Diagnosis Of Single Gene Disorders Research Articles

Non-invasive prenatal diagnosis of single gene disorders with enhanced relative haplotype dosage analysis for diagnostic implementation.

Non-invasive prenatal diagnosis of single-gene disorders (SGD-NIPD) has been widely accepted, but is mostly limited to the exclusion of either paternal or de novo mutations. Indeed, it is still difficult to infer the inheritance of the maternal allele from cell-free DNA (cfDNA) analysis. Based on the study of maternal haplotype imbalance in cfDNA, relative haplotype dosage (RHDO) was developed to address this challenge. Although RHDO has been shown to be reliable, robust control of statistical error and explicit delineation of critical parameters for assessing the quality of the analysis have not been fully addressed. We present here a universal and adaptable enhanced-RHDO (eRHDO) procedure through an automated bioinformatics pipeline with a didactic visualization of the results, aiming to be applied for any SGD-NIPD in routine care. A training cohort of 43 families carrying CFTR, NF1, DMD, or F8 mutations allowed the characterization and optimal setting of several adjustable data variables, such as minimum sequencing depth, type 1 and type 2 statistical errors, as well as the quality assessment of intermediate steps and final results by block score and concordance score. Validation was successfully performed on a test cohort of 56 pregnancies. Finally, computer simulations were used to estimate the effect of fetal-fraction, sequencing depth and number of informative SNPs on the quality of results. Our workflow proved to be robust, as we obtained conclusive and correctly inferred fetal genotypes in 94.9% of cases, with no false-negative or false-positive results. By standardizing data generation and analysis, we fully describe a turnkey protocol for laboratories wishing to offer eRHDO-based non-invasive prenatal diagnosis for single-gene disorders as an alternative to conventional prenatal diagnosis.

Non-invasive Prenatal Diagnosis of Single Gene Disorders by Paternal Mutation Exclusion: 3 Years of Clinical Experience

ABSTRACT Until recently, fetal genetic testing was possible only via invasive sampling (amniocentesis or chorionic villus sampling). Although such testing allows for prenatal diagnosis (PND) of inherited monogenetic disorders, it is also associated with a risk of miscarriage. Identification of cell-free fetal DNA (cfDNA) from maternal circulation allows for noninvasive fetal sex determination and detection of the common aneuploidies. In fact, the entire fetal genome is represented within the circulating cell-free DNA. Clinical services are now available that provide noninvasive PND for monogenetic disorders, although these remain sparse, and most tests of this nature focus on paternally inherited disorders, given that the fetal DNA is diluted by maternal haploidentical sequences. This study reports on an experimental protocol for droplet digital polymerase chain reaction for paternal pathogenic or de novo variants. Since then, this noninvasive PND service has been offered to couples at risk of monogenic disorders in the fetus who have requested PND as a part of standard care. This report summarizes 3 years of clinical experience. Referral indications included the following: those with 50% risk of transmission of an autosomal dominant disorder from the father, those at 25% risk of autosomal recessive disorders and with different parental pathogenic variants such that they could assess for inheritance of the paternal variant, and those at risk for single-gene disorders due to de novo variants based on evident skeletal dysplasia by ultrasound or possible parental germinal mosaicism in a previously affected child. As a matter of practicality and organization, only ongoing pregnancies had new assays designed and ordered. Local French law regarding prenatal genetic testing requires written consent from both parents. Blood from each pregnant woman and blood samples from both parents for extraction of conventional genomic DNA were also collected. Each new variant required creation of a new assay, whose performance was evaluated. All results were reported with summarized interpretations to the clinicians, and invasive diagnostic testing was recommended in cases of autosomal recessive variant identification where inheritance of the paternal variant was detected to identify maternal inheritance. Sampling errors and identity swaps were ruled out by taking a second sample for every negative result. Development of new assays took 7 to 43 days, and overall, these assays were designed to detect 57 individual variants in 16 genes. A result was obtained for all but 2 cases; these were unsuccessful because of a low proportion of fetal DNA. In the autosomal dominant cases, 27% found fetal inheritance of the paternal variant, whereas 73% ruled out such inheritance. In the autosomal recessive cases, the paternal variant was detected in 56% and not detected in the remainder. In cases in which the paternal variant was detected, invasive diagnostic testing was recommended to determine maternal inheritance and whether the fetus was affected. The single inconclusive result was from a pregnancy obtained after egg donation in which ultimately the egg donor and the father both had the same gene variant, making accurate assessment not possible. There were 198 referrals overall, including 22 referrals due to concern for autosomal dominant disorders, 69 due to risk for an autosomal recessive disorder, and 107 due to concern for a de novo variant either because of ultrasound findings or a family history. There were 202 tests performed for 175 different families. All results reported were considered valid, and there were no false-positive results following invasive sampling for maternal inheritance, and no false-negative results reported following delivery. A limitation of this technique is that it addresses only the paternal variant's fetal status. This approach does not allow testing for all types of disease-causing variations such as repetitive elements, copy number variations, or structural variants. Also, maternally transmitted diseases or recessive conditions with both parents as carriers are also not detectable through this method. In the case of multiple pregnancies, there is no method for determining which twin (or whether both twins) will carry the variant. This test allows couples to avoid the risk of miscarriage while being able to make informed decisions about the pregnancy management. In addition, as new treatments are developed for common disorders (CFTR modulators, gene-replacement therapies, uterine genic therapies, and splicing-modifying therapies), the prenatal testing landscape can be expected to drastically evolve to favor a noninvasive approach.

