Talk:Abnormal Development - Twinning

Early research on human genetics using the twin method: who really invented the method?

Twin Res Hum Genet. 2009 Jun;12(3):237-45.

Mayo O.

CSIRO Livestock Industries, Australia. Oliver.Mayo@csiro.au

Abstract The twin method consists of a formal comparison between the resemblance between identical (monozygotic, MZ) twins and the resemblance between fraternal (dizygotic, DZ) twins for some trait of interest. It was developed between 1900 and about 1940, as more accurate tools for diagnosis of zygosity and for statistically analyzing the resemblance between relatives were built. Its early use was in the demonstration that a trait was inherited or that part of the causation of a trait was genetical, but it has now evolved to the point that twin registries constitute an important resource for the identification of specific genes and their interactions both with other genes and with the internal and external environment. Who really invented the method is still an unsettled question, which this article explores.

PMID: 19456215

A genome wide linkage scan for dizygotic twinning in 525 families of mothers of dizygotic twins.

Hum Reprod. 2010 Jun;25(6):1569-80. Epub 2010 Apr 8.

Painter JN, Willemsen G, Nyholt D, Hoekstra C, Duffy DL, Henders AK, Wallace L, Healey S, Cannon-Albright LA, Skolnick M, Martin NG, Boomsma DI, Montgomery GW.

Molecular Epidemiology, Genetic Epidemiology and Neurogenetics Laboratories, Queensland Institute of Medical Research, Brisbane, Australia. jodie.painter@qimr.edu.au Abstract

BACKGROUND: The tendency to conceive dizygotic (DZ) twins is a complex trait influenced by genetic and environmental factors. To search for new candidate loci for twinning, we conducted a genome-wide linkage scan in 525 families using microsatellite and single nucleotide polymorphism marker panels.

METHODS AND RESULTS: Non-parametric linkage analyses, including 523 families containing a total of 1115 mothers of DZ twins (MODZT) from Australia and New Zealand (ANZ) and The Netherlands (NL), produced four linkage peaks above the threshold for suggestive linkage, including a highly suggestive peak at the extreme telomeric end of chromosome 6 with an exponential logarithm of odds [(exp)LOD] score of 2.813 (P = 0.0002). Since the DZ twinning rate increases steeply with maternal age independent of genetic effects, we also investigated linkage including only families where at least one MODZT gave birth to her first set of twins before the age of 30. These analyses produced a maximum expLOD score of 2.718 (P = 0.0002), largely due to linkage signal from the ANZ cohort, however, ordered subset analyses indicated this result is most likely a chance finding in the combined dataset. Linkage analyses were also performed for two large DZ twinning families from the USA, one of which produced a peak on chromosome 2 in the region of two potential candidate genes. Sequencing of FSHR and FIGLA, along with INHBB in MODZTs from two large NL families with family specific linkage peaks directly over this gene, revealed a potentially functional variant in the 5' untranslated region of FSHR that segregated with the DZ twinning phenotype in the Utah family.

CONCLUSION: Our data provide further evidence for complex inheritance of familial DZ twinning.

PMID: 20378614 http://www.ncbi.nlm.nih.gov/pubmed/20378614

Heritability of testis size.

Twin Res Hum Genet. 2009 Aug;12(4):351-5.

Estourgie-van Burk GF, Bartels M, Delemarre-van de Waal HA, Boomsma DI.

Department of Pediatrics, VU University Medical Center, Amsterdam, the Netherlands. f.estourgie@vumc.nl Abstract Testis size is an important feature of male pubertal development. The genetic and environmental contributions to variation in human testis size have hardly been studied. We estimated the heritability of human testicular size in a group of mono- and dizygotic twins and their non-twin brothers (145 twins and 20 brothers from 95 families). Participants were 18 years old on average and all had reached Tanner development stage 4 or higher. Dizygotic twins and their siblings had a larger mean testis volume than monozygotic twins and their siblings. There was significant familial resemblance, with higher correlations in monozygotic twin pairs (0.59) than in dizygotic twin and sibling pairs (0.34). Heritability was estimated at 59% (95% CI = 37-75%), but a model that excluded genetic influences and attributed all familial resemblance to shared environment, fitted the data only marginally worse. The finding of larger mean testis volume in dizygotic twins may be of interest for future research into the mechanisms underlying dizygotic twinning.

