Dizygous Twins Research Articles

PTPN11 mutation in a large family with Noonan syndrome and dizygous twinning.

Noonan syndrome (NS, MIM 163950) is an autosomal dominant condition characterised by facial dysmorphy, congenital cardiac defects and short stature. Recently missense mutations in PTPN11, the gene encoding the nonreceptor protein tyrosine phosphatase SHP-2 on 12q24, were identified in 50% of analysed Noonan cases. A large four-generation Belgian family with NS and some features suggestive of cardio-facio-cutaneous syndrome (CFC) was previously used to fine map the Noonan syndrome candidate region to a 5 cM region in 12q24. We now report the identification of a mutation (Gln79Arg) in the PTPN11 gene in this large family. In D. melanogaster and C. elegans the PTPN11 gene has been implicated in oogenesis. In this family two affected females had dizygous twins. This suggests that PTPN11 might also be involved in oogenesis and twinning in humans.

The epidemiology of sudden infant death syndrome

Background: Twins compared to singletons are at increased risk of sudden infant death syndrome (SIDS). Aims: To compare the epidemiology of SIDS in twins and singletons and to test the...

Urorectal septum malformation sequence: Insights into pathogenesis.

We characterize the urorectal septum malformation sequence (URSMS) in discordant fetal lambs and relate it to the human syndromes with which URSMS is associated. We found abnormal external genitalia, imperforate anus, and fistulous connections between the rectum, bladder, and vagina. Discordance among the dizygous twins eliminated teratogens as a likely etiologic factor. We summarize the relevant literature and propose a molecular model for the pathogenesis of the URSMS, in which alterations in sonic hedgehog and homeobox genes lead to caudal mesodermal deficiency during blastogenesis.

The St. Thomas' UK Adult Twin Registry.

The Registry consists of nearly 10,000 monozygous and dizygous adult caucasian twins aged 18-80 from all over the UK and was started in 1993. This is a volunteer sample recruited by successive media campaigns without selecting for particular diseases or traits. All twins receive a series of disease questionnaires. In addition over half the twins have been assessed in detail clinically for several hundred phenotypes related to common diseases or intermediate traits. The focus has been primarily on cardiovascular, metabolic, musculoskeletal, dermatological, and opthalmological diseases. Over 3000 DZ twins have had a genome wide scan performed as well as many candidate genes allowing both linkage and association studies. The registry has led to many successful innovative research projects, particularly in common diseases previously thought to be predominantly environmental and helped positionally clone some novel genes for common diseases.

The St. Thomas' UK Adult Twin Registry

The Registry consists of nearly 10,000 monozygous and dizygous adult caucasian twins aged 18–80 from all over the UK and was started in 1993. This is a volunteer sample recruited by successive media campaigns without selecting for particular diseases or traits. All twins receive a series of disease questionnaires. In addition over half the twins have been assessed in detail clinically for several hundred phenotypes related to common diseases or intermediate traits. The focus has been primarily on cardiovascular, metabolic, musculoskeletal, dermatological, and opthalmological diseases. Over 3000 DZ twins have had a genome wide scan performed as well as many candidate genes allowing both linkage and association studies. The registry has led to many successful innovative research projects, particularly in common diseases previously thought to be predominantly environmental and helped positionally clone some novel genes for common diseases.

Is birthweight associated with thyroid autoimmunity? A study in twins.

Although extensive studies have suggested that an individual's predisposition to develop autoantibodies to thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) has a genetic component, a recent report has suggested that growth restriction during fetal life may also contribute. We have therefore measured TPOAb and TgAb in a population-based study of twins (44 monozygous and 91 dizygous) born between 1950 and 1955 who were identified through a registry of birth records in Birmingham, United Kingdom. TPOAb and TgAb were measured by a highly sensitive immunoprecipitation assay in which 0.01 U/mL and 0.1 U/mL, respectively, were detectable. TPOAb were found in 49 of 156 (31%) of women and 7 of 116 (6%) of men with similar values for TgAb (31% and 9%, respectively). Of 28 monozygous pairs, 10 were concordant for TgAb and 7 discordant giving a probandwise concordance rate of 74%. Concordance rates for TPOAb were similar (64%) and were higher than concordance rates in dizygous twins. Monozygous twins had a higher prevalence of TgAb than dizygous twins (30% vs. 17%, p = 0.01). In addition, we found that where there was discordance in birth size within monozygous twin pairs, the smaller twin had a higher prevalence of TPOAb (p = 0.01). Our results suggest that both heritable and early environmental components contribute to the susceptibility to thyroid autoimmunity.

