThere was a significant genetic contribution, followed by non-shared environmental contribution, towards variation in appetitive traits in school-age children. Variation in emotional undereating was primarily explained by shared and non-shared environmental factors.Level of evidenceEvidence obtained from well-designed cohort or case–control analytic studies.

Cheiloscopy - A Tool For Identification in Twins

Introduction : Lip prints are an adjuvant tool for identification in forensic medicine. The grooves onthe lips have discrete characteristics to make it different from one other. This study was conductedon 24 pairs of twins out of which 22 pairs were Monozygotic twins and 2 pairs were Dizygotictwins. Dizygotic twins are unique in all aspects while Monozygotic twins are similar phenotypicallyand genotypically. The objective of this study is to find the most common pattern in the twins , thecommonest pattern among the male and female twins and to know the variations in the pattern of lipprints among Monozygotic and Dizygotic twins.Materials and Methods: A lipstick, drawing chart and magnifying lens were the materials used torecord the imprints of the lips. A four compartment method with a clockwise direction approach wasused and the analysis was done based on Suzuki and Tsuchihashi classification.Results: The present study shows Type 1’ was the most common lip prints observed among the 24pairs of twins. This pattern was predominantly present in the right lower lip quadrant. Out of the studysubjects of 24 pairs of twins, 38 were males and 10 were females in which Type I ‘ is common in malesand type I is common in females. Among the monozygotic twins those which had < 50 % resemblancewere 14 pairs, 50% resemblance were 6 pairs, >50% resemblance were 2 pairs in which Type is thecommonest. Among the dizygotic twins, both the pairs were totally different from each other yet Typewas the common pattern.Conclusion: Based on the analysis of the lip print patterns among monozygotic twins, though similaritieswere prevailing between them , they are not identical .Whereas among dizygotic twins both the pairs oftwins are unique. Hence Lip print can be utilized as a differentiating tool for identification.

Assessment of Dental Arch Parameters in Turkish Twins.

The aim of this study is to investigate the relative contributions of genetic and environmental factors to variations in dental dimensions in a sample of Turkish twins, and to estimate heritability using dental casts. The study samples were selected from the twin children between 3-15 years old who referred for their first dental examination. Fifty nine monozygotic and one hundred and forty three dizygotic twin pairs were examined in the study. The alginate impression material used to create the plaster model of maxilla and mandible. Anterior arch width, posterior arch width, arch length and arch circumference were measured on models prepared from measurements taken for both maxilla and mandible with digital caliper. The similarities and differences of the measurements were compared between pairs of twins and zygocytes. Morever, the effects of bad oral habits, bruxism, a result of psychosocial factors on measurements were examined. Statistical analysis was performed using Paired T Test, Wilcoxon Test and Mann Whitney U test. A total of 404 dental models of 118 (29.2%) monozygotic and 286 (70.8%) dizygotic twins were evaluated. There was no statistical difference between sibling pairs in both monozygotic and dizygotic twins. The measurement similarity between twin siblings differed according to zygosity in all measurements (p<0.05). It has been observed that the finger sucking and mouth breathing affect the dental arch measurements (p<0.05). These results indicate that the differences in dental arch dimensions between monozygotic twin pairs are less than the difference between dizygotic twin pairs.

Simultaneous occurrence of idiopathic trachyonychia in dizygotic twins.

Trachyonychia (or twenty-nail dystrophy) is an uncommon chronic disorder manifesting as thin, flattened, brittle nails with excessive longitudinal ridging and loss of luster creating a "sandpaper-like" texture that most commonly presents spontaneously in childhood as an isolated phenomenon; however, it has been historically associated with numerous dermatoses. Rarely, trachyonychia has been reported to occur in families, suggesting a potential hereditary predisposition. We report trachyonychia occurring simultaneously in dizygotic twins, further supporting a possible underlying genetic basis of this idiopathic nail disorder.

Suspected Down Syndrome in one of non-identical twins in Ile-Ife: A case report

Nigerian women of southwest extraction have the highest rate of dizygotic twinning worldwide, with a reported incidence as high as 49 per 1000 deliveries. Among the risk factors for dizygotic twinning is advanced maternal age, which is also an independent risk factor for Down syndrome (trisomy 21). Down syndrome is the most common chromosomal disorder affecting live born neonates. It occurs very rarely in twins, seen in 14-15 per million non-identical twins. Down syndrome in one of non-identical twins was first reported in Nigeria by Otaigbe in Port Harcourt, in 2007. Herein, we report another case of suspected Down syndrome in one of non-identical twins born to a 41-year-old grand multiparous woman at the Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun state, Nigeria. Keywords: Down Syndrome; dizygotic; fraternal; dichorionic; diamniotic.

CORR Insights®: Whole Exome Sequencing in Individuals with Idiopathic Clubfoot Reveals a Recurrent Filamin B (FLNB) Deletion.