PMID: 19653835

Lessons from BWS twins: complex maternal and paternal hypomethylation and a common source of haematopoietic stem cells.

Eur J Hum Genet. 2009 Dec;17(12):1625-34. Epub 2009 Jun 10.

Bliek J, Alders M, Maas SM, Oostra RJ, Mackay DM, van der Lip K, Callaway JL, Brooks A, van 't Padje S, Westerveld A, Leschot NJ, Mannens MM.

Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands. j.bliek@amc.uva.nl Abstract The Beckwith-Wiedemann syndrome (BWS) is a growth disorder for which an increased frequency of monozygotic (MZ) twinning has been reported. With few exceptions, these twins are discordant for BWS and for females. Here, we describe the molecular and phenotypic analysis of 12 BWS twins and a triplet; seven twins are MZ, monochorionic and diamniotic, three twins are MZ, dichorionic and diamniotic and three twins are dizygotic. Twelve twins are female. In the majority of the twin pairs (11 of 13), the defect on chromosome 11p15 was hypomethylation of the paternal allele of DMR2. In 5 of 10 twins, there was additional hypomethylation of imprinted loci; in most cases, the loci affected were maternally methylated, but in two cases, hypomethylation of the paternally methylated DLK1 and H19 DMRs was detected, a novel finding in BWS. In buccal swabs of the MZ twins who share a placenta, the defect was present only in the affected twin; comparable hypomethylation in lymphocytes was detected in both the twins. The level of hypomethylation reached levels below 25%. The exchange of blood cells through vascular connections cannot fully explain the degree of hypomethylation found in the blood cell of the non-affected twin. We propose an additional mechanism through which sharing of aberrant methylation patterns in discordant twins, limited to blood cells, might occur. In a BWS-discordant MZ triplet, an intermediate level of demethylation was found in one of the non-affected sibs; this child showed mild signs of BWS. This finding supports the theory that a methylation error proceeds and possibly triggers the twinning process.

PMID: 19513094 [PubMed - indexed for MEDLINE]

Mortality risk among preterm babies: immaturity versus underlying pathology.

Epidemiology. 2010 Jul;21(4):521-7.

Basso O, Wilcox A.

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. olga.basso@mcgill.ca Abstract BACKGROUND: Deaths among preterm births are presumably due to both immaturity and the conditions that cause preterm birth. Their relative contributions are unknown.

METHODS: Using US birth certificates (1995-2002), we estimated what portion of preterm neonatal mortality may be attributable to immaturity alone. Twins have elevated mortality, yet they usually have lower mortality than singletons at most preterm weeks. Twinning itself is a cause of early birth. Thus, at any given preterm week, singletons are more likely than twins to have pathologic causes of preterm delivery. If any such cause is associated with a mortality risk higher than that conferred by twinning, it is possible for singletons to have higher mortality than twins at some preterm weeks. Thus, mortality of twins at those weeks comes closer to describing the risk due to immaturity itself. To exclude high-risk babies, we focused on singletons and twins least likely to have suffered fetal growth disruptions (ie, those with "optimal" birth weight). At each gestational week from 24 to 36, we identified (for twins and singletons separately) the 500-gram weight category with the lowest neonatal mortality, and selected the lower of the 2 mortality rates.

RESULTS: Using the above as our best estimates of mortality due to immaturity alone, we calculated that about half the mortality of singleton preterm babies was due to the pathologies that cause early delivery.

CONCLUSIONS: Factors that cause preterm birth apparently contribute a large proportion of preterm mortality. If so, the prevention of preterm mortality requires more than the postponement of delivery.

PMID: 20407380 http://www.ncbi.nlm.nih.gov/pubmed/20407380

Temporal and territorial analysis of multiple deliveries in Spain (1900-2006).

Twin Res Hum Genet. 2010 Apr;13(2):207-16.

Fuster V, Zuluaga P, Román-Busto J, Colantonio SE.

