Heteropaternal Siblings Misclassified as Dizygotic Twins: A Potential Biasing Factor for Heritability Estimates?

Heteropaternal superfecundation (HP) occurs when two or more ova are fertilized by sperm from separate males. The resulting siblings are genetically equivalent to half-siblings and share, on average, 25% of their inherited genetic material. In the absence of genetic testing HP siblings could be treated as dizygotic (DZ) twins in behavioral genetic analyses and bias heritability estimates in phenotypic decomposition models. However, the extent to which such misclassification could affect calculated estimates of heritability is currently unknown. Employing simulation analyses, the current study assessed the potential biasing impact across a variety of conditions varying by proportions of DZ twins, sample sizes, and low, moderate, and high levels of genetic and environmental contribution to phenotypic variance. Overall, the results indicated that misclassified HP siblings had minimal impact on estimates of heritability. Nonetheless, greater attention should be paid to the identification of HP siblings within existing and future twin datasets.

Noninvasive prenatal paternity testing by maternal plasma DNA sequencing in twin pregnancies.

SNPs, combined with massively parallel sequencing technology, have proven applicability in noninvasive prenatal paternity testing (NIPPT) for singleton pregnancies in our previous research, using circulating cell-free DNA in maternal plasma. However, the feasibility of NIPPT in twin pregnancies has remained uncertain. As a pilot study, we developed a practical method to noninvasively determine the paternity of twin pregnancies by maternal plasma DNA sequencing based on a massively parallel sequencing platform. Blood samples were collected from 15 pregnant women (twin pregnancies at 9-18 weeks of gestation). Parental DNA and maternal plasma cell-free DNA were analyzed with custom-designed probes covering 5226 polymorphic SNP loci. A mathematical model for data interpretation was established, including the zygosity determination and paternity index calculations. Each plasma sample was independently tested against the alleged father and 90 unrelated males. As a result, the zygosity in each twin case was correctly determined, prior to paternity analysis. Further, the correct biological father was successfully identified, and the paternity of all 90 unrelated males was excluded in each case. Our study demonstrates that NIPPT can be performed for twin pregnancies. This finding may contribute to development in NIPPT and diagnosis of certain genetic diseases.

Is there a relationship between fetal sex and placental pathological characteristics in twin gestations?

BACKGROUND: Placenta plays a central role in mediating growth and development of fetuses. Sex-specific placentas may complicate this role. METHODS: The study aimed at investigating the association between fetal sex and placental pathological findings in twin gestations using generalized estimating equation modeling. We used a large population-based clinical data born in British Columbia (BC) and linked the fetal-maternal data to hand-searched pathology reports of 1493 twin placentas from twins born in BC Women hospital. We analyzed the data using generalized estimating equations taking the cluster nature of twins into consideration. RESULTS: About 26.5% of twins were monochorionic and 73.5% were dizygotic. Most twins were male (51.3%). About 2/3 of twins were sex concordant (66.6%). Of the sex concordant twins, similar percentages were male-male (34.7%) and female-female (31.2%). Of the sex discordant twins, the male-female (33.3%) group constituted about 1/3 of the whole population. Adjusted for chorionicity, birth weight discordance ≥30% and gestational age, the odds of chorionitis (1.38, 95% CI = 1.04-1.84), anastomosis (1.63, 95% CI = 1.22-2.19), unequal sharing of placenta (1.72, 95% CI = 1.11-2.64), placental inflammation (1.30, 95% CI = 1.05-1.62) and lesions (1.83, 95% CI = 1.02-3.31) were higher in male twins compared with females. Twins of either sex from sex-discordant pairs were less likely to have placental anastomosis compared to the reference category. Males from male-male pairs had higher odds of unequal placental sharing (74% higher) and composite inflammation (52% higher) compared with the reference twins. CONCLUSION: Our findings suggest a relationship between sex and placental pathological results.

Adequacy of Using a Three-Item Questionnaire to Determine Zygosity in Chinese Young Twins.

