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Objectives: To assess maternal characteristics and comorbidities in patients with persistent uninterpretable non‐invasive prenatal testing (NIPT) and to evaluate the association with adverse pregnancy outcome in a general risk population. Methods: A retrospective cohort study (July 2017–December 2020) was conducted of patients with persistent uninterpretable NIPT samples. Maternal characteristics and pregnancy outcomes were compared with the general Belgian obstetric population. Results: Of the 148 patients with persistent uninterpretable NIPT, 37 cases were due to a low fetal fraction (LFF) and 111 due to a low quality score (LQS). Both groups (LFF, LQS) showed more obesity (60.6%, 42.4%), multiple pregnancies (18.9%, 4.5%) and more obstetrical complications. In the LQS group, a high rate of maternal auto‐immune disorders (30.6%) was seen and hypertensive complications (17.6%), preterm birth (17.6%) and neonatal intensive care unit (NICU) admission (22%) were significantly increased. In the LFF group hypertensive complications (21.6%), gestational diabetes (20.6%), preterm birth (27%), SGA (25.6%), major congenital malformations (11.4%), c‐section rate (51.4%) and NICU admission (34.9%) were significantly increased. Chromosomal abnormalities were not increased in both groups. Conclusions: Patients with persistent uninterpretable NIPT have significantly more maternal obesity, comorbidities and adverse pregnancy outcome than the general population and should receive high‐risk pregnancy care. Distinguishing between LFF and LQS optimizes counseling because maternal characteristics and pregnancy outcome differ between these groups. Key points: What is already known about this topic? Non‐invasive prenatal testing (NIPT) failure due to low fetal fraction can have biological and technical causes.A low fetal fraction seems to be related with a higher rate of adverse pregnancy outcome. What does this study add? Persistent uninterpretable NIPT can be divided into two groups: a low fetal fraction group and a low quality score, revealing different patient characteristics.While both groups are associated with increased rates of obstetrical complications, this is even more pronounced in the low fetal fraction group. [ABSTRACT FROM AUTHOR]

Cancer is diagnosed in one in 1000 to 1500 pregnancies. Most frequently encountered malignancies during pregnancy are breast cancer, hematological cancer, cervical cancer and malignant melanoma. Maternal cancer is associated with an increased risk of IUGR and preterm labor, especially in patients with systemic disease or those receiving chemotherapy during pregnancy, requiring a high‐risk obstetrical follow‐up. Fetal aneuploidy screening by non‐invasive prenatal testing (NIPT) can lead to the incidental identification of copy number alterations derived from non‐fetal cell‐free DNA (cfDNA), as seen in certain cases of maternal malignancy. The identification of tumor‐derived cfDNA requires further clinical, biochemical, radiographic and histological investigations to confirm the diagnosis. In such cases, reliable risk estimation for fetal trisomy 21, 18 and 13 is impossible. Therefore, invasive testing should be offered when ultrasonographic screening reveals an increased risk for chromosomal anomalies, or when a more accurate test is desired. When the fetal karyotype is normal, long term implications for the fetus refer to the consequences of the maternal disease and treatment during pregnancy. This manuscript addresses parental questions when NIPT suggests a maternal malignancy. Based on current evidence and our own experience, a clinical management scheme in a multidisciplinary setting is proposed. Key points: What is already known about this topic? In cancer patients, a fraction of the cfDNA consists out of tumor derived DNA which can occasionally be detected during NIPTCancer diagnosed during pregnancy can be treated, in most cases with preservation of the pregnancy What does this review add? NIPT suggesting a maternal malignancy requires a multidisciplinary workup and follow upProviding answers to the questions of pregnant women and caretakers confronted with a NIPT suggesting a maternal malignancy [ABSTRACT FROM AUTHOR]

Objective: Belgian genetic centers established a database containing data on all chromosomal microarrays performed in a prenatal context. A study was initiated to evaluate postnatal development in children diagnosed prenatally with a non‐benign copy number variant (CNV). Methods: All children diagnosed with a prenatally detected non‐benign CNV in a Belgian genetic center between May 2013 and February 2015 were included in the patient population. The control population consisted of children who had undergone an invasive procedure during pregnancy, with no or only benign CNVs. Child development was evaluated at 36 months using three (3) questionnaires: Ages and Stages Questionnaire Third edition, Ages and Stages Questionnaire Social‐Emotional Second Edition and a general questionnaire. Results: A significant difference in communication and personal‐social development was detected between children with a reported susceptibility CNV and both children with an unreported susceptibility CNV and the control population. The outcome of children with a particular CNV is discussed in a case‐by‐case manner. Conclusion: Our postnatal follow‐up project of children with a prenatally detected non‐benign CNV is the first nationwide project of its kind. A higher number of cases for each CNV category is however needed to confirm our findings. [ABSTRACT FROM AUTHOR]

