Abstract
Down syndrome caused by presence of extra chromosome 21 originates from nondisjunction during parental gametogenesis. For overwhelming cases, the error occurs in oocyte and all the nondisjunction events are not stochastic. With increasing number of research efforts, it has come to know that maternal genetic architecture may be considered as risk factors for chromosomal errors. Polymorphisms of the genes involved in chromosome segregation, recombination and folic acid metabolisms have been investigated for their association with Down syndrome child birth. But the results are conflicting owing to ethnic and sociocultural differences. Here, we have discussed and summarized the outcome of the studies conducted on different population sample from different parts of world and tried to figure out the common polymorphisms, which could be used as makers for preconceptional screening of Down syndrome child birth risk among the women.
Keywords
- down syndrome
- maternal genotype
- polymorphism
- meiotic nondisjunction
1. Introduction
Down syndrome (DS), the most common form of live born intellectual disability in human is caused by trisomy condition of chromosome 21 (Ch21). The trisomy 21 condition arise from nonseparation or nondisjunction (NDJ) of Ch21 in germinal cells that leads to production of disomic gamete which upon fertilization with gamete with correct chromosome count from opposite sex produces trisomic zygote. For overwhelming majority of cases, the error arises in oocyte and this may be due to protracted phase of oocyte development. The lengthy process of oocyte maturation that includes two halts, one at meiotic I diplotene and another before the entry in second meiotic division, provides opportunity to environmental insults to accumulate in ovarian microenvironment that may perturb the process of chromosome segregation.
The first identified risk factor for Down syndrome birth is advanced maternal age of conception. It was identified that [1], women of age 32 years and above have higher risk of having Down syndrome baby. Subsequently, with the help of polymorphic variants of short tandem repeat (STR) makers on Ch21 scientists have characterized that recombination error may be the molecular risk factors for Ch21 NDJ. With elaborate analyses, considering both the maternal age and pattern of recombination, the US researcher group [2] and Indian researcher group [3] have characterized the interaction between maternal age and erroneous pattern of recombination on non-disjoined chromosome. No chiasma formation or single telomeric chiasma have been proved as risk of Ch21NDJ at MI among the younger mothers (age < 29 years). On contrary, single centromeric chiasma has been identified as risk factors for MII errors among the older women (age > 34 years).
With subsequent analyses of maternal molecular age, it has been proved that mothers of Down syndrome baby have shorter average telomere length than do the mothers of same chronological age and have euploid healthy baby [4, 5]. The authors proposed that a group of women may suffer from advanced molecular and genetic aging and intuitively carry predisposition for NDJ. It is really difficult to interpret whether NDJ is the result of rapid shortening of telomere or telomere shortening and NDJ are linked by some common risk factors, instead it can be said pleiotrophic effects of some genes may relate maternal aging with risk of NDJ. Moreover, frequent occurrence Ch21 NDJ among younger women reinforces the intuitive idea of genetic predisposition for Ch21 NDJ where advancing maternal age is not an issue.
As far as published literatures are concerned studies for identifying the genetic predisposition for DS child birth among the women are not sufficient. Very few initiatives in this regard have been recorded. Of them the recombination regulator genes and folate metabolism regulator genes are major. So, this chapter presents recent updates on finding of the gene polymorphisms that exhibited significant association with Down syndrome birth.
2. PR/SET domain 9 (PRDM9)
The gene is located on chromosome 5 (5p14.2). The protein coded by this gene is a zinc finger protein with histone methyltransferase activity that catalyzes trimethylation of histone H3 lysine 4 (H3K4me3) during meiotic prophase. This protein contains multiple domains, including a Kruppel-associated box (KRAB) domain, an SSX repression domain (SSXRD), a PRD1-BF1 and RIZ homologous region, a subclass of SET (PR/SET) domain, and a tandem array of C2H2 zinc fingers. The zinc finger array recognizes a short sequence motif of histone, leading to local H3K4me3, and meiotic recombination hotspot activity.