The present study examined the adequacy of a three-item parent questionnaire in determining the zygosity of young Chinese twins and whether there was any association between parent response accuracy and some demographic variables. The sample consisted of 334 pairs of same-sex Chinese twins aged from 3 to 11 years. Three scoring methods, namely the summed score, logistic regression, and decision tree, were employed to evaluate parent response accuracy of twin zygosity based on single nucleotide polymorphism (SNP) information. The results showed that all three methods achieved high level of accuracy ranging from 91 to 93 % which was comparable to the accuracy rates in previous Chinese twin studies. Correlation results also showed that the higher the parents' education level or the family income was, the more likely parents were able to tell correctly that their twins are identical or fraternal. The present findings confirmed the validity of using a three-item parent questionnaire to determine twin zygosity in a Chinese school-aged twin sample.

A twin study of schizoaffective-mania, schizoaffective-depression, and other psychotic syndromes.

The nosological status of schizoaffective disorders remains controversial. Twin studies are potentially valuable for investigating relationships between schizoaffective-mania, schizoaffective-depression, and other psychotic syndromes, but no such study has yet been reported. We ascertained 224 probandwise twin pairs [106 monozygotic (MZ), 118 same-sex dizygotic (DZ)], where probands had psychotic or manic symptoms, from the Maudsley Twin Register in London (1948-1993). We investigated Research Diagnostic Criteria schizoaffective-mania, schizoaffective-depression, schizophrenia, mania and depressive psychosis primarily using a non-hierarchical classification, and additionally using hierarchical and data-derived classifications, and a classification featuring broad schizophrenic and manic syndromes without separate schizoaffective syndromes. We investigated inter-rater reliability and co-occurrence of syndromes within twin probands and twin pairs. The schizoaffective syndromes showed only moderate inter-rater reliability. There was general significant co-occurrence between syndromes within twin probands and MZ pairs, and a trend for schizoaffective-mania and mania to have the greatest co-occurrence. Schizoaffective syndromes in MZ probands were associated with relatively high risk of a psychotic syndrome occurring in their co-twins. The classification of broad schizophrenic and manic syndromes without separate schizoaffective syndromes showed improved inter-rater reliability, but high genetic and environmental correlations between the two broad syndromes. The results are consistent with regarding schizoaffective-mania as due to co-occurring elevated liability to schizophrenia, mania, and depression; and schizoaffective-depression as due to co-occurring elevated liability to schizophrenia and depression, but with less elevation of liability to mania. If in due course schizoaffective syndromes show satisfactory inter-rater reliability and some specific etiological factors they could alternatively be regarded as partly independent disorders.

[Classification of twins and their ultrasonographic diagnosis]. / Klasifikace dvojcat a základy jejich ultrazvukové diagnostiky.

OBJECTIVE: Systematic classification of all forms of twins and mechanisms of twinning. DESIGN: Review of published cases. Morphogenesis based on personal experience related to human blastogenesis including observation of anterior twinning in two early human embryos. SETTING: Institute for the Care of Mother and Child, Prague, Department of Gynecology and Obstetrics, 1st Medical Faculty, Charles University, Prague, Department of Medical Genetics, Medical Faculty, Palacký University Olomouc, Institut Unica, Brno. METHODS: Analysis of cases described in literature completed by observed cases. RESULTS: Classification of twins. A) Separated twins: 1. dichorial a) monozygotic (very rare), b) dizygotic (most frequent); 2. monochorial (always monozygotic) a) diamnial, b) monoamnial. B) Conjoined twins (always monozygotic) 1. isopagi (equal conjoined twins) a) originating from peripheral fusions of two germ discs, b) originating from duplications of axial structures; 2. heteropagi (unequal conjoined twins): autosit (main twin), heterosit (parasitic twin). CONCLUSION: The developmental mechanisms of twinning are discussed, special attention is paid to equal conjoined twins and to the possibilities of their early prenatal ultrasonographic diagnostics.

The comparative constitution of twinship: strategies and paradoxes.

