Publications by authors named "Ignatia B Van den Veyver"

70 Publications

DNA Methylation Dynamics in the Female Germline and Maternal-Effect Mutations That Disrupt Genomic Imprinting.

Genes (Basel) 2021 Aug 6;12(8). Epub 2021 Aug 6.

Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, USA.

Genomic imprinting is an epigenetic marking process that results in the monoallelic expression of a subset of genes. Many of these 'imprinted' genes in mice and humans are involved in embryonic and extraembryonic growth and development, and some have life-long impacts on metabolism. During mammalian development, the genome undergoes waves of (re)programming of DNA methylation and other epigenetic marks. Disturbances in these events can cause imprinting disorders and compromise development. Multi-locus imprinting disturbance (MLID) is a condition by which imprinting defects touch more than one locus. Although most cases with MLID present with clinical features characteristic of one imprinting disorder. Imprinting defects also occur in 'molar' pregnancies-which are characterized by highly compromised embryonic development-and in other forms of reproductive compromise presenting clinically as infertility or early pregnancy loss. Pathogenic variants in some of the genes encoding proteins of the subcortical maternal complex (SCMC), a multi-protein complex in the mammalian oocyte, are responsible for a rare subgroup of moles, biparental complete hydatidiform mole (BiCHM), and other adverse reproductive outcomes which have been associated with altered imprinting status of the oocyte, embryo and/or placenta. The finding that defects in a cytoplasmic protein complex could have severe impacts on genomic methylation at critical times in gamete or early embryo development has wider implications beyond these relatively rare disorders. It signifies a potential for adverse maternal physiology, nutrition, or assisted reproduction to cause epigenetic defects at imprinted or other genes. Here, we review key milestones in DNA methylation patterning in the female germline and the embryo focusing on humans. We provide an overview of recent findings regarding DNA methylation deficits causing BiCHM, MLID, and early embryonic arrest. We also summarize identified SCMC mutations with regard to early embryonic arrest, BiCHM, and MLID.
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http://dx.doi.org/10.3390/genes12081214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394515PMC
August 2021

Improving the prenatal diagnosis of Beckwith-Wiedemann syndrome.

Prenat Diagn 2021 06 25;41(7):795-797. Epub 2021 May 25.

Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA.

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http://dx.doi.org/10.1002/pd.5971DOI Listing
June 2021

Overview and recent developments in cell-based noninvasive prenatal testing.

Prenat Diagn 2021 Sep 18;41(10):1202-1214. Epub 2021 May 18.

Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Investigators have long been interested in the natural phenomenon of fetal and placental cell trafficking into the maternal circulation. The scarcity of these circulating cells makes their detection and isolation technically challenging. However, as a DNA source of fetal origin not mixed with maternal DNA, they have the potential of considerable benefit over circulating cell-free DNA-based noninvasive prenatal genetic testing (NIPT). Endocervical trophoblasts, which are less rare but more challenging to recover are also being investigated as an approach for cell-based NIPT. We review published studies from around the world describing both forms of cell-based NIPT and highlight the different approaches' advantages and drawbacks. We also offer guidance for developing a sound cell-based NIPT protocol.
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http://dx.doi.org/10.1002/pd.5957DOI Listing
September 2021

Reproductive Outcomes from Maternal Loss of Nlrp2 Are Not Improved by IVF or Embryo Transfer Consistent with Oocyte-Specific Defect.

Reprod Sci 2021 07 22;28(7):1850-1865. Epub 2020 Oct 22.

Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, USA.

Nlrp2 encodes a protein of the oocyte subcortical maternal complex (SCMC), required for embryo development. We previously showed that loss of maternal Nlrp2 in mice causes subfertility, smaller litters with birth defects, and growth abnormalities in offspring, indicating that Nlrp2 is a maternal effect gene and that all embryos from Nlrp2-deficient females that were cultured in vitro arrested before the blastocysts stage. Here, we used time-lapse microscopy to examine the development of cultured embryos from superovulated Nlrp2-deficient and wild-type mice after in vivo and in vitro fertilization. Embryos from Nlrp2-deficient females had similar abnormal cleavage and fragmentation and arrested by blastocyst stage, irrespective of fertilization mode. This indicates that in vitro fertilization does not further perturb or improve the development of cultured embryos. We also transferred embryos from superovulated Nlrp2-deficient and wild-type females to wild-type recipients to investigate if the abnormal reproductive outcomes of Nlrp2-deficient females are primarily driven by oocyte dysfunction or if a suboptimal intra-uterine milieu is a necessary factor. Pregnancies with transferred embryos from Nlrp2-deficient females produced smaller litters, stillbirths, and offspring with birth defects and growth abnormalities. This indicates that the reproductive phenotype is oocyte-specific and is not rescued by development in a wild-type uterus. We further found abnormal DNA methylation at two maternally imprinted loci in the kidney of surviving young adult offspring, confirming persistent DNA methylation disturbances in surviving offspring. These findings have implications for fertility treatments for women with mutations in NLRP2 and other genes encoding SCMC proteins.
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http://dx.doi.org/10.1007/s43032-020-00360-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060370PMC
July 2021

The effect of maternal body mass index and gestational age on circulating trophoblast yield in cell-based noninvasive prenatal testing.