Experimental deletion of the gene in mice leads to the production of gametes blocked at pachytene of meiosis I that show a reduced number of Dmc1 loci, a protein that indicates the sites of meiotic crossovers [6]. The major allele A of PRDM9 binds a 13 bp DNA motif enriched at recombination hot spot, namely, CNCCNTNNCCNC [7]. Further, allelic variation in the zinc finger motif of PRDM9 exhibited association with differential hotspot usage in human recombination [8]. Carriers of PRDM9 minor alleles display reduced recombination at meiotic hotspots [8]. All these preceding observation led to the study [9] to inquire whether PRDM9 variants exhibit association with the recombination variation that underlies the NDJ events.
In this study [9] by US researcher group included 235 mothers having DS child and 85 controls having euploid baby. For characterizing the recombination profile along the 21q, the authors used genotyping with 1536 SNP loci on 21q by the Illumina Golden Gate Assay. The authors scored for 17% of cases of MI error without any recombination events carry homozygosity of minor alleles in contrast to only 2% of MI with single exchange category. The logistic regression analyses revealed women from MI without any exchange category are 2.45 times more likely to have risk of NDJ and Down syndrome birth than do the controls when carry at least one minor allele in heterozygous condition. The authors found less affinity of minor allele of ZF motif of PRDM9 and they tried to justify this reduced binding of PRDM9 to the recombination hotspot may cause lack of recombination events on 21q and NDJ of Ch21. This notion needs further confirmation by other studies on different DS populations of ethnic variations for considering as acceptable hypothesis.
3. Apolipoprotein E (APOE)
This gene is located on chromosome 19 (19q13.32) and encodes a protein which is essential for normal catabolism of triglyceride-rich lipoprotein. It binds to specific receptor on hepatocytes and peripheral cell receptors. Mutations in this gene leads to familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), which is characterized by increased plasma cholesterol and triglycerides due of impaired clearance of chylomicron and VLDL remnants. The gene is expressed specifically in liver, kidney, adipose, adrenal, spleen and neuronal tissues along with some other organs at low level.
Initial study that addressed the maternal APOE genotypes as risk factors of DS birth [10] reported presence of APOE4 allele among women may predispose them for MII NDJ at the younger age, but not at older age. The authors observed in young mothers with a meiosis II error, epsilon4 frequency was 30.0%, which was significantly higher than in older mothers with a meiosis II error (13.0%, P = 0.03).
But the study [11] conducted on Spanish population reported some opposite trend. The authors have observed an increased frequency of APOE4 allele among MI mother of age < 28 years as compared to MI mothers of age > 28 years. But this study did not confirm any association of maternal APOE4 genotype with MII error. The study on Colombian population [12] has revealed preferential occurrence of APOE4 allele in DS and their parents (11%) than among the controls (9%) though the difference was found insignificant statistically. More studies are needed to confirm the association between APOE4 allele in maternal genome and Ch21 NDJ.
4. Presenilin I (PSEN1)
This gene is located at the position 14q24.2 and known for its pleiotrophic effects. It has many isoforms that perform variety of functions. The polymorphisms of this gene were first reported for its association with Alzheimer disease. Later, it was tested for risk assessment in women having DS child.
As far as published literatures are concerned, only two studies have been conducted on PSEN 1 polymorphisms as a maternal risk factor for DS birth. The initial study was done on US population [13] where the authors find an association between a polymorphism in intron 8 of maternal genotype with DS birth. This study included168 probands with free trisomy 21 and recorded an increased frequency of allele 1 in mothers with a meiosis II error (70.8%) than among the mothers of meiosis I error (52.7%, P < 0.01), with an excess of the 11 genotype in the meiosis II mothers. Moreover, the author tested polymorphic variants of APOE gene and found the frequency of allele 1 in mothers carrying APOE4 allele (68.0%) was higher than in mothers without APOE4 (52.2%, P < 0.01). The author hypothesizes that the PSEN-1 intronic polymorphism might be involved in chromosomal nondisjunction through an influence on the expression level of PS-1 or due to linkage disequilibrium with biologically relevant polymorphisms in or outside the PS-1 gene.
Similar study was conducted on a population samples from India [14]. In this study, 170 Down syndrome patients, grouped according to maternal meiotic stage of NDJ and maternal age at conception, and their parents were genotyped for PSEN-1 intron-8 and APOE polymorphisms. The estimated frequencies of the PSEN-1 T allele and TT genotype, in the presence of the APOE4 allele, were significantly higher among young mothers (< 35 years) with meiosis II NDJ than in young control mothers (96.43 vs. 65.91% P = 0.0002 and 92.86 vs. 45.45% P < 0.0001, respectively) but not among mothers with meiosis I NDJ. The author hypothesized that the co-occurrence of the PSEN-1 T allele and the APOE 4 allele synergistically increases the risk of meiotic segregation error II among young.