Where Are We Now? Although only 20% of patients with clubfoot have a known associated genetic syndrome, there is strong evidence suggesting a genetic basis for isolated clubfoot [7]. Approximately 25% of patients with clubfoot have a family member with clubfoot as well [4]. Data from twin studies shows a higher concordance in identical (33%) than fraternal (3%) twins, and more recent data estimate heritability of isolated clubfoot at around 30% [3]. It seems likely that as we continue to investigate this topic, the proportion of patients who have an identifiable genetic cause for having clubfoot—now only about one in five [7]—will increase. Therapeutic opportunities are likely to increase correspondingly. In the current study, Quiggle et al. [6] determine whether there are any shared rare gene variants in unrelated patients with isolated clubfoot, as well as other rare variants of the already identified Filamin B (FLNB) gene in those patients. The authors analyzed whole-exome sequence data obtained from a discovery cohort of 183 unrelated probands with clubfoot and 2492 controls. They filtered their data to identify a candidate deletion that was further genotyped in a replication cohort of unrelated patients with clubfoot. The authors did not find any recurrent variants for any of the known genes causing clubfoot, but they did observe recurrent three-base pair in-frame codon deletion of FLNB in patients with isolated clubfoot. These results are important because identifying individuals in multigenerational families that carry genetic alterations related to nonsyndromic clubfoot, one of the most common congenital musculoskeletal birth defects, could help us determine which patients are at greater risk for recurrence following treatment. Perhaps we can soon anticipate its appearance in siblings or children of people who had clubfoot when they were younger. Where Do We Need To Go? We could build off the results of this study by working toward identifying the genetics of the early limb developmental pathway in clubfoot. This would expand our knowledge on the heritability of isolated clubfoot and help us provide accurate genetic counseling for at-risk families [2]. Additionally, establishing a genetic classification could lead to tailored treatment strategies, which could help researchers potentially identify those patients who are resistant to current treatment modalities. Still, more research is needed to determine the mechanism by which FLNB pathogenic variants may contribute to clubfoot, and in turn, which promoters could potentially trigger those gene alterations. There are already studies that linked DNA oxidative damage in N-acetylation genes to tobacco smoking, although this may not be the case of FLNB, as smoking is a common habit. We could, however, investigate whether FLNB acts as a promoter in patients with clubfoot. How Do We Get There? Animal models, which could serve as analogs to determine the mechanisms by which these genetic abnormalities cause clubfoot, should be on the horizon. Such studies could help us better understand the pathogenesis of early idiopathic clubfoot. Collaborative, multicenter studies with increased sample sizes and harmonizing phenotypes could also potentially determine whether FNLB variants contribute to the development of clubfoot. Determining the inheritance pattern of the disorder [1] could potentially lead to the development of a combined gene alteration/malformation classification. Although certainly a challenging endeavor, this approach could be the final step in the evolution of knowledge in this field.

Familial liability to asthma and ADHD: A Swedish national register-based study.

Studies have reported significant associations between asthma and attention-deficit/hyperactivity disorder (ADHD), but whether the association is due to shared etiology such as shared genetic risk factors remains unclear. We aimed to investigate patterns of familial co-aggregation of asthma and ADHD and also to quantify the relative contribution of genetic and environmental influences. Through Swedish register linkages, we obtained a cohort of 927,956 individuals born 1992-2001 and identified monozygotic twins (MZ), dizygotic twins (DZ), full- and half-siblings, and full- and half-cousins. Clinical diagnosis of asthma and ADHD were identified from the Swedish national registers. We used logistic regressions to investigate the within-individual association and familial co-aggregation between asthma and ADHD. We then used bivariate twin modeling to quantify the genetic and environmental correlations and their contributions to the familial liability. Individuals with asthma had significantly higher risk of ADHD (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.47-1.54). Relatives of individuals with asthma had an increased risk of ADHD compared to relatives of individuals without asthma; in familial co-aggregation analysis, the association was strongest in MZ twins (OR, 1.67; 95% CI, 0.99-2.84) and attenuated with degree of genetic relatedness. In the twin modeling, the phenotypic and genetic correlations between asthma and ADHD estimated from the ACE model were 0.09 (95% CI, 0.05-0.14) and 0.12 (95% CI, 0.02-0.21), respectively. The bivariate heritability was 0.88 (95% CI, 0.30-1.46). Estimates for contributions from shared and non-shared environment factors were not statistically significant. Asthma and ADHD co-aggregate in families primarily due to shared genetic risk factors. Within-individual and family history of either disorder should prompt clinical assessment of the other condition. Future studies should further investigate genetic variants underlying the co-occurrence of ADHD and asthma.

Joseph Murray: Pioneering Plastic Surgeon and Father of the First Organ Transplant.