Objective: With the replacement of karyotyping by chromosomal microarray (CMA) in invasive prenatal diagnosis, new challenges have arisen. By building a national database, we standardize the classification and reporting of prenatally detected copy number variants (CNVs) across Belgian genetic centers. This database, which will link genetic and ultrasound findings with postnatal development, forms a unique resource to investigate the pathogenicity of variants of uncertain significance and to refine the phenotypic spectrum of pathogenic and susceptibility CNVs.Methods: The Belgian MicroArray Prenatal (BEMAPRE) consortium is a collaboration of all genetic centers in Belgium. We collected data from all invasive prenatal procedures performed between May 2013 and July 2016.Results: In this three-year period, 13 266 prenatal CMAs were performed. By national agreement, a limited number of susceptibility CNVs and no variants of uncertain significance were reported. Added values for using CMA versus conventional karyotyping were 1.8% in the general invasive population and 2.7% in cases with an ultrasound anomaly. Of the reported CNVs, 31.5% would have remained undetected with non-invasive prenatal test as the first-tier test.Conclusion: The establishment of a national database for prenatal CNV data allows for a uniform reporting policy and the investigation of the prenatal and postnatal genotype-phenotype correlation. [ABSTRACT FROM AUTHOR]

Objective: Non-invasive prenatal detection of aneuploidies can be achieved with high accuracy through sequencing of cell-free maternal plasma DNA in the maternal blood plasma. However, false positive and negative non-invasive prenatal testing (NIPT) results remain. Fetoplacental mosaicism is the main cause for false positive and false negative NIPT. We set out to develop a method to detect placental chromosomal mosaicism via genome-wide circulating cell-free maternal plasma DNA screening.Method: Aneuploidy detection was combined with fetal fraction determination to enable the detection of placental mosaicism. This pipeline was applied to whole genome sequencing data derived from 19 735 plasma samples. Following an abnormal NIPT, test results were validated by conventional invasive prenatal or postnatal genetic testing.Results: Respectively 3.2% (5/154), 12.8% (5/39), and 13.3% (2/15) of trisomies 21, 18, and 13 were predicted and confirmed to be mosaic. The incidence of other, rare autosomal trisomies was ~0.3% (58/19,735), 45 of which were predicted to be mosaic. Twin pregnancies with discordant fetal genotypes were predicted and confirmed.Conclusion: This approach permits the non-invasive detection of fetal autosomal aneuploidies and identifies pregnancies with a high risk of fetoplacental mosaicism. Knowledge about the presence of chromosomal mosaicism in the placenta influences risk estimation, genetic counseling, and improves prenatal management. [ABSTRACT FROM AUTHOR]

Noninvasive prenatal testing (NIPT) can very accurately determine fetal sex during pregnancy. We present an exceptional case where NIPT contradicts the ultrasound-based sex determination. The pregnant woman was recipient of a liver transplant from a male donor. Graft-derived cell-free DNA released into the maternal circulation clouded the NIPT-based sex determination. Hence, NIPT is not advisable when the pregnant mother underwent an organ transplant. [ABSTRACT FROM AUTHOR]

Synpolydactyly (SPD, OMIM 186000) is a rare congenital limb disorder characterized by syndactyly between the third and fourth fingers and between the fourth and fifth toes, with partial or complete digit duplication in the syndactylous web. The majority of these anomalies co-segregate with mutations in the HOXD13 gene, a homeobox transcription factor crucial for distal limb development. Different classes of HOXD13 mutations are involved in the pathogenesis of synpolydactyly, but an unequivocal genotype-phenotype correlation cannot always be achieved due to the clinical heterogeneity and reduced penetrance of SPD. All mutations identified so far mapped to the N-terminal polyalanine tract or to the C-terminal homeodomain of HOXD13, causing typical or atypical features of SPD, respectively. However, mutations outside of these domains cause a broad variety of clinical features that complicate the differential diagnosis. The existing animal models that are currently used to study HOXD13 (mal)function are therefore instrumental in unraveling potential genotype-phenotype correlations. Both mouse- and chick-based approaches allow the in vivo study of the pathogenic mechanism by which HOXD13 mutations cause SPD phenotypes as well as help in identifying the transcriptional targets. Developmental Dynamics 243:37-48, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

In recent years, several recurrent copy number variations (CNVs) that confer risk of neurodevelopmental disorders have been identified (e.g., del and dup 16p11.2, del15q13.3, del and dup 1q21.1, del16p13.3, del15q11.2). They are often inherited from an unaffected parent and lack phenotypic specificity. Although there is growing evidence from association studies to consider them as susceptibility CNVs, their clinical utility is debated. Yet the clinician is frequently challenged to deal with these counseling situations without guidelines or consensus. In this report, counseling issues and research opportunities are discussed, with the recurrent 15q11.2 BP1-BP2 (including CYFIP1, NIPA1, NIPA2, TUBGCP5) as an example. Several clinical reports have been published describing patients with del15q11.2 featuring intellectual disability, developmental delay, neurological problems, autism spectrum disorder (ASD), attention problems, speech delay, and dysmorphism. The del15q11.2 was found to be significantly associated with intellectual disability, schizophrenia, epilepsy, and ASD. In this report we discuss how patient-specific and family-specific information may alter the interpretation of del15q11.2 as a contributing factor to the disorder in practical counseling situations. In addition, an association study for ASD in a Belgian Flemish cohort and an overview of reported association studies, clinical reports and genomics data for del15q11.2 are presented. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]