Non-invasive prenatal diagnosis of single gene disorders by paternal mutation exclusion: 3 years of clinical experience.

Cell-free fetal DNA (cffDNA) analysis is performed routinely for aneuploidy screening, RhD genotyping or sex determination. Although applications to single gene disorders (SGD) are being rapidly developed worldwide, only a few laboratories offer cffDNA testing routinely as a diagnosis service for this indication. In a previous report, we described a standardised protocol for non-invasive exclusion of paternal variant in SGD. Three years later, we now report our clinical experience with the protocol. Descriptive study. Multi-centre French. Indications for referral included pregnancies at risk of 25% or 50% of paternally inherited SGD, and pregnancies associated with an increased risk of SGD due to a de novo variant, either from strongly suggestive ultrasound findings or from a possible parental germinal mosaicism in the context of a previously affected child. Non-invasive prenatal diagnosis was performed using custom assays for droplet digital PCR. Feasibility, diagnostic performance and turn-around time were evaluated. Mean time for a new assay design and validation was evaluated at 14 days, and mean result reporting time was 6 days. All referred pathogenic variants could be targeted except one located in a complex genomic region. A result was obtained for every 198 referrals except two. This service was successfully implemented as a routine laboratory practice. It has been widely adopted by French clinicians and patients for paternal variant exclusion in various disorders. A robust approach to non-invasive prenatal exclusion of paternal pathogenic variant in a diagnosis setting.

The Genetic Basis of Strokes in Pediatric Populations and Insight into New Therapeutic Options.

Strokes within pediatric populations are considered to be the 10th leading cause of death in the United States of America, with over half of such events occurring in children younger than one year of life. The multifactorial etiopathology that has an influence on stroke development and occurrence signify the importance of the timely recognition of both modifiable and non-modifiable factors for adequate diagnostic and treatment approaches. The early recognition of a stroke and stroke risk in children has the potential to advance the application of neuroprotective, thrombolytic, and antithrombotic interventions and rehabilitation strategies to the earliest possible timepoints after the onset of a stroke, improving the outcomes and quality of life for affected children and their families. The recent development of molecular genetic methods has greatly facilitated the analysis and diagnosis of single-gene disorders. In this review, the most significant single gene disorders associated with pediatric stroke are presented, along with specific therapeutic options whenever they exist. Besides monogenic disorders that may present with stroke as a first symptom, genetic polymorphisms may contribute to the risk of pediatric and perinatal stroke. The most frequently studied genetic risk factors are several common polymorphisms in genes associated with thrombophilia; these genes code for proteins that are part of the coagulation cascade, fibrolysis, homocystein metabolism, lipid metabolism, or platelets. Single polymorphism frequencies may not be sufficient to completely explain the stroke causality and an analysis of several genotype combinations is a more promising approach. The recent steps forward in our understanding of the disorders underlying strokes has given us a next generation of therapeutics and therapeutic targets by which to improve stroke survival, protect or rebuild neuronal connections in the brain, and enhance neural function. Advances in DNA sequencing and the development of new tools to correct human gene mutations have brought genetic analysis and gene therapy into the focus of investigations for new therapeutic options for stroke patients.