5. Methylenetetrahydrofolate reductase (MTHFR)
This gene is located at 1p36.22 and the 12 exon long reading frame encodes an enzyme that catalyzes the reduction of 5,10-methylene tetra hydro folate to 5-methyl tetra hydro folate, which is required for the remethylation of homocystein to methionine. A common MTHFR 677C > T polymorphism (rs1801133) that results in Ala222Val amino acid substitution, is responsible for reduced enzyme activity. The homozygous TT genotype causes dimer destabilization under conditions of reduced folate availability [15, 16]. It was reported initially [17] in the year 1999, that increased plasma hcy level and an increased frequency of both MTHFR 677CT and TT genotypes among the mothers of DS individuals are strongly linked and since then this polymorphism has been tested in more than 30 case-control studies across the globe and confirmed this association with very few exceptions. As far as published literatures are concerned five large meta-analyses have been done till date between the year 2013 and 2014 to address this issue [18, 19, 20, 21, 22], with the latest one that includes data from 34 case-control studies for a total of 3.098 women having DS child and 4.852 control mothers [21]. The outcome of all these meta-analyses suggest that the overall risk as represented by odds ratio (OR), for the birth of a child with Trisomy21 to the women who are carriers of the 677 T allele ranges from 1.2 to 1.5 according to the various genetic models under investigation, i.e., allele contrast, dominant, recessive, co-dominant, etc. Subsequent data stratification into ethnic groups revealed that the risk is higher in Asians (OR = 1.5), and lower in Caucasians and/or other groups (OR usually ranging between 1.0 and 1.4) [19, 20, 22]. The meta-analyses performed by Wu et al. [19]; Yang et al. [20]; Rai et al. [21]; Victorino et al. [22] revealed that the frequency of the MTHFR 677 T allele is higher in Caucasian mother of DS child (ranging from 35.6 to 41.5%), followed by Brazilians (ranging from 33.5 to 33.9%), and lower in Asian populations (ranging from 20.0 to 32.3%). When epidemiological data were stratified according to the geographic origin of the mothers and found that the higher risk in Asians (OR = 1.53; 95% CI = 1.29–1.82), followed by Americans (OR = 1.23; 95% CI = 1.07–1.39), and the association remain insignificant for Europeans (OR = 1.04; 95% CI = 0.93–1.16) [21]. When the data was stratified according to latitude, exhibited a significant association of the MTHFR 677C > T polymorphism with DS birth insub-tropical populations (both TT vs. CC and CT vs. CC carriers), followed by tropical regions (only CT vs. CC carriers), but no significant effect was evident in the population from northern temperate region of the globe. These observations suggest complex gene–environment interactions, which might be a product of differences in allele frequencies among different populations in association with different nutritional status and exposure to environmental factors, such as solar radiation, that could interfere with folate bioavailability [16, 18, 22, 23]. Interestingly, scientists have observed association of the MTHFR 677C > T polymorphism with both chromosome 13 and 21 malsegregation events in lymphocytes from the mothers of DS child [23, 24].
Another common MTHFR polymorphism, the MTHFR 1298A > C one (rs1801131), causes Glu429Ala aminoacidic change. Meta-analysis revealed that the frequency of the MTHFR minor 1298C allele is higher in Asians (~40.0%), with little less frequency among Caucasians (~35.0%) and Brazilians (upto 25.0%) [22]. Interestingly, no studies have demonstrated MTHFR 1298A > C polymorphism is an independent maternal risk factor for the birth of a child with DS. Instead, However, case-control studies demonstrated that genotypes that carry both the MTHFR 677C > T and 1298A > C polymorphisms increase the maternal risk synergistically for a birth of a child with trisomy 21 more than the presence of the single polymorphic site MTHFR 677C > T one alone. These observations suggest intuitive functional interaction of both polymorphisms on protein stability and activity [25, 26, 27, 28, 29]. The maternal double homozygous 677TT-1298CC genotype leads to MTHFR protein instability and inactivity, often resulting in prenatal death [16].