Prenat Diagn 2020 10 5;40(11):1383-1389. Epub 2020 Aug 5.

Luna Genetics, Houston, Texas, USA.

Objective: To examine the effects of maternal body mass index (BMI) and gestational age (GA) on the number of single circulating trophoblasts (SCT).

Methods: Maternal blood was collected in 20 to 40 mL. All singleton pregnant women at any gestation were recruited. Trophoblasts were recovered by immunomagnetic enrichment and stained for cytokeratin and CD45. Candidate trophoblasts were identified by fluorescence microscopy.

Results: Blood samples were collected from 425 singleton pregnancies from April 2018 to December 2019. At least one candidate cell was identified in 88% (373/425). There was an inverse correlation between trophoblasts yield and increasing BMI (r = -0.19, P < .001). The mean ± SD number of trophoblasts/mL was 0.12  ± 0.22 in the underweight group (n = 5), 0.23 ± 0.25 in the normal weight (n = 169), 0.18 ± 0.19 in the overweight (n = 114), and 0.13 ± 0.15 in the obese (n = 109). Significantly more cells were identified in the normal weight than those in the obese (P = .001). In addition, the mean ± SD number of cells/mL was 0.21  ± 0.21 at GA of 10 to 14 weeks (n = 260), 0.14 ± 0.23 at GA ≥15 (n = 102) and 0.12 ± 0.12 at GA <10 (n = 63); P < .001.

Conclusion: The lower number of SCT was identified from the samples of women with a high BMI. Cell recovery for SCT testing seems optimal at GA of 10 to 14 weeks, but earlier and later testing is still possible.
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http://dx.doi.org/10.1002/pd.5755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688572PMC
October 2020

Prenatal testing in pregnancies conceived by in vitro fertilization with pre-implantation genetic testing.

Prenat Diagn 2020 06 20;40(7):846-851. Epub 2020 May 20.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Objective: Women with pregnancies resulting from in vitro fertilization (IVF) with normal pre-implantation genetic testing for aneuploidy (PGT-A) are advised to undergo prenatal screening and testing during pregnancy. It is not well known how many follow these recommendations. Our objective was to study prenatal testing decisions made by women with pregnancies conceived through IVF with PGT-A.

Methods: We performed a retrospective review of women who received genetic counseling during pregnancies conceived through IVF with normal PGT-A. We excluded those who received genetic counseling preconceptionally prior to IVF. Statistical analysis included descriptive statistics and after testing for normality by the Kolmogorov-Smirnov test, independent t test, Mann-Whitney U test, or Chi-square/Fisher's exact test.

Results: Data from 83 women were included. Of these, 53 (63.9%) had at least one of the following prenatal tests: first trimester combined screening (16.9%), non-invasive prenatal screening (NIPS) (45.8%), second trimester serum screening (6%), and invasive diagnostic testing (6%). 10.8% had more than one of the above tests and 36.1% declined all tests.

Conclusion: Almost two-thirds of women who were pregnant after IVF with normal PGT-A had prenatal aneuploidy screening or testing. Future prospective studies with larger cohorts are needed to further ascertain decision making in this population.
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http://dx.doi.org/10.1002/pd.5711DOI Listing
June 2020

Current controversies in prenatal diagnosis 2: The 59 genes ACMG recommends reporting as secondary findings when sequencing postnatally should be reported when detected on fetal (and parental) sequencing.

Prenat Diagn 2020 12 17;40(12):1508-1514. Epub 2020 Apr 17.

Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA.

Genome sequencing is increasingly being used to aid genetic diagnosis in fetuses with structural abnormalities detected on ultrasound examination. However, with clinical exome and genome sequencing, there is potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing, but of potential medical value for patient care. In the postnatal setting, the American College of Medical Genetics and Genomics (ACMG) has clear guidelines that state that when offering sequencing, secondary findings should be reported in 59 genes for which ACMG consider there is a clinical evidence that pathogenic variants may result in disease that might be prevented or treated, with the option to opt out of receiving this information. However, these guidelines specifically exclude prenatal sequencing. Here, we report the debate on whether or not pathogenic findings in these 59 genes should or should not be reported in the prenatal setting. Although more were in favour of reporting before the debate, there was no significant consensus from the audience. After the debate there was a swing toward not reporting, but a slim majority (55%) remained in favour, indicating that this is an area requiring further research and the development of evidence-based guidelines applicable to prenatal proband and trio sequencing.
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http://dx.doi.org/10.1002/pd.5670DOI Listing
December 2020

Validation Studies for Single Circulating Trophoblast Genetic Testing as a Form of Noninvasive Prenatal Diagnosis.