Genetics of isolated and syndromic strabismus: Facts and perspectives

Family studies have demonstrated the genetic etiology of concomitant strabismus (prevalence in different populations 1–5%, positive family history in 37% on average), as have twin studies (mean concordance in monozygous twins 73% compared to 35% in dizygous twins). In Duane's syndrome, three chromosomal loci have been identified to date: 2q31, 8q13, and 22q11; loci have also been identified in Moebius syndrome (various inheritance patterns): 13q12.2–q13, 3q21–q22, and 10q21.3–q22, as well as in congenital fibrosis of the extraocular muscles (CFEOM; 3 loci, 1 gene).¹ Already identified are the genes for a number of rarer muscular dystrophy syndromes with ocular involvement, various forms of congenital myasthenia, and mitochondrial diseases (with the primary defect located either in the mtDNA, resulting in a mitochondrial inheritance pattern, or in the nuclear DNA with Mendelian inheritance). A number of hereditary retinal diseases (Mendelian inheritance) may also be associated with strabismus. More than one gene is likely to be involved in the frequently occurring concomitant strabismus, making the analysis more difficult. Patients with chromosomal rearrangements, large families and isolated populations (see also the contributions by Preising and Zitzlsperger et al. in this issue)²,³ will be instrumental in gene identification. In view of the high prevalence of concomitant strabismus, the disclosure of its etiology will have considerable medical, psychosocial and health-cost impact.

Relationship of twin zygosity and risk of preeclampsia

Objective: Twin gestations are known to be at higher risk for preeclampsia. One theory suggests that maternal recognition of fetal and trophoblastic tissues as foreign may be a factor. If that hypothesis is true, mothers carrying monozygous (MZ) gestations (ie a single fetal graft) might be predicted to have a lower rate of preeclampsia than those carrying dizygous (DZ) gestations. To evaluate this hypothesis, we compared the rate of preeclampsia in mothers with MZ and DZ twin gestations. Study Design: Seven hundred sixty-eight twin deliveries from 1994 to 1999 were reviewed. Placental pathology reports were reviewed to determine the chorionic state of each placenta. Monochorionic placentas were assumed to be MZ. Dichorionic placentas were categorized as DZ if the neonates were of different sexes or different blood types. Maternal and fetal data were abstracted from the medical records. Preeclampsia was defined by standard criteria of the National Institutes of Health Working Group on High Blood Pressure. Our analysis was limited to women with pregnancies reaching at least 30 weeks of gestation where zygosity could be determined. Results: Our analysis included 464 twin pregnancies, 154 MZ and 310 DZ. Among nulliparous women, the rate of preeclampsia was 15% (25/170) for DZ twins versus 20% (15/75) for MZ twins (P =.3). Among multiparous women, the rate was 8% (11/140) for DZ twins and 5% (4/79) for MZ twins (P =.4). In a logistic regression performed to control for confounding by maternal age, gestational age at delivery, assisted reproduction, and male sex, dizygotic state was associated with an odds ratio of 1.4 (95% CI = 0.5-3.9) for developing preeclampsia in nulliparous women and 1.2 in multiparous women (95% CI = 0.3-5.0). Conclusions:: These results do not support the hypothesis that zygosity affects the rate of preeclampsia in twin gestations, though the number of subjects in our study was too small to allow definitive conclusions. Larger studies are needed to evaluate this finding. (Am J Obstet Gynecol 2001;185:819-21.)

Heritability and Gene–Environment Interactions for Melanocytic Nevus Density Examined in a U.K. Adolescent Twin Study

