Prenatal Diagnosis最新文献

Objective: Advancements in non-invasive prenatal screening (NIPS) could significantly alter prenatal screening by expanding the range of genetic conditions screened. This study aims to explore the perspectives of healthcare professionals (HCP) on the expanded use of NIPS and explore specifications for the inclusion of genetic conditions.

Method: Semi-structured interviews were conducted with Canadian HCPs who counsel pregnant individuals about NIPS. The findings were organized around the four ethical pillars of Kater-Kuiper's framework: proportionality (benefits and harms), aim of screening, justice, and societal aspects.

Results: Participants chose to assess the proportionality of NIPS using general terms to describe the additional conditions rather than discussing specific conditions to add. They emphasized the importance of clinical validity as crucial for expanding NIPS and ensuring its utility. Participants believed that the aim of NIPS is to enhance reproductive autonomy, and therefore that screening for late-onset conditions could create ethical tensions between parents and the prospective children. Participants also worried that expanded use of NIPS could impact the quality of counselling provided by HCPs and affect autonomy. Justice considerations include the allocation of resources in prenatal care instead of other areas of healthcare. Societal aspects highlighted the different definitions HCPs used to describe 'life-limiting conditions' that could severely affect the future child's health.

Conclusion: With expanded use of NIPS, clinical validity will vary for each screened condition. Specificity for each condition will influence the quality of consent. HCP estimates that clinical validity, clinical utility, availability of counselling, availability of resources, and societal impacts should be considered when adding genetic conditions to NIPS.

Objective: To determine the exome sequencing results in fetuses with bilateral renal agenesis (BRA).

Methods: This was a retrospective study of 14 cases with BRA diagnosed on second trimester anatomy ultrasound. All cases underwent invasive prenatal diagnosis. Genetic investigations were performed by chromosomal microarray analysis and trio exome sequencing. Clinical and laboratory data were collected and reviewed for these cases, including maternal demographics, prenatal sonographic findings, molecular sequencing results, and pregnancy outcomes.

Results: Pathogenic and likely pathogenic variants in three genes (FRAS1, PBX1, and KMT2D) were detected by exome sequencing in 6 (6/14) cases. One gene (FRAS1) is inherited in an autosomal recessive (AR) manner and two (PBX1 and KMT2D) are autosomal dominant (AD); both AD variants were de novo. Only the FRAS1 variants were detected in more than one case. Variants in five cases were believed to be the cause of BRA, and the variants detected in PBX1 and KMT2D were likely the cause of fetal phenotype suggesting that the two genes can present with BRA. The yield of exome sequencing in our series is one third (4/12) after excluding two families with a previous family history.

Conclusion: Fraser syndrome, resulting from FRAS1 variants, is the most common cause of genetic BRA identified in this specific cohort. The determination of genetic etiology will be valuable in the possible choices for pregnancy management and risk assessment of recurrence in future pregnancies.

Objective: To report a case of a fetus with multiple congenital anomalies and suspected Barth syndrome, highlighting potential phenotypic expansion of the syndrome.

Methods: A 32-year-old G4P2011 patient was referred at 18w5d gestation for suspected fetal encephalocele. Serial imaging, including ultrasound and MRI, was performed to evaluate fetal anomalies. Doppler studies assessed fetal development and postnatal findings were documented. Genetic variants were identified using trio whole exome sequencing.

Results: Initial ultrasound revealed occipital encephalocele, right renal aplasia, and abnormal vertebral curvature. Follow-up MRI confirmed occipital encephalocele and identified Chiari malformation but normal renal morphology. Phenotypic evolution included intrauterine growth restriction (IUGR), right renal hypoplasia, cardiomegaly, polyhydramnios, and hydrops fetalis. Delivery occurred via cesarean section at 30w6d due to non-reassuring Doppler findings. Postnatally, the neonate exhibited esophageal atresia, vertebral segmentation and rib morphology defects, and right renal aplasia. The neonate died on the first day of life due to cardiac decompensation. Genetic testing identified a TAFAZZIN c.589G>A p.(Gly197Arg) pathogenic variant, consistent with Barth syndrome.