930 Prenatal diagnosis of single gene disorders: indication, timing, and trends

Expanded or panethnic carrier screening for Single Gene Disorders (SGD) has increased the number of pregnancies identified as high-risk. Testing for SGD may also be performed when ultrasound (US) abnormalities are found. Our objective is to describe the circumstances of testing for SGD and to assess the impact of expanded screening. We identified pregnancies from 2015-2019 undergoing invasive testing in which testing for SGD was performed. SGD identified by carrier screening were categorized as those detectable by targeted screening, or only by expanded screening. Pregnancies in which invasive testing for SGD was performed due to carrier screening vs. US findings were compared using Fisher’s exact test, chi-square analysis, and Mann-Whitney U. Continuous data are expressed as Median [IQ Range]. A p-value <.05 was considered statistically significant. Of 1761 pregnancies undergoing invasive testing, testing for SGD was performed in 309 (17.5%). Testing was done due to carrier screening in 200 (64.7%) cases, for US findings in 86 (27.8%), and for other indications in 23 (7.4%). Preconception carrier screening was performed in most cases (53.1%). In 200 pregnancies at high-risk due to carrier screening, the most common SGD tested for were SMA (n=39), Fragile X (n=37), and CF (n=25). In 86 pregnancies at high-risk due to US, testing for Noonan Syndrome (n=64) and Skeletal Dysplasia (n=7) were most common. Invasive testing for SGD due to US findings was done at a later median gestational age, associated with higher rate of abortion, and a trend towards later median gestational age at abortion (Table 1). Between 2015 and 2019, a higher proportion of SGD identified by carrier testing could only be identified with expanded rather than targeted screening (Table 2). Though most invasive testing was performed for SGD that can be identified with targeted screening, the proportion of invasive testing for conditions detected only with expanded screening increased over time. Testing due to US findings is less common, though the majority of abortions for SGD were in this group.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Prenatal and preimplantation genetic diagnosis for single gene disorders: A population-based study from 1977 to 2016.

To examine the statewide utilisation of prenatal diagnosis (PNDx) and preimplantation genetic diagnosis (PGT-M) for single gene disorders. Population-based study of all women utilising PNDx in the Australian state of Victoria from 1977 to 2016. Single gene disorders were categorised using a systematic approach that aimed to reflect aspects of the PNDx decision-making process. Data on PGT-M for single gene disorders from 2005 to 2016 were similarly examined for comparison. Statistical significance testing was performed with χ2 test. Following an initial uptake period, annual PNDx rates for single gene disorders stabilised between 1.3 and 2.2 per 1000 births after the year 2000. The majority of PNDx (72%) was performed for disorders that primarily impair physical ability, while PNDx for adult onset conditions was rare (3%). PGT-M for single gene disorders has seen rapid growth since its introduction, and annual numbers now equal that of PNDx. In contrast to PNDx, one quarter of PGT-M tests were performed for adult onset conditions. Our population-wide analysis has demonstrated a steady demand for PNDx for single gene disorders over the past decade, in contrast to the rapidly increasing utilisation of PGT-M. PGT-M appears to be the preferred testing modality for adult onset disorders.

Concurrent preimplantation genetic diagnosis for single gene disorders and comprehensive chromosomal aneuploidy testing without whole genome amplification

Concurrent preimplantation genetic diagnosis for single gene disorders and comprehensive chromosomal aneuploidy testing without whole genome amplification

Noninvasive prenatal diagnosis for single gene disorders.

Noninvasive prenatal diagnosis for single gene disorders is coming to fruition in its clinical utility. The presence of cell-free DNA in maternal plasma has been recognized for many years, and a number of applications have developed from this. Noninvasive prenatal diagnosis for single gene disorders has lagged behind due to complexities of technology development, lack of investment and the need for validation samples for rare disorders. Publications are emerging demonstrating a variety of technical approaches and feasibility of clinical application. Techniques for analysis of cell-free DNA including digital PCR, next-generation sequencing and relative haplotype dosage have been used most often for assay development. Analysis of circulating fetal cells in the maternal blood is still being investigated as a viable alternative and more recently transcervical trophoblast cells. Studies exploring ethical and social issues are generally positive but raise concerns around the routinization of prenatal testing. Further work is necessary to make testing available to all patients with a pregnancy at risk of a single gene disorder, and it remains to be seen if the development of more powerful technologies such as isolation and analysis of single cells will shift the emphasis of noninvasive prenatal diagnosis. As testing becomes possible for a wider range of conditions, more ethical questions will become relevant.