Am J Hum Genet 2019 12 27;105(6):1262-1273. Epub 2019 Nov 27.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address:

It has long been appreciated that genetic analysis of fetal or trophoblast cells in maternal blood could revolutionize prenatal diagnosis. We implemented a protocol for single circulating trophoblast (SCT) testing using positive selection by magnetic-activated cell sorting and single-cell low-coverage whole-genome sequencing to detect fetal aneuploidies and copy-number variants (CNVs) at ∼1 Mb resolution. In 95 validation cases, we identified on average 0.20 putative trophoblasts/mL, of which 55% were of high quality and scorable for both aneuploidy and CNVs. We emphasize the importance of analyzing individual cells because some cells are apoptotic, in S-phase, or otherwise of poor quality. When two or more high-quality trophoblast cells were available for singleton pregnancies, there was complete concordance between all trophoblasts unless there was evidence of confined placental mosaicism. SCT results were highly concordant with available clinical data from chorionic villus sampling (CVS) or amniocentesis procedures. Although determining the exact sensitivity and specificity will require more data, this study further supports the potential for SCT testing to become a diagnostic prenatal test.
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http://dx.doi.org/10.1016/j.ajhg.2019.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904821PMC
December 2019

The current and future impact of genome-wide sequencing on fetal precision medicine.

Hum Genet 2020 Sep 21;139(9):1121-1130. Epub 2019 Nov 21.

Department of Obstetrics and Gynecology, Baylor College of Medicine, 1250 Moursund Street, Room 1025.14, Houston, TX, 77030, USA.

Next-generation sequencing and other genomic technologies are transforming prenatal and reproductive screening and testing for fetal genetic disorders at an unprecedented pace. Original approaches of screening and testing for fetal genetic and genomic disorders were focused on a few more prevalent conditions that were easily diagnosable with pre-genomic era diagnostic tools. First, chromosomal microarray analysis and then next-generation sequencing brought technology capable of more detailed genomic evaluation to prenatal genetic screening and diagnosis. This has facilitated parallel introduction of a variety of new tests on maternal blood samples, including expanded carrier screening and cell-free DNA-based non-invasive screening for fetal aneuploidy, selected copy number variants, and single-gene disorders. Genomic tests on fetal DNA samples, obtained primarily through amniocentesis or chorionic villus sampling, include chromosomal microarray analysis and gene panel and exome sequencing. All these form the diagnostic pillar of the emerging field of fetal precision medicine, but their implementation is associated with ethical, counseling and healthcare resource utilization challenges. We discuss where in the reproductive and prenatal care continuum these exciting new technologies are integrated, along with associated challenges. We propose areas of priority for research to gain the data in support of their responsible implementation into clinical reproductive and prenatal care.
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http://dx.doi.org/10.1007/s00439-019-02088-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239720PMC
September 2020

Maternal stress in Shank3ex4-9 mice increases pup-directed care and alters brain white matter in male offspring.

PLoS One 2019 8;14(11):e0224876. Epub 2019 Nov 8.

Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, United States of America.

Gene-environment interactions contribute to the risk for Autism Spectrum Disorder (ASD). Among environmental factors, prenatal exposure to stress may increase the risk for ASD. To examine if there is an interaction between exposure to maternal stress and reduced dosage or loss of Shank3, wild-type (WT), heterozygous (HET) and homozygous (HOM) female mice carrying a deletion of exons four through nine of Shank3 (Shank3ex4-9) were exposed to chronic unpredictable mild stress (CUMS) from prior to conception throughout gestation. This study examined maternal care of these dams and the white matter microstructure in the brains of their adult male offspring. Overall, our findings suggest that maternal exposure to CUMS increased pup-directed care for dams of all three genotypes. Compared to WT and HET dams, HOM dams also exhibited increased maternal care behaviors with increased time spent in the nest and reduced cage exploration, regardless of exposure to CUMS. Diffusion tensor imaging showed higher mean fractional anisotropy in the hippocampal stratum radiatum of WT and HOM male offspring from dams exposed to CUMS and HOM offspring from unexposed dams, compared to WT male offspring from unexposed dams. These data support that CUMS in Shank3-mutant dams results in subtle maternal care alterations and long-lasting changes in the white matter of the hippocampus of their offspring.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224876PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839842PMC
March 2020

Prenatally diagnosed developmental abnormalities of the central nervous system and genetic syndromes: A practical review.