Dr. Joseph Murray was a plastic surgeon who is best known for performing the first successful human organ transplant. After graduating from Harvard Medical School and completing a surgical internship at Peter Bent Brigham Hospital, Murray enlisted in the US Army Medical Corp and spent 5years at Valley Forge General Hospital treating World War II soldiers injured in combat. He treated hundreds of burn victims with skin grafts and took an interest in the variable process of graft rejection based on both the patient's relation to the graft donor and the patient's level of immunocompetency. His work at Valley Forge set the stage for his research investigating the feasibility of kidney transplantation and immunosuppression. He went on to perform the first successful kidney transplant between identical twins in 1954, between fraternal twins in 1959, and between an unrelated donor and recipient in 1962. For his efforts, he was awarded the 1990 Nobel Prize in Medicine.

Infantile Macrocephaly: Complicated Familial Benign Enlargement of Subarachnoid Space in Twins of Suspected Nonaccidental Injury

A 3-month-old first of dizygotic male twins, born at 34+ 5 weeks gestational age, presented with a 4-week history of increasing head circumference and vomiting. He had a tense anterior fontanelle and a head circumference above the 97th percentile. Magnetic resonance imaging showed large bilateral subdural collection with hemosiderin deposits suggestive of hemorrhage. Nine days of bilateral subdural drainage reduced the collection size and blood load. On postoperative day 16, magnetic resonance imaging confirmed persistent but smaller subdural collections, unmasking the underlying subarachnoid space enlargement. On day 18, a right subdural-peritoneal valveless shunt was inserted as definitive treatment. As part of a nonaccidental injury investigation, Twin 2 was also found to have macrocephaly secondary to benign enlargement of subarachnoid space, which was managed conservatively. Benign enlargement of subarachnoid space has an assumed autosomal/multifactorial inheritance and predisposes to subdural hemorrhage. Ultimately, no safeguarding issues were raised. Both twins continued to be neurologically stable at 2-year follow-up with head circumferences between the 98th and 99th percentiles.

Facial asymmetry and chewing sides in twins

Objective To resolve how the preferred chewing side (PCS) affects facial asymmetry in twins, whether there are differences between monozygotic (MZ) and dizygotic (DZ) twins, and whether the twins with PCS have more asymmetric faces compared to symmetrically chewing twins. Material and methods The study included 106 Lithuanian twin pairs of the same sex, 59 MZ and 47 DZ pairs. The data were analysed from facial 3D images and manually added landmarks. 3D images were analysed by Rapidform2006 software and statistical analyses were done by using the R software environment version 4.1.0. Results The contralateral effect of PCS and larger chin side was dominant among right and non-right side chewing twins. Being female increased the whole face symmetry. Conclusion The volume of the chin becomes larger on the side opposite to the twins’ habitual chewing side. As the results are quite similar in both twin types, functional factors are more prominent than heredity.

Heritability Analysis in Twins Indicates a Genetic Basis for Velopharyngeal Morphology.

The velopharyngeal mechanism is comprised of several muscular components that act in a coordinated manner to control airflow through the nose and mouth. Proper velopharyngeal function is essential for normal speech, swallowing, and breathing. The genetic basis of normal-range velopharyngeal morphology is poorly understood. The purpose of this study was to estimate the heritability of velopharyngeal dimensions. We measured five velopharyngeal variables (velar length, velar thickness, effective velar length, levator muscle length and pharyngeal depth) from MRIs of 155 monozygotic and 208 dizygotic twin pairs and then calculated heritability for these traits using a structural equation modeling approach. The heritability estimates were statistically significant (95% confidence intervals excluded zero) and ranged from 0.19 to 0.46. There was also evidence of significant genetic correlations between pairs of traits, pointing to the influence of common genetic effects. These results indicate that genetic factors influence variation in clinically relevant velopharyngeal structures.

Exome sequencing implicates a novel heterozygous missense variant in DSTYK in autosomal dominant lower urinary tract dysfunction and mild hereditary spastic paraparesis

IntroductionDSTYK encodes dual serine/threonine and tyrosine protein kinase. DSTYK has been associated with autosomal-dominant congenital anomalies of the kidney and urinary tract and with autosomal-recessive hereditary spastic paraplegia type 23. Here, we report a father and his two dizygotic twin sons carrying a novel heterozygous missense variant in DSTYK, presenting with early onset lower urinary tract dysfunction due to dysfunctional voiding. Moreover, in the later course of the disease, both sons presented with bilateral spasticity in their lower limbs, brisk reflexes, and absence seizures.Materials and methodsExome sequencing in the affected father and his affected sons was performed. The sons presented clinically with urinary hesitancy, dysfunctional voiding, and night incontinence till adolescence, while the father reported difficulty in voiding. In the sons, cystoscopy excluded urethral valves and revealed hypertrophy of the bladder neck and trabeculated bladder. Additionally, both sons were diagnosed with absence epilepsy in early childhood. Filtering of exome data focused on rare (MAF < 0.01%), autosomal-dominant variants, predicted to be deleterious, residing in highly conserved regions of the exome.ResultsExome analysis identified a novel, heterozygous missense variant (c.271C>A (p.Leu91Met)) in DSTYK segregating with the disease. In silico prediction analyses uniformly rated the variant to be deleterious suggesting the variant to be disease-causing in the family.ConclusionTo the best of our knowledge, this is the first report of early onset dysfunctional voiding, seizures, and bilateral spasticity of the lower limbs associated with a novel heterozygous dominant missense variant in DSTYK.