Department of Zoology and Physical Anthropology, Faculty of Biology, Complutense University of Madrid and GEPS, Spain. vfuster@bio.ucm.es

Abstract Temporal variations in the frequency of multiple maternities in many Western European countries have been described. However, within a single country, regional differences are observed. Urban industrialized regions and rural agricultural areas have experienced in recent decades a distinct decline in multiple deliveries, which in cases have been related to maternal age and parity changes. Research on multiple deliveries in Spain is scarce and none of the studies go back to the beginning of the 20th century or consider regional variation over an extended period of time. The present paper is a yearly study on multiple deliveries in Spain since 1900 including a geographical analysis. Rather than dealing with recent changes in multi-parity, this paper is concerned with Spain's long-term national variation (between 1900 and 2006). The changing pattern of double and triple deliveries was analyzed using data from the Spanish National Statistics Institute (INE). Twinning rates in Spain are low in comparison to those of equivalent periods in other countries, and the minimum rates correspond to the 1980s decade. Results were interpreted by taking into account the influence of age at maternity and reproductive variation up to 1990. A good fit between observed and predicted rates was obtained after the application of models, which besides maternal age and parity, include their interaction. Regarding territorial variability, the values corresponding to southern, northern and insular Spanish provinces are consistent with an earlier reduction of the crude birth rate in the north-east regions and latter in the southern regions and the Canary Islands.

PMID: 20397751 http://www.ncbi.nlm.nih.gov/pubmed/20397751

Long-term neurodevelopmental outcome of monochorionic and matched dichorionic twins.

PLoS One. 2009 Aug 28;4(8):e6815.

Hack KE, Koopman-Esseboom C, Derks JB, Elias SG, de Kleine MJ, Baerts W, Go AT, Schaap AH, van der Hoeven MA, Eggink AJ, Sollie KM, Weisglas-Kuperus N, A Visser GH.

Department of Obstetrics, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, The Netherlands. k.e.a.hack@umcutrecht.nl Abstract BACKGROUND: Monochorionic (MC) twins are at increased risk for perinatal mortality and serious morbidity due to the presence of placental vascular anastomoses. Cerebral injury can be secondary to haemodynamic and hematological disorders during pregnancy (especially twin-to-twin transfusion syndrome (TTTS) or intrauterine co-twin death) or from postnatal injury associated with prematurity and low birth weight, common complications in twin pregnancies. We investigated neurodevelopmental outcome in MC and dichorionic (DC) twins at the age of two years.

METHODS: This was a prospective cohort study. Cerebral palsy (CP) was studied in 182 MC infants and 189 DC infants matched for weight and age at delivery, gender, ethnicity of the mother and study center. After losses to follow-up, 282 of the 366 infants without CP were available to be tested with the Griffiths Mental Developmental Scales at 22 months corrected age, all born between January 2005 and January 2006 in nine perinatal centers in The Netherlands. Due to phenotypic (un)alikeness in mono-or dizygosity, the principal investigator was not blinded to chorionic status; perinatal outcome, with exception of co-twin death, was not known to the examiner.

FINDINGS: Four out of 182 MC infants had CP (2.2%) - two of the four CP-cases were due to complications specific to MC twin pregnancies (TTTS and co-twin death) and the other two cases of CP were the result of cystic PVL after preterm birth - compared to one sibling of a DC twin (0.5%; OR 4.2, 95% CI 0.5-38.2) of unknown origin. Follow-up rate of neurodevelopmental outcome by Griffith's test was 76%. The majority of 2-year-old twins had normal developmental status. There were no significant differences between MC and DC twins. One MC infant (0.7%) had a developmental delay compared to 6 DC infants (4.2%; OR 0.2, 95% 0.0-1.4). Birth weight discordancy did not influence long-term outcome, though the smaller twin had slightly lower developmental scores than its larger co-twin.

CONCLUSIONS: There were no significant differences in occurrence of cerebral palsy as well as neurodevelopmental outcome between MC and DC twins. Outcome of MC twins seems favourable in the absence of TTTS or co-twin death.

PMID: 19714240 [PubMed - indexed for MEDLINE]