Risk factors for melanoma include environmental (particularly ultraviolet exposure) and genetic factors. In rare families, susceptibility to melanoma is determined by high penetrance mutations in the genes CDKN2A or CDK4, with more common, less penetrant genes also postulated. A further, potent risk factor for melanoma is the presence of large numbers of melanocytic nevi so that genes controlling nevus phenotype could be such melanoma susceptibility genes. A large Australian study involving twins aged 12 y of predominantly U.K. ancestry showed strong evidence for genetic influence on nevus number and density. We carried out essentially the same study in the U.K. to gain insight into gene-environment interactions for nevi. One hundred and three monozygous (MZ) and 118 dizygous (DZ) twin pairs aged 10-18 y were examined in Yorkshire and Surrey, U.K. Nevus counts were, on average, higher in boys (mean = 98.6) than girls (83.8) (p = 0.009) and higher in Australia (110.4) than in the U.K. (79.2, adjusted to age 12 y, p < 0.0001), and nevus densities were higher on sun-exposed sites (92 per m2) than sun-protected sites (58 per m2) (p < 0.0001). Correlations in sex and age adjusted nevus density were higher in MZ pairs (0.94, 95%CI 0.92-0.96) than in DZ pairs (0.61, 95%CI 0.49-0.72), were notably similar to those of the Australian study (MZ = 0.94, DZ = 0.60), and were consistent with high heritability (65% in the U.K., 68% in Australia). We conclude that emergence of nevi in adolescents is under strong genetic control, whereas environmental exposures affect the mean number of nevi.

Mechanisms for differences in monozygous twins.

Monozygous (MZ) twins are often described as being physically and genetically identical. Clinical determination of zygosity relies on the assumption that any physical differences between a pair of twins imply they are dizygous. Most twin research relies on the assumption that dizygous twins share approximately 50% of the same genes, whereas monozygous twins share 100%. There is, however, increasing evidence to challenge both these assumptions. In this review, we describe a number of intrauterine effects and genetic mechanisms that may result in phenotypic, genotypic, and epigenetic differences between monozygous twins. Newer molecular techniques are resulting in such differences being increasingly commonly recognised. The potential for differences in monozygotic twin pairs is an important consideration for both clinicians and researchers involved in twin work.

A study of occlusal variation in the primary dentition of Australian twins and singletons

In this study, we quantified the extent of variation in different occlusal features of Australian children of European descent with complete primary dentitions, but no permanent teeth present in the mouth. The study group consisted of 412 individuals, aged between 3 and 7 years, including 70 monozygous (MZ) twin pairs, 68 same-sexed dizygous (DZ) twin pairs, 11 opposite-sexed DZ twin pairs, and 114 singletons. Occlusal traits, including inter-dental spacing, incisal overbite and overjet, arch breadth and arch depth, were obtained directly from dental casts or indirectly from photocopies or impressions of the casts. Descriptive statistics summarised the data and indicated that distributions were similar to those published for other populations. Univariate genetic analysis, using the structural equation modelling package Mx, was carried out on the quantitative data using the normal assumptions of the twin model. Genetic modelling indicated that a model incorporating additive genetic (A) and unique environmental variation (E) was the most parsimonious for interdental spacing, overbite, overjet and arch dimensions. Estimates of heritability for interdental spacing ranged from 0.62 to 0.81. Estimates for overbite and overjet were 0.53 and 0.28, respectively, and estimates for arch dimensions ranged from 0.69 to 0.89. These results indicated a moderate to relatively high genetic contribution to observed variation.

The impact of genetic and environmental influences on blood pressure variance across age-groups.

The purpose of the present investigation was to examine the age-dependency of blood pressure heritability by use of the twin method in different age groups. In 272 (150 monozygous and 122 dizygous) twin pairs, aged 18 to 76 years, both conventional and ambulatory blood pressure were measured. After correction for possible confounders, model fitting was used to estimate heritability and 95% confidence limits in three age groups of similar size, i.e. 18-29, 30-39 and > or = 40 years. Heritability estimates were significant in each age group, ranging from 35 to 67% for the various blood pressure measurements. The estimates tended to decrease with increasing age, except for conventional diastolic blood pressure, but the intergroup differences did not reach statistical significance, despite adequate power. In conclusion, blood pressure heritability is significant in various age groups, but does not substantially change with advancing age. Twin analysis does not indicate that models for blood pressure regulation in various age groups should take into account the possibility of age-related changes in the expression of relevant genes, in the presence of relevant environmental agents, or in the susceptibility to the latter (gene-environment interaction).

Twins and cerebral palsy.

In a national follow-up study of twin births, monozygous compared with dizygous twins were at significantly increased for both to die in utero, one to die in utero and the co-twin to die in infancy, or both to be livebirths but both die in infancy. The prevalence of cerebral palsy among survivors of a co-twin fetal death was 80.2 and other cerebral impairment was 107.0 per 1000. Many apparently singleton cases of cerebral palsy and impairment may be due to fetal death of a twin that has not been recognized or has been recognized but not registered.