In both traditional and modern societies, twinship, as an unusual mode of reproduction, involves difficulties for social systems in maintaining consistent classification systems. It is proposed that the most prevalent response to twinship involves various 'strategies of normalisation' to defuse and contain the potential disruption. This proposition is illustrated and analysed in relation to ethnographic maternal drawn mainly (but not exclusively) from African communities in the twentieth century. Following a discussion of twin infanticide as the most extreme of the normalising strategies, the article concludes by identifying a number of paradoxes in the social construction of twinship.

Errors in birth registrations and coding of twins and higher order multiples.

Dizygotic compared with monozygotic conceptions are at decreased risk of fetal and infant death and serious morbidity in surviving infants. Different sex twin maternities must be dizygotic but miscoding and incorrect registration of sex and number of fetuses may lead to an incorrect assignment of zygosity. The aim of the study was to validate the coding and registration of number and sex of births in multiple pregnancies. Fetal and infant death registrations from all multiple maternities in England and Wales 1993-1998 were examined. There were 51,792 twin, 1627 triplet and 51 higher order multiple maternities that were registered. Among these there were 1926 fetal deaths, 58 of which were registered as being of indeterminate sex but were coded as male in 56 and female in 2 cases. A fetus papyraceous was registered as male in 19 and as female in 19 cases. Other fetal deaths weighing >/= 100g, with no mention of papyraceous on the death certificate, nevertheless, likely to be of indeterminate sex, were registered as male in 26 and as female in 23 cases. In 13 maternities, the number of infants registered at birth was less than the number mentioned on the registration certificate. It cannot be assumed that multiple births of different registered sex are dizygotic. As surviving infants from a monozygotic multiple birth are at much greater risk of infant death and serious morbidity than dizygotic multiple births, incorrect assignment of sex has important implications for parental counselling and may have medico-legal relevance when attributing negligence as the cause of morbidity in a survivor from a multiple pregnancy.

Temperament, emotion, and cognition at fourteen months: the MacArthur Longitudinal Twin Study.

200 pairs of twins were assessed at 14 months of age in the laboratory and home. Measures were obtained of temperament, emotion, and cognition/language. Comparisons between identical and fraternal twin correlations suggest that individual differences are due in part to heritable influences. For temperament, genetic influence was significant for behavioral observations of inhibition to the unfamiliar, tester ratings of activity, and parental ratings of temperament. For emotion, significant genetic influence was found for empathy and parental ratings of negative emotion. The estimate of heritability for parental report of expression of negative emotions was relatively high, whereas that for expression of positive emotions was low, a finding consistent with previous research. For cognition and language, genetic influence was significant for behavioral indices of spatial memory, categorization, and word comprehension. Shared rearing environment appears influential for parental reports of language and for positive emotions, but not for other measures of emotion or for temperament.

Evaluation of zygosity diagnosis in twin pairs below age seven by means of a mailed questionnaire.

The mothers of a consecutive series of 125 same sexed pairs of twins aged 6 months to 6 1/2 years completed a mailed questionnaire concerning the physical similarity of the twin partners. Zygosity diagnoses were first determined blindly on the basis of the answers given by the mothers, who did not know the result of the blood group test when fulfilling the questionnaire. Next, the results were compared with the zygosity determination based on examination of erythrocyte-, serum- and enzyme-groups. It turned out that a few simple questions distinguished well enough between MZ and DZ pairs, with a frequency of misclassification of 4%, leaving 5% as unclassifiable. It is concluded that twin zygosity can be estimated by a simple questionnaire with sufficient accuracy even in very young twin pairs. This has relevant implications for more extensive twin studies where the use of a wide spectrum of serological characters would imply too high expenses.

Fetal growth and systolic blood pressure in young adulthood: the Swedish Young Male Twins Study.