6. Methionine synthase and methionine synthase reductase (MTR and MTRR )
The gene named as 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) or methionine synthase in short is located at 1q43 and carries 33 exons. It is a cobalamin-dependent enzyme that catalyzes the transmethylation of homocystein to methionine and MTRR, which is a NADPH-dependent diflavin enzyme, needed for activation of MTR. On the other hand the gene5-methyltetrahydrofolate-homocysteine methyltransferase reductase of MTRR is located at 5p15.31 in human genome. This protein functions in the synthesis of methionine by regenerating methionine synthase (MTR) to a functional state.
The second polymorphism of the gene
Recently, another
As far as published literatures on the MTR gene polymorphisms are concerned, the
7. Reduced folate carrier (RFC1 or SLC19A1 )
The gene is actually named
8. Cystathionine β-synthase (CBS )
The gene is located on chromsome21 at 21q22.3 and encodes a hemoprotein that catalyzes the condensation of hcy and serine to form cystathionine in the transsulfuration pathway. This enzyme is activated by adenosyl methionine and pyridoxal phosphate acts as co-factor in this reaction. So far published literatures are concerned two common polymorphisms have been studied as maternal risk factors for DS birth. One of them is an insertion of 68-bp within exon 8 that results in the duplication of a splice site at the intron7/exon 8 junction of the gene [43]. Very recent meta-analyses, performed with 825 mothers of DS child and 1.034 control did not find association of the
9. Methylenetetrahydrofolate dehydrogenase (MTHFD1 )
The genetic position of this gene is 14q23.3 and three distinct enzymatic activities, 5,10-methylenetetrahydrofolate-dehydrogenase,-5,10-methenyltetrahydrofolate-cyclohydrolase and 10-formyltetrahydrofolate synthetase. Each of these activities catalyzes one of the three sequential reactions in the interconversion of 1-carbon derivatives of tetrahydrofolate. The
10. Transcobalamin (TCN2 )
The gene is located on chromosome 22 at 22q12.2. This protein can bind cobalamin and helps in its cellular uptake by specific membrane receptors (TCR). The study of this gene for its association with DS birth is limited. A common variant
11. DNA methyltransferase 3B (DNMT3B )
This gene is located on chromosome 20 at 20q11.21 and encodes a de novo DNA methyl transferase. The enzyme is located primarily in nucleus and developmentally regulated. Two recent independent studies one on Italian and another on Indian population suggested the polymorphisms of DNMT3B might be associated with DS birth as maternal risk factors. In the study on Italian population [37] the authors genotyped 172 mothers with DS and 157 control mothers and found a decreased risk of birth of a child with DS among the mother who are carrier of DNMT3B 579G > T (rs1569686) minor allele T. Further, the author suggested that the combined
12. Serine-hydroxymethyltransferase (SHMT ), thymidylate synthase (TYMS ), and dihydrofolate reductase (DHFR )
The gene
13. Discussion and conclusion
Risk factors associated with Down syndrome birth the enigmatic. Both the genetic and environmental and habitual implications are known to be associated with DS birth. Regarding maternal genotypes that may impose risk of chromosome 21 nondisjunction in oocyte is extremely complicated owing to multifactorial nature of chromosome segregation system. It includes genes that are involved directly in chromosome segregation and also, cell cycle regulators, replication and recombination regulators, and metabolism regulators that maintain the optimum nutrient level affecting the genetic and epigenetic environment. In respect to recombination regulators, only gene that has been investigated in maternal genome is PRDM9. This study [9] is only known analyses on that gene and is needed to be replicated in other populations. Another gene is APOE that exhibited association with DS birth when APOE4 allele is present. Again very limited study has been conducted in this regard. Rest of the genes that have analyses so far in maternal genome for association with DS child are from folate metabolism regulators. Since the initial publication [17] on relation between DS birth risk and folate metabolism regulator polymorphisms in the year1999, several studies on different ethnic populations have been carried and the results are conflicting. But considering the gene X environment concept, it can be justified. The defects in folate metabolism pathways can only be manifested in term of chromosome segregation errors when genetic background interacts with nutritional status of the women. As the genetic background is different for different ethnic populations and as the nutritional level vary according to social architecture of given population, the association study gives different and contradictory results. Moreover, level of folic acid in grand maternal genome is of scientific concern as the oocytes starts growing in the fetal ovary.