Association between Bovine GDF9 SNPs and Calving Rate (Superovulation) in Holstein-Friesian Cows.

The present study aimed to assess the relationship of Growth Differentiation Factor 9 (GDF9) genotypes with calving rate, Follicle-stimulating hormone (FSH), and Estradiol (E2) in the Iraqi Holstein-Friesian breed. A number of 15 blood samples were collected from a mother of dizygotic twin birth (DZTB) (with high calving rate records), and another blood sample was collected from 15 single birth (SB) cows. The DNA was extracted and six primers were designed for PCR and sequencing analysis. The FSH and E2 levels were tested through the estrus phase for the two groups (n=10 in each group). The sequence evaluation revealed the presence of two single nucleotide polymorphisms (SNPs) in exon II: A (1109) T and G (1133) A.The genotypic frequency for mutant genotypes was higher significantly (P<0.01) in DZTB cows (with calving rate), as compared to wild genotypes at the same loci. On the other hand, the wild genotypes recorded a significant increment (P<0.01) for SB cows, when compared to mutant genotypes in the same loci. Moreover,a significant rise (P<0.05) was reported in E2 and FSH levels for DZTB cows and mutant genotypes(P<0.01) against SB cows and wild genotypes in 0 and 24 h of estrus phase, respectively. Furthermore, non-significant differences were recorded in E2 concentration among the same genotypes at the same period.In conclusion, the GDF9exon II SNPs increased the calving rate in Holstein-Friesian cows. The blood FSH and E2 concentrations were higher in the DZTB cows and control the superovulation. Finally, these SNPs can be regarded as markers to accelerate the breeding programs and used in embryo transfer and in vitro embryo production for Iraqi Holstein-Friesian cow breed.

Reconstructing the Dynamics of the Outer Electron Radiation Belt by Means of the Standard and Ensemble Kalman Filter With the VERB‐3D Code

AbstractReconstruction and prediction of the state of the near‐Earth space environment is important for anomaly analysis, development of empirical models, and understanding of physical processes. Accurate reanalysis or predictions that account for uncertainties in the associated model and the observations, can be obtained by means of data assimilation. The ensemble Kalman filter (EnKF) is one of the most promising filtering tools for nonlinear and high dimensional systems in the context of terrestrial weather prediction. In this study, we adapt traditional ensemble‐based filtering methods to perform data assimilation in the radiation belts. By performing a fraternal twin experiment, we assess the convergence of the EnKF to the standard Kalman filter (KF). Furthermore, with the split‐operator technique, we develop two new three‐dimensional EnKF approaches for electron phase space density that account for radial and local processes, and allow for reconstruction of the full 3D radiation belt space. The capabilities and properties of the proposed filter approximations are verified using Van Allen Probe and GOES data. Additionally, we validate the two 3D split‐operator Ensemble Kalman filters against the 3D split‐operator KF. We show how the use of the split‐operator technique allows us to include more physical processes in our simulations and is a computationally efficient data assimilation tool that delivers an accurate approximation of the optimal KF solution, and is suitable for real‐time forecasting. Future applications of the EnKF to direct assimilation of fluxes and nonlinear estimation of electron lifetimes are discussed.

Genetic etiologies of central precocious puberty

Pubertal onset is a complex process, which is influenced by genetic and environmental factors, such as obesity and endocrine-disrupting chemicals. In addition, the timing of normal puberty varies between individuals and is a highly polygenic trait with both rare and common variants. Central precocious puberty (CPP) is defined as the early activation of the hypothalamic-pituitary-gonadal axis. Genetic factors are suggested to account for 50% to 80% of the variation in puberty initiation, as indicated by the greater concordance of pubertal timing observed in monozygotic twins than in dizygotic twins. Although genetic factors play a crucial role in CPP development, only few associated genes have been identified. To date, four monogenic genes have been identified: KISS1, KISS1R, MKRN3, and DLK1. Moreover, mutation prevalence in these genes varies considerably depending on the ethnicity of patients with CPP. This article reviews the current knowledge on the normal pubertal timing and physiology and discusses the CPP-causing genes.