Testing the fetal origins hypothesis in twins: the Birmingham twin study.

To test whether the link between birthsize and raised blood pressure or glucose tolerance is due to genetic or intrauterine factors, we studied whether differences in birthweight between pairs of monozygous and dizygous twins are associated with adult differences in blood pressure and glucose tolerance. A sample of 58 monozygous and 140 dizygous twins were identified from a register of births in Birmingham, United Kingdom, between 1950 and 1954. The twins had their blood pressure measured and underwent an oral glucose tolerance test. There were no statistically significant associations between birthweight, length or ponderal index, and either blood pressure or glucose tolerance in the twins. Although there were substantial within-pair differences in birthweight between monozygous and dizygous twin pairs, these differences did not correlate with the adult outcomes. Monozygous correlations, however, for both blood pressure and glucose tolerance were statistically significantly higher than dizygous correlations and a quantitative genetic model suggested statistically significant heritability for these traits. In contrast correlations of birthsize were similar in monozygous and dizygous pairs suggesting only a small genetic component in determining fetal size. Our results show that birthsize in twins does not predict adult blood pressure or glucose tolerance. We also suggest that shared genetic determinants for fetal growth and adult outcomes are not likely to be prevalent or powerful.

Consequences of In-Utero Death in a Twin Pregnancy

Previous reports suggest that when one twin dies in utero, the survivor is more likely to suffer serious adverse outcomes, such as cerebral palsy, gut atresia, and learning disability. An attempt was made to quantify the risk of cerebral impairment in a series of 434 same-sex twin pairs in which one twin died before birth. Cases included all twin births registered in England and Wales between 1993 and 1995. Fifty-nine of the liveborn infants died neonatally, seven others within the first 28 days, and five within 1 year of birth. Three of the latter deaths were a result of cerebral palsy. Ten children who lived through infancy were lost to follow-up. Of 241 infants for whom follow-up information was available, 23 had cerebral palsy and 28 had other forms of cerebral impairment. Of those surviving to infancy, the prevalences of cerebral palsy and cerebral impairment were 106 and 114 per 1000, respectively. Among 163 different-sex twin pairs, 13 survivors died neonatally. Three of 102 survivors had cerebral palsy, and 12 had other forms of cerebral dysfunction for prevalences of 29 and 118 per 1000 infant survivors, respectively. Analysis of the combined data demonstrated a 40-fold higher prevalence of cerebral palsy in these infants than in the general population. Including other cerebral impairment, the overall risk of serious cerebral dysfunction is 20 percent. It is likely that most cases of cerebral impairment in the infants of this series were the product of monochorionic twin pregnancies. If this is the case, the risk of serious cerebral morbidity in survivors of such pregnancies will exceed one in five. The risk could approach 40 percent to 50 percent, assuming that all cases in same-sex twins involved monochorionic twins. The chances of in utero death and of a liveborn infant dying during infancy are considerably increased in monozygous as compared with dizygous twins. Reason may include disseminated intravascular coagulation resulting from the release of thromboplastic material and infarction from emboli originating in the dead twin. Unstable blood pressure and severe hypotension also have been implicated. If these factors are in fact responsible, early obstetrical intervention after the in utero death of one twin probably will not prevent morbidity in the surviving twin. These findings emphasize the need to accurately record placentation. Lancet 2000;355:1597–1602

60,XY/60,XX chimerism in the germ cell line of mature bulls born in heterosexual twinning

According to present knowledge there is a germ cell chimerism (XY/XX) in young bulls born in heterosexual twinning due to exchange of primordial germ cells in embryonic life. These germ cells were believed to have been eliminated in the young bull. Two-color fluorescence in situ hybridization (FISH) identification of the sex chromosomes by biotinylated and digoxygenin labeled probes have been used. The material consisted of three bulls born in heterosexual twinning. The results obtained indicated that even mature bulls (more than two years old) demonstrate spermatogonial chimerism. Several authors state that the bulls with blood cell chimerism, originating from dizygous twinning, are characterized by decreased fertility. Changes of the sex ratio of offspring due to proliferation of the female cells have also been proposed. The present observations should give a renewed interest in checking the possibility of survival and differentiation of germ cells from the female partner in the germ cell lines.

Epidemiology of familial sarcoidosis in the UK.