Prenat Diagn 2019 08 28;39(9):666-678. Epub 2019 Jul 28.

Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas.

Developmental brain abnormalities are complex and can be difficult to diagnose by prenatal imaging because of the ongoing growth and development of the brain throughout pregnancy and the limitations of ultrasound, often requiring fetal magnetic resonance imaging as an additional tool. As for all major structural congenital anomalies, amniocentesis with chromosomal microarray and a karyotype is the first-line recommended test for the genetic work-up of prenatally diagnosed central nervous system (CNS) abnormalities. Many CNS defects, especially neuronal migration defects affecting the cerebral and cerebellar cortex, are caused by single-gene mutations in a large number of different genes. Early data suggest that prenatal diagnostic exome sequencing for fetal CNS defects will have a high diagnostic yield, but interpretation of sequencing results can be complex. Yet a genetic diagnosis is important for prognosis prediction and recurrence risk counseling. The evaluation and management of such patients is best done in a multidisciplinary team approach. Here, we review general principles of the genetic work-up for fetuses with CNS defects and review categories of genetic causes of prenatally diagnosed CNS phenotypes.
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http://dx.doi.org/10.1002/pd.5520DOI Listing
August 2019

Paralog Studies Augment Gene Discovery: DDX and DHX Genes.

Am J Hum Genet 2019 08 27;105(2):302-316. Epub 2019 Jun 27.

Division of Nephrology, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.

Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.
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http://dx.doi.org/10.1016/j.ajhg.2019.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698803PMC
August 2019

Publisher Correction: Non-invasive prenatal sequencing for multiple Mendelian monogenic disorders using circulating cell-free fetal DNA.

Nat Med 2019 Apr;25(4):701-702

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

In the version of this article originally published, some cases that were presented in Fig. 3 should have been underlined but were not. The appropriate cases have now been underlined. The error has been corrected in the print, PDF and HTML versions of the article.
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http://dx.doi.org/10.1038/s41591-019-0391-9DOI Listing
April 2019

The uptake of pan-ethnic expanded carrier screening is higher when offered during preconception or early prenatal genetic counseling.

Prenat Diagn 2019 03 1;39(4):319-323. Epub 2019 Mar 1.

Department of Obstetrics and Gynecology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA.

Objective: To examine factors that influence uptake of expanded carrier screening (ECS) among women undergoing preconception and prenatal genetic counseling.

Methods: We retrospectively reviewed 500 medical records from women with prenatal or preconception genetic counseling at a prenatal genetic counseling service. We tabulated acceptance of ECS by indication for genetic counseling along with demographic and pregnancy-related factors.

Results: ECS was offered to 483 of 500 women, and 192 (39.8%) accepted. Of the 67 women counseled preconceptionally, 46 (68.7%) accepted ECS. This was significantly more than for 416 women counseled during pregnancy, of whom 146 (35.1%) accepted (P ≤ 0.001). For pregnant patients, the mean gestational age of those accepting ECS (12 weeks 3 days; n = 146) was significantly lower than those declining (13 weeks 4 days; n = 270; P ≤ 0.001). The acceptance rates were 7 of 12 (58.3%, P = 0.195) for Ashkenazi Jewish women, 12 of 41 (29.3%; P = 0.186) for Asian women, and 7 of 25 (28.0%; P = 0.241) for women of mixed ethnicity.

Conclusions: These results suggest that receiving genetic counseling prior to or earlier in the first trimester is associated with acceptance of ECS and support the importance of early genetic counseling about carrier screening options.
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http://dx.doi.org/10.1002/pd.5434DOI Listing
March 2019

Non-invasive prenatal sequencing for multiple Mendelian monogenic disorders using circulating cell-free fetal DNA.

Nat Med 2019 03 28;25(3):439-447. Epub 2019 Jan 28.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Current non-invasive prenatal screening is targeted toward the detection of chromosomal abnormalities in the fetus. However, screening for many dominant monogenic disorders associated with de novo mutations is not available, despite their relatively high incidence. Here we report on the development and validation of, and early clinical experience with, a new approach for non-invasive prenatal sequencing for a panel of causative genes for frequent dominant monogenic diseases. Cell-free DNA (cfDNA) extracted from maternal plasma was barcoded, enriched, and then analyzed by next-generation sequencing (NGS) for targeted regions. Low-level fetal variants were identified by a statistical analysis adjusted for NGS read count and fetal fraction. Pathogenic or likely pathogenic variants were confirmed by a secondary amplicon-based test on cfDNA. Clinical tests were performed on 422 pregnancies with or without abnormal ultrasound findings or family history. Follow-up studies on cases with available outcome results confirmed 20 true-positive, 127 true-negative, zero false-positive, and zero-false negative results. The initial clinical study demonstrated that this non-invasive test can provide valuable molecular information for the detection of a wide spectrum of dominant monogenic diseases, complementing current screening for aneuploidies or carrier screening for recessive disorders.
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http://dx.doi.org/10.1038/s41591-018-0334-xDOI Listing
March 2019

Causative Mutations and Mechanism of Androgenetic Hydatidiform Moles.