In summary, it can be said that genetic architecture of maternal genome is needed to be explored in relation to prevention of DS child birth. Population specific genetic markers are needed to be developed in order to screen the women prior to their conception to test the genetic susceptibility for DS fetal conception. The biggest break through will come with highest level of application of basic research in biomedical field.
References
- 1.
Penrose LS. The relative effects of paternal and maternal age in mongolism. Journal of Genetics. 1933; 88 (1):9-14 - 2.
Oliver TR, Feingold E, Yu K, Cheung V, Tinker S, Yadav-Shah M, et al. New insights into human nondisjunction of chromosome 21 in oocytes. PLoS Genetics. 2008; 4 (3):e1000033. DOI: 10.1371/journal.pgen.1000033 - 3.
Ghosh S, Feingold E, Dey SK. Etiology of down syndrome: Evidence for consistent association among altered meiotic recombination, nondisjunction, and maternal age across populations. American Journal of Medical Genetics. Part A. 2009; 149A (7):1415-1420. DOI: 10.1002/ajmg.a.32932 - 4.
Ghosh S, Feingold E, Chakraborty S, Dey SK. Telomere length is associated with types of chromosome 21 nondisjunction: A new insight into the maternal age effect on down syndrome birth. Human Genetics. 2010; 127 (4):403-409. DOI: 10.1007/s00439-009-0785-8 - 5.
Albizua I, Rambo-Martin BL, Allen EG, He W, Amin AS, Sherman SL. Association between telomere length and chromosome 21 nondisjunction in the oocyte. Human Genetics. 2015; 134 (11-12):1263-1270. DOI: 10.1007/s00439-015-1603-0 - 6.
Hayashi K, Yoshida K, Matsui Y. A histone H3 methyltransferase controls epigenetic events required for meiotic prophase. Nature. 2005; 438 :374-378 - 7.
Myers S, Freeman C, Auton A, Donnelly P, McVean G. A common sequence motif associated with recombination hot spots and genome instability in humans. Nature Genetics. 2008; 40 :1124-1129 - 8.
Berg IL, Neumann R, Lam KWG, Sarbajna S, Odenthal-Hesse L, et al. PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans. Nature Genetics. 2010; 42 :859-863 - 9.
Oliver TR, Middlebrooks C, Harden A, Scott N, Johnson B, Jones J, et al. Variation in the zinc finger of PRDM9 is associated with the absence of recombination along nondisjoined chromosomes 21 of maternal origin. Journal of Down Syndrome & Chromosome Abnormalities. 2016; 2 (2):115. DOI: 10.4172/2472-1115.1000115 - 10.
Avramopoulos D, Mikkelsen M, Vassilopoulos D, Grigoriadou M, Petersen MB. Apolipoprotein E allele distribution in parents of down’s syndrome children. Lancet. 1996; 347 (9005):862-865 - 11.
Ezquerra M, Ballesta F, Queralt R, Aledo R, Gómez D, Guitart M, et al. Apolipoprotein E epsilon 4 alleles and meiotic origin of non-disjunction in down syndrome children and in their corresponding fathers and mothers. Neuroscience Letters. 1998; 248 (1):1-4 - 12.
Rengifo L, Gaviria D, Serrano H. APOE gene polymorphisms associated with down syndrome in Colombian populations. Biomédica. 2012; 32 (2):224-232. DOI: 10.1590/S0120-41572012000300010 - 13.
Petersen MB, Karadima G, Samaritaki M, Avramopoulos D, Vassilopoulos D, Mikkelsen M. Association between presenilin-1 polymorphism and maternal meiosis II errors in down syndrome. American Journal of Medical Genetics. 2000; 93 (5):366-372 - 14.
Bhaumik P, Ghosh P, Ghosh S, Feingold E, Ozbek U, Sarkar B, et al. Combined association of Presenilin-1 and Apolipoprotein E polymorphisms with maternal meiosis II error in down syndrome births. Genetics and Molecular Biology. 2017; 40 (3):577-585. DOI: 10.1590/1678-4685-GMB-2016-0138 - 15.