The objective was to test the fetal origins hypothesis by examining the association between fetal growth and systolic blood pressure in a large cohort of adult male twins of known zygosity. This cohort study is based on a record linkage of routinely collected data from the Swedish Medical Birth Registry, the Swedish Military Conscription Registry and a mailed questionnaire. It comprises 886 pairs of same-sex male twins born in Sweden in 1973-79 for whom data were available on size at birth and systolic blood pressure, height and weight at age 17-19 years. Based on self-reported similarity of appearance in childhood, 384 twin pairs were classified as monozygotic (MZ), 269 as dizygotic (DZ) and 233 as of uncertain zygosity (XZ). Differences in systolic blood pressure within and between twin pairs were analysed in relation to birthweight and birthweight-for-gestational-age z-score using random effects linear models. Within twin pairs, a 1 kg difference in birthweight was associated with a difference of -1.30 mmHg in systolic blood pressure [95% confidence interval -4.15, +1.54] for MZ twins and +0.14 [-3.49, +3.76] for DZ twins; for all twins combined it was -0.21 [-2.13, +1.71]. Between twin pairs, a 1 kg difference in birthweight was associated with a difference of -2.68 mmHg in systolic blood pressure [-4.95, -0.42] for MZ twins and +0.28 [-2.35, +2.91] for DZ twins; for all twins combined -1.68 [-3.15, -0.22]. All these estimates included adjustment for age, year and conscription centre of examination, gestational age and height and weight at conscription. These results provide little support for the fetal origins hypothesis. The estimates of the within-pair effect in MZ twins and their wide confidence intervals (including zero) cannot exclude the existence of common genetic mechanisms, but are also not inconsistent with an in utero programming effect. This study highlights some methodological problems with twin studies.

The East Flanders Prospective Twin Survey (Belgium): a population-based register.

The East Flanders Prospective Twin Survey (EFPTS), started in 1964, is unique among the 17 major European twin registers because it is population based, the twins (and higher order births) are ascertained at birth, basic perinatal data are collected, chorion type is established and, when appropriate, genetic markers including DNA fingerprints, are determined. The total number of sets is 5089 twin, 158 triplet and 14 of higher order. Zygosity has been diagnosed on the basis of sex, placental structure and genetic markers in more than 95% of pairs. The EFPTS is the only large register that includes placental data and allows differentiation of three subtypes of monozygotic twins based on the time of the initial zygotic division: the dichorionic-diamnionic pairs (early), the monochorionic-diamnionic pairs (intermediate), and the monochorionic-monoamnionic pairs (late). Methodology and basic results in twins are considered in this article; detailed studies will be reported later. The sex proportion in dizygotic (DZ) twins is the same as in singletons, whereas monozygotic (MZ) twins number more girls than boys. The difference in perinatal mortality between DZ and MZ twins is limited to the monochorionic MZ subgroup. Birth weight is highest in DZ twins and diminishes stepwise in MZ dichorionic and MZ monochorionic twins. Duration of pregnancy follows the same trend but is limited to a few days. Iatrogenic pregnancies are increasing to the point of representing almost 50% of the twin births in 1997.

The East Flanders Prospective Twin Survey (EFPTS).

The East Flanders Prospective Twin Survey (EFPTS) is a registry of multiple births in the province of East-Flanders, Belgium. It has several unique features: it is population-based and prospective, with the possibility of long-term follow-up; the twins (and higher order multiple births) are ascertained at birth; basic perinatal data are recorded; chorion type and zygosity are established; and since 1969 placental biopsies have been taken and frozen at -20 degrees C for later determination of genetic markers. The EFPTS is the only large register that includes placental data and allows differentiation of three subtypes of monozygotic (MZ) twins based on the time of the initial zygotic division: the dichorionic-diamnionic pairs (early, before the fourth day after fertilisation), the monochorionic-diamnionic pairs (intermediate, between the fourth and the seventh day post fertilisation), and the monochorionic-monoamnionic pairs (late, after the eight day post fertilisation). This added a new dimension to didymology (the science of twins; delta iota delta upsilon mu omicron zeta = twins): the timing of twinning. Studies can be initiated on primary biases, those originating "in utero". Such studies may throw new light on the controversy over the validity of the classic twin method, the consequences of early embryological events (before and just after implantation of the embryo), the origin of congenital malformations, the sex proportion of multiples, the gene-environment interactions as far as intrauterine environment is concerned, to name but a few.