Am J Hum Genet 2018 11;103(5):740-751

Department of Human Genetics, McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Obstetrics and Gynecology, McGill University Health Centre, Montréal, QC H4A 3J1, Canada. Electronic address:

Androgenetic complete hydatidiform moles are human pregnancies with no embryos and affect 1 in every 1,400 pregnancies. They have mostly androgenetic monospermic genomes with all the chromosomes originating from a haploid sperm and no maternal chromosomes. Androgenetic complete hydatidiform moles were described in 1977, but how they occur has remained an open question. We identified bi-allelic deleterious mutations in MEI1, TOP6BL/C11orf80, and REC114, with roles in meiotic double-strand breaks formation in women with recurrent androgenetic complete hydatidiform moles. We investigated the occurrence of androgenesis in Mei1-deficient female mice and discovered that 8% of their oocytes lose all their chromosomes by extruding them with the spindles into the first polar body. We demonstrate that Mei1 oocytes are capable of fertilization and 5% produce androgenetic zygotes. Thus, we uncover a meiotic abnormality in mammals and a mechanism for the genesis of androgenetic zygotes that is the extrusion of all maternal chromosomes and their spindles into the first polar body.
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http://dx.doi.org/10.1016/j.ajhg.2018.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218808PMC
November 2018

Clinical exome sequencing for fetuses with ultrasound abnormalities and a suspected Mendelian disorder.

Genome Med 2018 09 28;10(1):74. Epub 2018 Sep 28.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Background: Exome sequencing is now being incorporated into clinical care for pediatric and adult populations, but its integration into prenatal diagnosis has been more limited. One reason for this is the paucity of information about the clinical utility of exome sequencing in the prenatal setting.

Methods: We retrospectively reviewed indications, results, time to results (turnaround time, TAT), and impact of exome results for 146 consecutive "fetal exomes" performed in a clinical diagnostic laboratory between March 2012 and November 2017. We define a fetal exome as one performed on a sample obtained from a fetus or a product of conception with at least one structural anomaly detected by prenatal imaging or autopsy. Statistical comparisons were performed using Fisher's exact test.

Results: Prenatal exome yielded an overall molecular diagnostic rate of 32% (n = 46/146). Of the 46 molecular diagnoses, 50% were autosomal dominant disorders (n = 23/46), 41% were autosomal recessive disorders (n = 19/46), and 9% were X-linked disorders (n = 4/46). The molecular diagnostic rate was highest for fetuses with anomalies affecting multiple organ systems and for fetuses with craniofacial anomalies. Out of 146 cases, a prenatal trio exome option designed for ongoing pregnancies was performed on 62 fetal specimens, resulting in a diagnostic yield of 35% with an average TAT of 14 days for initial reporting (excluding tissue culture time). The molecular diagnoses led to refined recurrence risk estimates, altered medical management, and informed reproductive planning for families.

Conclusion: Exome sequencing is a useful diagnostic tool when fetal structural anomalies suggest a genetic etiology, but other standard prenatal genetic tests did not provide a diagnosis.
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http://dx.doi.org/10.1186/s13073-018-0582-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162951PMC
September 2018

Chromosomal microarray analysis on uncultured chorionic villus sampling can be complicated by confined placental mosaicism for aneuploidy and microdeletions.

Prenat Diagn 2018 10 5;38(11):858-865. Epub 2018 Sep 5.

Baylor Genetics Laboratories, Houston, Texas.

Objective: This study aims to establish the incidence and implications of confined placental mosaicism (CPM) in the context of prenatal chromosomal microarray analysis (CMA).

Methods: We retrospectively reviewed prenatal array data on 1382 consecutive chorionic villus sampling (CVS) specimens spanning the past 6 years, focusing on those for which whole CVS biopsy (both cytotrophoblast and mesenchymal cells) was used for CMA and cultured cells (primarily mesenchyme) was also analyzed or amniotic fluid (AF)/newborn blood was used for confirmation, to determine the frequency of mosaic abnormal findings that were the result of CPM.

Results: Out of a total of 1382 consecutive CVS cases, we identified 42 (42/1382 = 3.0%) cases with abnormal array findings suggestive of mosaicism. Among them, 10 cases were unequivocally interpreted as CPM based on a normal AF/newborn blood confirmatory result. In addition, another 10 cases were interpreted as provisional CPM based on normal results on cultured cells. Notably, 40% (8/20) of the cases revealed complex findings, including multiple mosaic aneuploidies, mosaic submicroscopic copy number variation (CNV), and mosaic aneuploidy plus mosaic CNV.