Karyomapping: the gold standard for preimplantation genetic diagnosis

Preimplantation Genetic Diagnosis (PGD) has helped couples avoid inherited genetic diseases for over 25 years. Karyomapping can streamline this process with a high resolution and rapid result test design. This study is an evaluation of the Single Nucleotide Polymorphism (SNP)-based karyomapping platform as the best standard for preimplantation genetic diagnosis of single gene disorders, using an analysis of over 9,000 trophectoderm biopsies and 304 diverse genetic conditions.

Concise Review: Human Embryonic Stem Cells-What Have We Done? What Are We Doing? Where Are We Going?

Human pluripotent stem cells possess remarkable proliferative and developmental capacity and thus have great potential for advancement of cellular therapy, disease modeling, and drug discovery. Twelve years have passed since the first reported isolation of human embryonic stem cell lines (hESC), followed in October 2010 by the first treatment of a patient with hESC-based cellular therapy at the Shepherd Center in Atlanta. Despite seemingly insurmountable challenges and obstacles in the early days, hESC clinical potential reached application in an extraordinarily short time. Eight currently ongoing clinical trials are yielding encouraging results, and these are likely to lead to new trials for other diseases. However, with the discovery of induced pluripotent stem cells (iPSC), disease-specific hESC lines derived from patients undergoing preimplantation genetic diagnosis for single gene disorders fell short of expectations. Lack of ethical controversy made human iPSC (hiPSC) with specific genotypes/phenotypes more appealing than hESC for drug discovery and toxicology-related studies, and in time, lines from HLA-homologous hiPSC banks are likely to take over from hESC in clinical applications. Currently, hESC are indispensable; the results of hESC-based clinical trials will set a gold standard for future iPSC-based cellular therapy. Stem Cells 2017;35:17-25.

Prenatal diagnosis of single gene disorders using amniotic fluid as the starting material for PCR.

A rapid and inexpensive method for fetal genetic diagnosis using amniotic fluid (AF) as the starting material was demonstrated in this study. Raw AF was added directly to polymerase chain reaction (PCR) mixtures with HpH buffer (a high pH buffer), without any pre-treatment. Amplified products were detected by gel electrophoresis and then subjected to Sanger sequencing. The AF from four fetuses, each expressing a single gene disorder (achondroplasia, hypochondroplasia, thanatophoric dysplasia, or X-linked hypohidrotic ectodermal dysplasia), were analyzed. DNA fragments of different lengths were efficiently amplified from 8 μl of AF, allowing each of these single gene disorders to be successfully diagnosed. Although the amplification efficiency of the AF-PCR method is comparable to that of the Chelex method, the amount of the AF sample required was considerably lower than that required for the Chelex method (10 ml). This proposed method of diagnosis is more efficient, simpler, and less expensive, and reduces the chance of cross-contamination relative to the Chelex method, which requires purified DNA or other pre-treatment processes. Our method offers a promising tool that can be used for the diagnosis of various gene disorders in fetuses.

Development and validation of concurrent preimplantation genetic diagnosis for single gene disorders and comprehensive chromosomal aneuploidy screening without whole genome amplification

To develop a novel and robust protocol for multifactorial preimplantation genetic testing of trophectoderm biopsies using quantitative polymerase chain reaction (qPCR). Prospective and blinded. Not applicable. Couples indicated for preimplantation genetic diagnosis (PGD). None. Allele dropout (ADO) and failed amplification rate, genotyping consistency, chromosome screening success rate, and clinical outcomes of qPCR-based screening. The ADO frequency on a single cell from a fibroblast cell line was 1.64% (18/1,096). When two or more cells were tested, the ADO frequency dropped to 0.02% (1/4,426). The rate of amplification failure was 1.38% (55/4,000) overall, with 2.5% (20/800) for single cells and 1.09% (35/3,200) for samples that had two or more cells. Among 152 embryos tested in 17 cases by qPCR-based PGD and CCS, 100% were successfully given a diagnosis, with 0% ADO or amplification failure. Genotyping consistency with reference laboratory results was >99%. Another 304 embryos from 43 cases were included in the clinical application of qPCR-based PGD and CCS, for which 99.7% (303/304) of the embryos were given a definitive diagnosis, with only 0.3% (1/304) having an inconclusive result owing to recombination. In patients receiving a transfer with follow-up, the pregnancy rate was 82% (27/33). This study demonstrates that the use of qPCR for PGD testing delivers consistent and more reliable results than existing methods and that single gene disorder PGD can be run concurrently with CCS without the need for additional embryo biopsy or whole genome amplification.

