Methylenetetrahydrofolate Reductase Dimer Configuration as a Risk Factor for Maternal Meiosis I-Derived Trisomy 21

<b><i>Background:</i></b> Evidence suggests that the dimer configuration of methylenetetrahydrofolate reductase (MTHFR) enzyme might be destabilized by polymorphisms in monomers at the positions C677T and A1298C. It has been observed that these polymorphisms may lead to stable (CCAA, CCAC, CCCC) and unstable (CTAA, CTAC, TTAA) enzyme dimer configurations. <b><i>Objective:</i></b> The aim of this study was to evaluate the association of the MTHFR enzyme dimer configuration and folate dietary intake with the stage of meiotic nondisjunction in mothers of children with maternally derived trisomy 21. <b><i>Methods:</i></b> A total of 119 mothers of children with maternally derived free trisomy 21 were included in the study. The mean maternal age at the time of the birth of the child with trisomy 21 was 32.3 ± 6.4 (range 16–43) years. All mothers were Caucasian. Parental origin of trisomy 21 and meiotic stage of nondisjunction was determined using short tandem repeat markers spanning from the centromere to the telomere of chromosome 21q. The <i>MTHFR</i> C677T and <i>A1298C</i> polymorphism was evaluated by PCR-RFLP. <b><i>Results:</i></b> Increased frequency of the <i>MTHFR</i> genotype combinations CTAA, CTAC, and TTAA was found in the group of mothers with meiosis I (MI) nondisjunction (<i>p</i> = 0.007). No differences were found between study participants regarding dietary and lifestyles habits. <b><i>Conclusion:</i></b> The risk for MI nondisjunction of chromosome 21 was 4.6-fold higher in cases who had CTAA, CTAC, and TTAA <i>MTHFR</i> genotype combinations and who did not used folic acid supplements in the preconception period.

Mosaic Small Supernumerary Marker Chromosome Derived from Five Discontinuous Regions of Chromosome 8 in a Patient with Neutropenia and Oral Aphthous Ulcer

Small supernumerary marker chromosomes (sSMCs) are characterized as additional centric chromosome fragments which are too small to be classified by cytogenetic banding alone and smaller than or equal to the size of chromosome 20 of the same metaphase spread. Here, we report a patient who presented with slight neutropenia and oral aphthous ulcers. A mosaic de novo sSMC, which originated from 5 discontinuous regions of chromosome 8, was detected in the patient. Formation of the sSMC(8) can probably be explained by a multi-step process beginning with maternal meiotic nondisjunction, followed by post-zygotic anaphase lag, and resulting in chromothripsis. Chromothripsis is a chromosomal rearrangement which occurs by breakage of one or more chromosomes leading to a fusion of surviving chromosome pieces. This case is a good example for emphasizing the importance of conventional karyotyping from PHA-induced peripheral blood lymphocytes and examining tissues other than bone marrow in patients with inconsistent genotype and phenotype.

Characterization of prevalence and health consequences of uniparental disomy in four million individuals from the general population

SummaryMeiotic nondisjunction and resulting aneuploidy can lead to severe health consequences in humans. Aneuploidy rescue can restore euploidy but may result in uniparental disomy (UPD), the inheritance of both homologs of a chromosome from one parent with no representative copy from the other. Current understanding of UPD is limited to ~3,300 cases for which UPD was associated with clinical presentation due to imprinting disorders or recessive diseases. Thus, the prevalence of UPD and its phenotypic consequences in the general population are unknown. We searched for instances of UPD in over four million consented research participants from the personal genetics company 23andMe, Inc., and 431,094 UK Biobank participants. Using computationally detected DNA segments identical-by-descent (IBD) and runs of homozygosity (ROH), we identified 675 instances of UPD across both databases. Here we present the first characterization of UPD prevalence in the general population, a machine-learning framework to detect UPD using ROH, and a novel association between autism and UPD of chromosome 22.