Conclusion: Abnormal CMA results from CVS specimens should be interpreted with caution when mosaicism is evident or suspected. Furthermore, confirmatory testing on amniotic fluid, which contains cells derived from the fetus, is recommended in these cases.
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http://dx.doi.org/10.1002/pd.5342DOI Listing
October 2018

Exome and genome sequencing in reproductive medicine.

Fertil Steril 2018 02 1;109(2):213-220. Epub 2018 Feb 1.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas. Electronic address:

The advent of next-generation sequencing has enabled clinicians to assess many genes simultaneously and at high resolution. This is advantageous for diagnosing patients in whom a genetic disorder is suspected but who have a nonspecific or atypical phenotype or when the disorder has significant genetic heterogeneity. Herein, we describe common clinical applications of next-generation sequencing technology, as well as their respective benefits and limitations. We then discuss key considerations of variant interpretation and reporting, clinical utility, pre- and posttest genetic counseling, and ethical challenges. We will present these topics with an emphasis on their applicability to the reproductive medicine setting.
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http://dx.doi.org/10.1016/j.fertnstert.2017.12.010DOI Listing
February 2018

Positive predictive value estimates for cell-free noninvasive prenatal screening from data of a large referral genetic diagnostic laboratory.

Am J Obstet Gynecol 2017 12 13;217(6):691.e1-691.e6. Epub 2017 Oct 13.

Baylor Genetics, Baylor College of Medicine, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX. Electronic address:

Background: Since its debut in 2011, cell-free fetal DNA screening has undergone rapid expansion with respect to both utilization and coverage. However, conclusive data regarding the clinical validity and utility of this screening tool, both for the originally included common autosomal and sex-chromosomal aneuploidies as well as the more recently added chromosomal microdeletion syndromes, have lagged behind. Thus, there is a continued need to educate clinicians and patients about the current benefits and limitations of this screening tool to inform pre- and posttest counseling, pre/perinatal decision making, and medical risk assessment/management.

Objective: The objective of this study was to determine the positive predictive value and false-positive rates for different chromosomal abnormalities identified by cell-free fetal DNA screening using a large data set of diagnostic testing results on invasive samples submitted to the laboratory for confirmatory studies.

Study Design: We tested 712 patient samples sent to our laboratory to confirm a cell-free fetal DNA screening result, indicating high risk for a chromosome abnormality. We compiled data from all cases in which the indication for confirmatory testing was a positive cell-free fetal DNA screen, including the common trisomies, sex chromosomal aneuploidies, microdeletion syndromes, and other large genome-wide copy number abnormalities. Testing modalities included fluorescence in situ hybridization, G-banded karyotype, and/or chromosomal microarray analysis performed on chorionic villus samples, amniotic fluid, or postnatally obtained blood samples. Positive predictive values and false-positive rates were calculated from tabulated data.

Results: The positive predictive values for trisomy 13, 18, and 21 were consistent with previous reports at 45%, 76%, and 84%, respectively. For the microdeletion syndrome regions, positive predictive values ranged from 0% for detection of Cri-du-Chat syndrome and Prader-Willi/Angelman syndrome to 14% for 1p36 deletion syndrome and 21% for 22q11.2 deletion syndrome. Detection of sex chromosomal aneuploidies had positive predictive values of 26% for monosomy X, 50% for 47,XXX, and 86% for 47,XXY.

Conclusion: The positive predictive values for detection of common autosomal and sex chromosomal aneuploidies by cell-free fetal DNA screening were comparable with other studies. Identification of microdeletions was associated with lower positive predictive values and higher false-positive rates, likely because of the low prevalence of the individual targeted microdeletion syndromes in the general population. Although the obtained positive predictive values compare favorably with those seen in traditional screening approaches for common aneuploidies, they highlight the importance of educating clinicians and patients on the limitations of cell-free fetal DNA screening tests. Improvement of the cell-free fetal DNA screening technology and continued monitoring of its performance after introduction into clinical practice will be important to fully establish its clinical utility. Nonetheless, our data provide valuable information that may aid result interpretation, patient counseling, and clinical decision making/management.
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http://dx.doi.org/10.1016/j.ajog.2017.10.005DOI Listing
December 2017

A non-mosaic mutation in a male with severe congenital anomalies overlapping focal dermal hypoplasia.