Validation of next-generation sequencing for comprehensive chromosome screening of embryos

Massively parallel genome sequencing, also known as next-generation sequencing (NGS), is the latest approach for preimplantation genetic diagnosis. The purpose of this study was to determine whether NGS can accurately detect aneuploidy in human embryos. Low coverage genome sequencing was applied to trophectoderm biopsies of embryos at the blastocyst stage of development. Sensitivity and specificity of NGS was determined by comparison of results with a previously validated platform, array-comparative genomic hybridization (aCGH). In total, 156 samples (116 were blindly assessed) were tested: 40 samples were re-biopsies of blastocysts where the original biopsy specimen was previously tested for aCGH; four samples were re-biopsies of single blastomeres from embryos previously biopsied at the cleavage stage and tested using aCGH; 18 samples were single cells derived from well-characterized cell lines; 94 samples were whole-genome amplification products from embryo biopsies taken from previous preimplantation genetic screening cycles analysed using aCGH. Per embryo, NGS sensitivity was 100% (no false negatives), and 100% specificity (no false positives). Per chromosome, NGS concordance was 99.20%. With more improvement, NGS will allow the simultaneous diagnosis of single gene disorders and aneuploidy, and may have the potential to provide more detailed insight into other aspects of embryo viability.

Non‐invasive prenatal diagnosis for single gene disorders: experience of patients

The aim of this study is to explore women's experiences of using newly developed non-invasive prenatal diagnosis (NIPD) for single gene disorders. Methods used in this study include qualitative one-to-one interviews with eight women with pregnancies at risk of achondroplasia, Apert syndrome, thanatophoric dysplasia or a neuromuscular condition. The results of the study show that the women were positive about an accurate, safe, and early test. Where the foetus was at increased risk of inheriting a genetic condition, the benefits of NIPD over invasive testing were that it reduced the period of uncertainty and worry by being conducted within the first trimester. For those women for whom there was a low recurrence risk, the period of uncertainty could be reduced and pregnancy 'normalized' earlier. For women who would not have risked invasive testing, NIPD enabled them to have an early diagnostic test that was more accurate than ultrasound. Where ultrasound abnormalities were detected, NIPD ended the 'diagnostic odyssey', enabling women to make practical and psychological preparations for the birth. NIPD conducted through specialist services was considered most appropriate. NIPD for these particular single gene disorders was appreciated by women and appears to be satisfactory. Further exploration of stakeholder views may be required to inform more widespread implementation of NIPD for a broader range of genetic conditions.

Views and preferences for the implementation of non‐invasive prenatal diagnosis for single gene disorders from health professionals in the united kingdom

Non-invasive prenatal diagnosis (NIPD) will offer new options in prenatal diagnosis for carriers of single gene disorders. This will affect carrier couples and health professionals involved in prenatal care. The aim of this study was to determine health professional opinions on NIPD for single gene disorders to guide development of infrastructure required for implementation. A qualitative approach was adopted using focus groups (N = 17) and one-to-one interviews (N = 30) with health professionals from a range of backgrounds involved in caring for carriers of single gene disorders. Data were digitally recorded, transcribed verbatim and analyzed using thematic analysis. Participants were very positive about the introduction of NIPD, describing benefits arising from no risk of miscarriage, earlier testing and a simple procedure. A number of concerns for implementation were raised. Participants emphasized the need for the new test to be highly accurate and thoroughly validated. There was concern that people may not give as much thought to having a blood test compared to an invasive test or that it may be viewed as routine and as such NIPD may negatively impact on informed consent. In addition there was concern that the simplicity of a blood test may lead to increased pressure to test and terminate. However, participants felt these concerns could be overcome with thorough pre- and post-test counseling. To ensure high quality care, offering NIPD through genetics or other specialist services is essential. Ongoing education and training of health professionals will be important, and guidelines and regulation are needed for effective implementation.