Meiotic nondisjunction and sperm aneuploidy in humans

Infertility is relatively common affecting approximately 1-in-6 couples. Although the genetic basis of infertility is increasingly being uncovered, the contribution of male infertility often remains unexplained. The leading cause of pregnancy loss and cognitive impairment in humans is chromosome aneuploidy. Sperm aneuploidy is routinely evaluated by fluorescence in-situ hybridization. The majority of studies have reported similar findings, namely: 1) all men produce aneuploid sperm; 2) certain chromosomes are more prone to undergo chromosome nondisjunction; 3) infertile men typically have significantly higher levels of sperm aneuploidy compared to controls; and 4) the level of aneuploidy is often correlated with the severity of the infertility. Despite this, sperm aneuploidy screening is rarely evaluated in the infertility clinic. Within recent years, there appears to be renewed interest in the clinical relevance of sperm aneuploidy. We shall examine the gender differences in meiosis between the sexes, and explore why less emphasis is placed on the paternal contribution to aneuploidy. Increased sperm aneuploidy is often perceived to be modest and not clinically relevant, compared to the female contribution. However, even small increases in sperm aneuploidy may impact fertility and IVF cycle outcomes. Evidence demonstrating the clinical relevance of sperm aneuploidy will be discussed, as well as some of the challenges precluding widespread clinical implementation. Technological developments that may lead to widespread clinical implementation will be discussed. Recommendations will be suggested for specific patient groups that may benefit from sperm aneuploidy screening and whether preimplantation genetic testing for aneuploidy should be discussed with these patients.

A terhességet megelőzően alkalmazott hosszabb távú orális fogamzásgátlás mint a magzati 21-es triszómia lehetséges kockázatcsökkentő tényezője idős anyai életkorban vállalt terhességben

Down syndrome is the most common autosomal chromosomal abnormality. According to the classical interpretation, it is the result of meiotic nondisjunction. Its occurrence is more common in advanced maternal age. Despite intensive research, pathophysiology of this genetic disorder is not fully understood. According to recent studies, a different kind of mechanism may be found in the background of trisomy 21 than was previously considered. Based on the ovarian mosaicism model, the cause of trisomy 21 (or any common trisomy) is a segregation error of a chromosome in premeiotic mitosis. The cell entering meiosis will be an oocyte with preexisting trisomy, where its (so-called “secondary”) nondisjunction is essential. Maturation of the trisomic oocytes appears to fall behind the disomic oocytes, resulting in their relative accumulation in the ovaries as time progresses. The ratio of trisomic/disomic cells becomes less favorable in maternal maturity. If ovulation is inhibited – although the number of oocytes will continue to decline due to apoptosis – it can be assumed that the trisomic/disomic oocyte ratio remains more favorable with the progression of age. In our summary report, presenting and updating our previous data, we would like to propose that – according to ovarian mosaicism model – long-term oral contraception in the anamnesis may be beneficial in pregnancies with advanced maternal age. Orv Hetil. 2018; 159(28): 1146–1152.

The Origins and Consequences of Chromosome Pathology

To deal intelligently with common questions from “chromosomal families,” counselors need a broad knowledge of how gametes form, how chromosomes behave, and how the early conceptus grows. This chapter describes the ways in which chromosomes are transmitted, and the ways in which these processes can go wrong and lead to clinical abnormality. The distinction is made between “pure” aneuploidies, and abnormalities due to structural rearrangement. In particular, meiotic nondisjunction, with respect to the generation of pure aneuploidy, is discussed in considerable detail. The origins of chromosome mosaicism are reviewed. Mention is made of abnormalities due to epigenetic mechanisms.

Karyotype Analysis Activity

This classroom activity is based on a constructivist learning design and engages students in physically constructing a karyotype of three mock patients. Students then diagnose the chromosomal aneuploidy based on the karyotype, list the symptoms associated with the disorder, and discuss the implications of the diagnosis. This activity is targeted at undergraduates in a nonmajors genetics course, but the goals align with AP Biology Big Idea 3 and Next Generation Science Standards HS-LS3. The activity illustrates the relationship between genotype and phenotype, reinforces the chromosome theory of inheritance, and includes mapping of meiotic nondisjunction events.