Mol Genet Metab Rep 2017 Sep 7;12:57-61. Epub 2017 Jun 7.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Mutations in the gene cause the X-linked dominant condition focal dermal hypoplasia (FDH). Features of FDH include striated pigmentation of the skin, ocular and skeletal malformations. FDH is generally associated with lethality in non-mosaic males and most of the currently reported male patients show mosaicism due to post-zygotic mutations in the gene. There is only one previous report of a surviving male with an inherited mutation in the gene. Here, we report two male siblings with multiple malformations including skeletal, ocular and renal defects overlapping with FDH. A novel mutation (p.Ser250Phe) was identified in a non-mosaic, hemizygous state in one of the siblings who survived to 8 years of age. The mother is a heterozygous carrier, has a random X-inactivation pattern and is asymptomatic. Findings unusual for FDH include dysplastic clavicles and bilateral Tessier IV facial clefts. This is the second case report of a non-mosaic mutation in a male individual with multiple congenital anomalies. While the pathogenicity of this mutation remains to be further investigated, the survival of a male with a non-mosaic mutation in is suggestive of a functionally mild mutation leading to an X-linked recessive mode of inheritance.
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http://dx.doi.org/10.1016/j.ymgmr.2017.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466597PMC
September 2017

Missed opportunities: unidentified genetic risk factors in prenatal care.

Prenat Diagn 2018 01 24;38(1):75-79. Epub 2017 Apr 24.

Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA.

Objective: Prenatal and preconception care guidelines recommend obtaining family history to screen for reproductive genetic risk. The effectiveness of this screening and subsequent referral for genetic counseling is not well established. This study describes how often pregnant women with reproductive genetic risks were not referred for prenatal genetic counseling and the indications frequently missed.

Method: We retrospectively reviewed genetic consultation medical records for first-trimester screen pretest counseling. These women had no documented indications for genetic counseling. We used the American College of Medical Genetics and Genomics referral guidelines for genetic counseling to identify missed indications within the parents' personal and family histories. Patients with advanced maternal age were excluded.

Results: We reviewed 416 consultation notes. The counselor elicited a genetic risk for which a referral had not been made in 27% of the pregnant women. Of these, 70% were genetic risks in the family history, 23% in the couple's history, and 7% in the prenatal history. The most common missed indications were personal or family history of birth defects (38%), intellectual disability or autism (19%), and a prior positive genetic carrier screening test (14%).

Conclusion: Genetic risk factors are not consistently identified as a referral indication for reproductive genetic counseling. © 2017 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/pd.5048DOI Listing
January 2018

Independent variant analysis of and in 38 Aicardi syndrome patients.

Mol Genet Genomic Med 2017 Mar 25;5(2):117-121. Epub 2017 Jan 25.

Department of Obstetrics and GynecologyBaylor College of MedicineHoustonTexas; Jan and Dan Duncan Neurological Research InstituteTexas Children's HospitalHoustonTexas; Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas.

Background: Aicardi syndrome is a severe neurodevelopmental disorder characterized by infantile spasms, typical chorioretinal lacunae, agenesis of the corpus callosum, and other neuronal migration defects. It has been reported recently that de novo variants in and each may cause Aicardi syndrome in a single individual of a small cohort of females with this clinical diagnosis. These data were interpreted to suggest that the clinical diagnosis of Aicardi syndrome may be genetically heterogeneous.

Methods: To investigate this further, we sequenced and coding regions using DNA from 38 clinically well-characterized girls with Aicardi syndrome.

Results: We did not detect the previously reported or any other deleterious variants in any of the analyzed samples.

Conclusions: This suggests that the published variants represent either an extremely rare cause of Aicardi syndrome or an incidental finding.
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http://dx.doi.org/10.1002/mgg3.250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5370232PMC
March 2017

Maternally expressed NLRP2 links the subcortical maternal complex (SCMC) to fertility, embryogenesis and epigenetic reprogramming.

Sci Rep 2017 03 20;7:44667. Epub 2017 Mar 20.

Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, 77030, USA.

Mammalian parental genomes contribute differently to early embryonic development. Before activation of the zygotic genome, the maternal genome provides all transcripts and proteins required for the transition from a highly specialized oocyte to a pluripotent embryo. Depletion of these maternally-encoded transcripts frequently results in failure of preimplantation embryonic development, but their functions in this process are incompletely understood. We found that female mice lacking NLRP2 are subfertile because of early embryonic loss and the production of fewer offspring that have a wide array of developmental phenotypes and abnormal DNA methylation at imprinted loci. By demonstrating that NLRP2 is a member of the subcortical maternal complex (SCMC), an essential cytoplasmic complex in oocytes and preimplantation embryos with poorly understood function, we identified imprinted postzygotic DNA methylation maintenance, likely by directing subcellular localization of proteins involved in this process, such as DNMT1, as a new crucial role of the SCMC for mammalian reproduction.
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http://dx.doi.org/10.1038/srep44667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357799PMC
March 2017

Chronic Maternal Low-Protein Diet in Mice Affects Anxiety, Night-Time Energy Expenditure and Sleep Patterns, but Not Circadian Rhythm in Male Offspring.