Guenther BD, Sheppard CA, Tran P, Rozen R, Matthews RG, Ludwig ML. The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia. Nature Structural Biology. 1999;6 :359-365. DOI: 10.1038/7594 - 16.
Martínez-Frías ML. The biochemical structure and function of methylenetetrahydrofolate reductase provide the rationale to interpret the epidemiological results on the risk for infants with down syndrome. American Journal of Medical Genetics Part A. 2008; 146A :1477-1482. DOI: 10.1002/ajmg.a.32308 - 17.
James SJ, Pogribna M, Pogribny IP, Melnyk S, Hine RJ, Gibson JB, et al. Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for down syndrome. The American Journal of Clinical Nutrition. 1999; 70 :495-501 - 18.
Costa-Lima MA, Amorim MR, Orioli IM. Association of methylenetetrahydrofolate reductase gene 677C>T polymorphism and down syndrome. Molecular Biology Reports. 2013; 40 :2115-2125. DOI: 10.1007/s11033-012-2270-z - 19.
Wu X, Wang X, Chan Y, Jia S, Luo Y, Tang W. Folate metabolism gene polymorphisms MTHFR C677T and A1298C and risk for down syndrome offspring: A meta-analysis. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2013; 167 :154-159. DOI: 10.1016/j.ejogrb.2012.11.022 - 20.
Yang M, Gong T, Lin X, Qi L, Guo Y, Cao Z, et al. Maternal gene polymorphisms involved in folate metabolism and the risk of having a down syndrome offspring: A meta-analysis. Mutagenesis. 2013; 28 :661-671. DOI: 10.1093/mutage/get045 - 21.
Rai V, Yadav U, Kumar P, Yadav SK, Mishra OP. Maternal methylenetetrahydrofolate reductase C677T polymorphism and down syndrome risk: A meta-analysis from 34 studies. PLoS One. 2014; 9 :e108552. DOI: 10.1371/journal.pone.0108552 - 22.
Victorino DB, Godoy MF, Goloni-Bertollo EM, Pavarino EC. Meta-analysis of methylenetetrahydrofolate reductase maternal gene in down syndrome: Increased susceptibility in women carriers of the MTHFR 677T allele. Molecular Biology Reports. 2014; 41 :5491-5504. DOI: 10.1007/s11033-014-3424-y - 23.
Coppedè F, Grossi E, Migheli F, Migliore L. Polymorphisms in folate-metabolizing genes, chromosome damage, and risk of Down syndrome in Italian women: Identification of key factors using artificial neural networks. BMC Med Genomics. 2010; 3 :42. DOI 10.1186/1755-8794-3-42 - 24.
Coppedè F. The complex relationship between folate/homocysteine metabolism and risk of down syndrome. Mutation Research. 2019; 682 :54-70. DOI: 10.1016/j.mrrev.2009.06.001 - 25.
Coppedè F, Colognato R, Bonelli A, Astrea G, Bargagna S, Siciliano G, et al. Polymorphisms in folate and homocysteine metabolizing genes and chromosome damage in mothers of down syndrome children. American Journal of Medical Genetics Part A. 2007; 143A :2006-2015. DOI: 10.1002/ajmg.a.31886 - 26.
Grillo LB, Acácio GL, Barini R, Pinto W Jr, Bertuzzo CS. Mutations in the methylene-tetrahydrofolate reductase gene and down syndrome. Cadernos de Saúde Pública. 2002; 18 :1795-1797. DOI: 10.1590/S0102-311X2002000600035 - 27.
Acácio GL, Barini R, Bertuzzo CS, Couto EC, Annichino-Bizzacchi M, Júnior WP. Methylenetetrahydrofolate reductase gene polymorphisms and their association with trisomy 21. Prenatal Diagnosis. 2005; 25 :1196-1199. DOI: 10.1002/pd.1296 - 28.
Scala I, Granese B, Sellitto M, Salomè S, Sammartino A, Pepe A, et al. Analysis of seven maternal polymorphisms of genes involved in homocysteine/folate metabolism and risk of down syndrome offspring. Genetics in Medicine. 2006; 8 :409-416. DOI: 10.1097/01.gim.0000228206.21793.82 - 29.