The last comprehensive epidemiological studies on familial sarcoidosis in the UK were more than 25 years ago, reporting another affected family member in 1.7% of index cases. A significant proportion of like-sex over unlike-sex pairs, an excess of mother-child over father-child associations, and a preponderance of monozygous over dizygous twins was noted. Another study reported ethnic heterogeneity in familial disease. This study was undertaken to identify the risk ratio (lambda(S)) for siblings of familial sarcoidosis in the UK, to determine if the previous epidemiological findings have persisted, and to reassess whether ethnic heterogeneity prevails in familial disease. Questionnaires were sent to 406 index patients. Two hundred and sixty eight replies (66%) were received. Twenty four of the original 406 index patients (5.91%) were found to have at least one other relative (first, second or third degree) with biopsy proven sarcoidosis. A lambda(S) value of 36-73 was calculated indicating significant familial clustering of the disease. Ethnically the families comprised 62.5% Caucasian, 29.2% Afro-Caribbean, and 8.3% Asian. Mean age at diagnosis was 39.8 years for women and 40.9 years for men with a male to female ratio of 1:1.7. This differed for the Asian families in which all the affected members were male. Three sets of female twins (two monozygous and one dizygous) were included. There was an equal distribution of like-sex (primarily female) and unlike-sex families as well as mother-child and father-child pairs. Pulmonary involvement was predominant irrespective of ethnicity, as was the need for corticosteroid treatment. These results support the theory that a shared determinant (either genetic or environmental) is operating in familial sarcoidosis and suggest that this determinant is similar for all ethnic groups.

Do placentation issues bias twin studies?

Because monozygous twins are almost genetically identical whereas dizygous twins are genetically no more similar than siblings, greater similarity between members of a monozygotic twin pair than between a dizygotic pair is usually taken as evidence that the condition or trait being studied has a genetic contribution. However, besides greater similarity of genes, monozygous pairs may share more similar environments than do dizygotic pairs. This environmental sharing may occur in fetal life where close placental relationships lead to more similar fetal environments. It may also occur postnatally. If the twins are of the same sex and look alike, the parents may dress, feed and in other ways treat the twins more similarly. Whereas the effects of a more similar postnatal environment have been explored by comparisons of twins raised together or separately, remarkably little is known about the influence of prenatal exposures.

Reproductive and menstrual history of females with fragile X expansions.

FRAXA premutations have been associated with premature ovarian failure (POF) or menopause before the age of 40. We have studied women in families ascertained because of a mentally retarded full mutation relative and determined their age of menopause, serum hormone levels in premenopausal individuals and the outcome of any pregnancies. Survival analysis was used as a measure of menopause and demonstrated a significant decrease in age of menopause in premutation carriers compared with their full mutation carrier and normal relatives. Serum FSH was also raised in premutation carriers, although oestradiol, inhibin A and inhibin B were not significantly different. However, we did not find an excess of dizygous twins or pregnancy loss/trisomies, both of which are associated with aging ovaries. Thus premutation carriers as a group have an earlier menopause and raised serum FSH but do not appear to manifest other features of an aging ovary.

Genetic and environmental influence on the asymmetry of dermatoglyphic traits.

Fluctuating asymmetry (FA) is defined as random deviations from bilateral symmetry of the body. Thus, its magnitude is often used to evaluate developmental homeostasis. In this study we evaluate the following hypotheses: 1) FA of dermatoglyphic traits has a significant genetic component; 2) prenatal maternal environment (PME) has a significant effect on the FA of dermatoglyphic traits in developmentally healthy individuals; and 3) genetic or environmental factors affect FA on organismal or systemic levels. Therefore, their effect is better seen in composite scores of FA rather than in FA indices for single traits. We analyzed 15 dermatoglyphic traits from 140 pairs of monozygous twins, 120 pairs of dizygous twins, and 106 pairs of mothers and daughters. All individuals were developmentally healthy. The influence of genetic and environmental factors on FA was evaluated by analysis of variance and regression analysis. For a majority of the traits in our study, FA showed significant but weak heritabilities, with values falling within the 0.20-0.35 range. None of the traits taken separately demonstrated the effect of PME on FA to be significantly greater than zero. The composite score of FA tended to have greater heritability values than individual traits. One of them, obtained in principal components analysis, showed a significant PME effect, supporting the hypothesis that FA is a systemic property.