PLoS One 2017 18;12(1):e0170127. Epub 2017 Jan 18.

Department of Obstetrics & Gynecology, Baylor College of Medicine, Houston, TX, United States of America.

Offspring of murine dams chronically fed a protein-restricted diet have an increased risk for metabolic and neurobehavioral disorders. Previously we showed that adult offspring, developmentally exposed to a chronic maternal low-protein (MLP) diet, had lower body and hind-leg muscle weights and decreased liver enzyme serum levels. We conducted energy expenditure, neurobehavioral and circadian rhythm assays in male offspring to examine mechanisms for the body-weight phenotype and assess neurodevelopmental implications of MLP exposure. C57BL/6J dams were fed a protein restricted (8%protein, MLP) or a control protein (20% protein, C) diet from four weeks before mating until weaning of offspring. Male offspring were weaned to standard rodent diet (20% protein) and single-housed until 8-12 weeks of age. We examined body composition, food intake, energy expenditure, spontaneous rearing activity and sleep patterns and performed behavioral assays for anxiety (open field activity, elevated plus maze [EPM], light/dark exploration), depression (tail suspension and forced swim test), sociability (three-chamber), repetitive (marble burying), learning and memory (fear conditioning), and circadian behavior (wheel-running activity during light-dark and constant dark cycles). We also measured circadian gene expression in hypothalamus and liver at different Zeitgeber times (ZT). Male offspring from separate MLP exposed dams had significantly greater body fat (P = 0.03), less energy expenditure (P = 0.004), less rearing activity (P = 0.04) and a greater number of night-time rest/sleep bouts (P = 0.03) compared to control. MLP offspring displayed greater anxiety-like behavior in the EPM (P<0.01) but had no learning and memory deficit in fear-conditioning assay (P = 0.02). There was an effect of time on Per1, Per 2 and Clock circadian gene expression in the hypothalamus but not on circadian behavior. Thus, transplacental and early developmental exposure of dams to chronic MLP reduces food intake and energy expenditure, increases anxiety like behavior and disturbs sleep patterns but not circadian rhythm in adult male offspring.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170127PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242516PMC
August 2017

Are First Trimester Nuchal Septations Independent Risk Factors for Chromosomal Anomalies?

J Ultrasound Med 2017 Jan 28;36(1):155-161. Epub 2016 Nov 28.

Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital Pavilion for Women, Houston, Texas, USA.

Objectives: There is conflicting information regarding the role of nuchal septations during first-trimester genetic screening. This study was designed to determine whether nuchal septations are risk factors for chromosomal anomalies, independent of increased nuchal translucency (NT), in the first trimester of pregnancy.

Methods: This retrospective cohort study included all women who underwent first-trimester genetic screening between November 2011 and December 2014. The 95th percentile for the NT measurement was calculated for each gestational week. A multivariable logistic regression analysis was performed to determine whether the visualization of nuchal septations was an independent risk factor for chromosomal analysis while controlling for confounding variables. P < .05 was considered significant.

Results: Chromosomal abnormalities were present in 1.0% of the population (33 of 3275). The prevalence of chromosomal abnormalities was significantly higher among fetuses with nuchal septations compared to fetuses with normal NT without septations (P < .001) and those with NT above the 95th percentile without septations (P < .001). The sonographic evidence of septations was associated with high risk of chromosomal abnormalities (odds ratio, 40.0; 95% confidence interval, 9.1-174.0) after controlling for NT measurements and other confounding variables.

Conclusions: Visualization of nuchal septations during first-trimester genetic screening is a powerful risk factor for chromosomal anomalies, independent of increased NT.
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http://dx.doi.org/10.7863/ultra.16.01066DOI Listing
January 2017

Recent advances in prenatal genetic screening and testing.

F1000Res 2016 28;5:2591. Epub 2016 Oct 28.

Department of Obstetrics and Gynecology and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030, USA.

The introduction of new technologies has dramatically changed the current practice of prenatal screening and testing for genetic abnormalities in the fetus. Expanded carrier screening panels and non-invasive cell-free fetal DNA-based screening for aneuploidy and single-gene disorders, and more recently for subchromosomal abnormalities, have been introduced into prenatal care. More recently introduced technologies such as chromosomal microarray analysis and whole-exome sequencing can diagnose more genetic conditions on samples obtained through amniocentesis or chorionic villus sampling, including many disorders that cannot be screened for non-invasively. All of these options have benefits and limitations, and genetic counseling has become increasingly complex for providers who are responsible for guiding patients in their decisions about screening and testing before and during pregnancy.
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http://dx.doi.org/10.12688/f1000research.9215.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089140PMC
October 2016
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