Brandalize AP, Bandinelli E, dos Santos PA, Roisenberg I, Schüler-Faccini L. Evaluation of C677T and A1298C polymorphisms of the MTHFR gene as maternal risk factors for down syndrome and congenital heart defects. American Journal of Medical Genetics Part A. 2009; 149A :2080-2087. DOI: 10.1002/ajmg.a.32989 - 30.
Zampieri BL, Biselli JM, Goloni-Bertollo EM, Vannucchi H, Carvalho VM, Cordeiro JA, et al. Maternal risk for down syndrome is modulated by genes involved in folate metabolism. Disease Markers. 2012; 32 :73-81. DOI: 10.1155/2012/693864 - 31.
Hobbs CA, Sherman SL, Yi P, Hopkins SE, Torfs CP, Hine RJ, et al. Polymorphisms in genes involved in folate metabolism as maternal risk factors for down syndrome. American Journal of Human Genetics. 2000; 67 :623-630. DOI: 10.1086/303055 - 32.
Medica I, Maver A, Goncalo Figueiredo A, Peterlin B. Polymorphisms in genes involved in folate metabolism as maternal risk factors for down syndrome—Meta-analysis. Central European Journal of Medicine. 2009; 4 :395-408. DOI: 10.2478/s11536-009-0055-0 - 33.
BalduinoVictorino D, de Godoy MF, Goloni-Bertollo EM, Pavarino ÉC. Genetic polymorphisms involved in folate metabolism and maternal risk for down syndrome: A meta-analysis. Disease Markers. 2014; 2014 :517504. DOI: 10.1155/2014/517504 - 34.
Coppedè F. The genetics of folate metabolism and maternal risk of birth of a child with down syndrome and associated congenital heart defects. Frontiers in Genetics. 2015; 6 :223. DOI: 10.3389/fgene.2015.00223 - 35.
Wang SS, Qiao FY, Feng L, Lv JJ. Polymorphisms in genes involved in folate metabolism as maternal risk factors for down syndrome in China. Journal of Zhejiang University Science B. 2008; 9 (2):93-99. DOI: 10.1631/jzus.B0710599 - 36.
Wang SS, Wang C, Qiao FY, Lv JJ, Feng L. Polymorphisms in genes RFC-1/CBS as maternal risk factors for down syndrome in China. Archives of Gynecology and Obstetrics. 2013; 288 :273-277. DOI: 10.1007/s00404-013-2760-9 - 37.
Bosco P, Guéant-Rodriguez RM, Anello G, Barone C, Namour F, Caraci F, et al. Methionine synthase (MTR) 2756 (A > G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are three risk factors for having a child with down syndrome. American Journal of Medical Genetics Part A. 2003; 121A :219-224. DOI: 10.1002/ajmg.a.20234 - 38.
Coppedè F, Bosco P, Tannorella P, Romano C, Antonucci I, Stuppia L, et al. DNMT3B promoter polymorphisms and maternal risk of birth of a child with down syndrome. Human Reproduction. 2013; 28 :545-550. DOI: 10.1093/humrep/des376 - 39.
Liao YP, Bao MS, Liu CQ , Liu H, Zhang D. Folate gene polymorphism and the risk of down syndrome pregnancies in young Chinese women. Yi Chuan. 2010; 32 :461-466. DOI: 10.3724/SP.J.1005.2010.00461 - 40.
Brandalize AP, Bandinelli E, Dos Santos PA, Schüler-Faccini L. Maternal gene polymorphisms involved in folate metabolism as risk factors for down syndrome offspring in Southern Brazil. Disease Markers. 2010; 29 :95-101. DOI: 10.1155/2010/250324 - 41.
Hou Z, Matherly LH. Biology of the major facilitative folate transporters SLC19A1 and SLC46A1. Current Topics in Membranes. 2014; 73 :175-204. DOI: 10.1016/b978-0-12-800223-0.00004-9 - 42.
Chango A, Fillon-Emery N, Mircher C, Bléhaut H, Lambert D, Herbeth B, et al. No association between common polymorphisms in genes of folate and homocysteine metabolism and the risk of down’s syndrome among French mothers. The British Journal of Nutrition. 2005; 94 :166-169. DOI: 10.1079/BJN20051490 - 43.
Coppedè F, Marini G, Bargagna S, Stuppia L, Minichilli F, Fontana I, et al. Folate gene polymorphisms and the risk of down syndrome pregnancies in young Italian women. American Journal of Medical Genetics Part A. 2006; 140 :1083-1091. DOI: 10.1002/ajmg.a.31217 - 44.