O-21 Preimplantation genetic diagnosis for single gene disorders applied in GENETIKS Laboratory

O-21 Preimplantation genetic diagnosis for single gene disorders applied in GENETIKS Laboratory

O-24 Preimplantation genetic diagnosis of single-gene disorders: Experience with more than 250 cycles for 57 different monogenic conditions

O-24 Preimplantation genetic diagnosis of single-gene disorders: Experience with more than 250 cycles for 57 different monogenic conditions

Prenatal diagnosis of single gene disorders

Genetic disease can be due to imbalance of whole chromosomes, smaller microdeletions/duplications or at the single gene level where even a single base change can cause significant disease. This review focuses on those disorders caused by single gene defects and their diagnosis during pregnancy. In many cases the genomic location of a specific gene is known and the disease-causing mutation in a particular family may have been identified. In others, diagnosis may rely on other methodologies such as ultrasound or biochemical testing. Until recently this testing has relied upon invasive testing of a pregnancy. However non-invasive prenatal diagnosis to detect fetal DNA in maternal blood has now been introduced and its current and future utility is discussed.

Thymidylate synthase polymorphisms and risk of conotruncal heart defects

In this study, we investigated whether the two TYMS functional variants (28 bp VNTR and 1494del6) (275 cases and 653 controls) and six selected SNPs (265 case infants, 535 control infants; 169 case mothers and 276 control mothers) were associated with risks of conotruncal heart defects. Further, we evaluated interaction effects between these gene variants and maternal folate intake for risk of CTD. Cases with diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. DNA samples were collected using buccal brushes or drawn from the repository of newborn screening blood specimens when available. Genetic variants were treated as categorical variables (homozygous referent, heterozygote, homozygous variant). Odds ratios and 95% confidence intervals (CI) were computed to estimate risks among all subjects, Hispanic and non-Hispanic whites, respectively, using logistic regression. Gene-folate interactions were assessed for these variants by adding an interaction term to the logistic model. A dichotomized composite variable, "combined folate intake," was created by combining maternal peri-conceptional use of folic acid-containing vitamin supplements with daily dietary intake of folate. In general, the results do not show strong gene-only effects on risk of CTD. We did, however, observe a 3.6-fold increase in CTD risk (95% CI: 1.1-11.9) among infants who were homozygotes for the 6 bp deletion in the 3'-untranslated region (UTR) (1694del6) and whose mothers had low folate intake during the peri-conceptional period.

Gene variants in the folate‐mediated one‐carbon metabolism (FOCM) pathway as risk factors for conotruncal heart defects

We evaluated 35 variants among four folate-mediated one-carbon metabolism pathway genes, MTHFD1, SHMT1, MTHFR, and DHFR as risk factors for conotruncal heart defects. Cases with a diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. Odds ratios (OR) and the 95% confidence intervals (CI) were computed for each genotype (homozygous variant or heterozygote, vs. homozygous wildtype) and for increase of each less common allele (log-additive model). Interactions between each variant and three folate intake variables (maternal multivitamin use, maternal dietary folate intake, and combined maternal folate intake) were also evaluated under the log-additive model. In general, we did not identify notable associations. The A allele of MTHFD1 rs11627387 was associated with a 1.7-fold increase in conotruncal defects risk in both Hispanic mothers (OR = 1.7, 95% CI = 1.1-2.5) and Hispanic infants (OR = 1.7, 95% CI = 1.2-2.3). The T allele of MTHFR rs1801133 was associated with a 2.8-fold increase of risk among Hispanic women whose dietary folate intake was ≤ 25th centile. The C allele of MTHFR rs1801131 was associated with a two-fold increase of risk (OR = 2.0, 95% CI = 1.0-3.9) only among those whose dietary folate intake was >25th centile. Our study suggested that MTHFD1 rs11627387 may be associated with risk of conotruncal defects through both maternal and offspring genotype effect among the Hispanics. Maternal functional variants in MTHFR gene may interact with dietary folate intake and modify the conotruncal defects risk in the offspring.