Sperandeo MP, de Franchis R, Andria G, Sebastio G. A 68-bp insertion found in a homocystinuric patient is a common variant and is skipped by alternative splicing of the cystathionine beta-synthase mRNA. American Journal of Human Genetics. 1996; 59 :1391-1393 - 45.
Shao Y, Zhang CG, Cui JH. Association of plasma homocysteine and cystathionine beta-synthase polymorphism with cerebral thrombosis. Di Yi Jun Yi Da Xue Xue Bao. 2005; 25 :351-353 - 46.
Zampieri BL, Biselli JM, Goloni-Bertollo EM, Pavarino EC. BHMT G742A and MTHFD1 G1958A polymorphisms and down syndrome risk in the Brazilian population. Genetic Testing and Molecular Biomarkers. 2012; 16 :628-631. DOI: 10.1089/gtmb.2011.0257 - 47.
Izci Ay O, Ay ME, Erdal ME, Cayan F, Tekin S, Soylemez F, et al. Folate metabolism gene polymorphisms and risk for down syndrome offspring in Turkish women. Genetic Testing and Molecular Biomarkers. 2015; 19 :191-197. DOI: 10.1089/gtmb.2014.0262 - 48.
von Castel-Dunwoody KM, Kauwell GP, Shelnutt KP, Vaughn JD, Griffin ER, Maneval DR, et al. Transcobalamin 776C->G polymorphism negatively affects vitamin B-12 metabolism. The American Journal of Clinical Nutrition. 2005; 81 (6):1436-1441. DOI: 10.1093/ajcn/81.6.1436 - 49.
Fintelman-Rodrigues N, Corrêa JC, Santos JM, Pimentel MM, Santos-Rebouças CB. Investigation of CBS, MTR, RFC-1 and TC polymorphisms as maternal risk factors for down syndrome. Disease Markers. 2009; 26 :155-161. DOI: 10.1155/2009/504625 - 50.
Jaiswal SK, Sukla KK, Kumari N, Lakhotia AR, Kumar A, Rai AK. Maternal risk for down syndrome and polymorphisms in the promoter region of the DNMT3B gene: A case-control study. Birth Defects Research Part A: Clinical and Molecular Teratology. 2015; 103 :299-305. DOI: 10.1002/bdra.23348 - 51.
Coppedè F, Migheli F, Bargagna S, Siciliano AI, Stuppia L, et al. Association of maternal polymorphisms in folate metabolizing genes with chromosome damage and risk of down syndrome offspring. Neuroscience Letters. 2009; 449 :15-19. DOI: 10.1016/j.neulet.2008.10.074 - 52.
Mendes CC, Biselli JM, Zampieri BL, Goloni-Bertollo EM, Eberlin MN, Haddad R, et al. 19-base pair deletion polymorphism of the dihydrofolate reductase (DHFR) gene: Maternal risk of down syndrome and folate metabolism. São Paulo Medical Journal. 2010; 128 :215-218. DOI: 10.1590/S1516-31802010000400008 - 53.
Marucci GH, Zampieri BL, Biselli JM, Valentin S, Bertollo EM, Eberlin MN, et al. Polymorphism C1420T of serine hydroxymethyltransferase gene on maternal risk for down syndrome. Molecular Biology Reports. 2012; 39 :2561-2566. DOI: 10.1007/s11033-011-1008-7 - 54.
Woeller CF, Anderson DD, Szebenyi DM, Stover PJ. Evidence for small ubiquitin-like modifier-dependent nuclear import of the thymidylate biosynthesis pathway. The Journal of Biological Chemistry. 2007; 282 :17623-17631. DOI: 10.1074/jbc.M702526200 - 55.
Horie N, Aiba H, Oguro K, Hojo H, Takeishi K. Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene for thymidylate synthase. Cell Structure and Function. 1995; 20 :191-197. DOI: 10.1247/csf.20.191 - 56.
Ulrich CM, Bigler J, Bostick R, Fosdick L, Potter JD. Thymidylate synthase promoter polymorphism, interaction with folate intake, and risk of colorectal adenomas. Cancer Research. 2002; 62 :3361-3364