Conclusion: The presentation of IUGR, cardiomyopathy, and hydrops fetalis aligns with Barth syndrome. However, the additional findings of occipital encephalocele, renal aplasia, and vertebral and rib anomalies suggest a potential phenotypic expansion of Barth syndrome.

Objective: Accurate recurrence risks are essential for genomic counselling and parental reproductive choices. Historically, Sanger sequencing was used to test parental samples, which has a limited sensitivity of ∼ 10% for detecting somatic mosaicism. Next generation sequencing (NGS) methods, utilised for non-invasive prenatal diagnosis (NIPD) and trio prenatal exome sequencing in our laboratory, have greater sensitivity. Here we review the cases of parental somatic mosaicism we have detected and discuss its impact on management.

Method: Laboratory databases from 1 January 2015 to 30 September 2022 were reviewed to identify all cases where parental somatic mosaicism was detected during NIPD and prenatal exome testing.

Results: During the development of NIPD testing, we identified 10/131 (7.6%) families with parental somatic mosaicism. In six cases where NGS detected levels between 0.37% and 8.82%, prior testing with Sanger sequencing had not detected mosaicism. In our exome sequencing cohort, we detected parental mosaicism in 4/101 (3.96%) cases. Clinical features of the condition were identified in 2/14 parents.

Conclusion: The sensitivity of the testing technique needs to be considered when counselling parents on recurrence risk. Parents need to be aware that modern approaches to prenatal diagnosis may allow identification of mosaicism, which may have implications for their own health and change recurrence risks for future pregnancies.

Introduction: Fetoscopic laser surgery (FLS) is the gold standard treatment for monochorionic (MC) twin pregnancies complicated by twin-twin transfusion syndrome (TTTS). The aim of our study was to evaluate the rate and risk factors for cord entanglement in the presence of iatrogenic monoamnioticity (iMA), a consequence of inadvertent septostomy during FLS.

Methods: This is a retrospective analysis of two consecutive cohorts of FLS performed either using the selective technique from January 2004 to January 2012, or with the Solomon technique, from that date onwards. Maternal and fetal characteristics, technical details, and obstetrical and perinatal outcomes were recorded. Cord entanglement was identified based on the presence of a galloping sign observed during prenatal ultrasound in the presence of iMA. At our center, mono-amniotic twins are electively delivered at 32 completed weeks.

Results: The mean gestational age of the 558 FLS, 52.3% selective and 47.6% Solomon, was 19.8 weeks (15.1-26.4). Solomon laser coagulation was associated with a lower occurrence of TAPS or TTTS (5.3% vs. 13%, p = 0.001) after the FLS and a higher number of placental abruption (9% vs. 2% p < 0.001) and by more cord entanglement in the presence of iMA (9.4% vs. 2.4% respectively, p < 0.001). The presence of iMA was correlated with a higher occurrence of limb defects (6.2% vs. 1% in non-iMA twins, p 0.001).

Conclusions: Solomon FLS was associated with a higher risk of cord entanglement and placental abruptio. As a consequence, we delivered twins with iMA earlier.

Introduction: Genome-wide non-invasive prenatal testing (gwNIPT) has screening limitations for detectable genetic conditions and cannot detect microdeletions/microduplications (MD) or triploidy. Nuchal translucency (NT) increases with gestation and with genetic or structural abnormalities. This study aims to determine the utility of NT measurement in detecting genetic abnormalities not identified by gwNIPT and the optimal NT threshold value.

Methods: A 4-year retrospective study of singleton pregnancies undergoing first-line gwNIPT aneuploidy screening where invasive prenatal testing by CVS/or amniocentesis was subsequently undertaken. Population proportions for static and multiple of the median (MoM) NT cut-offs were derived from all 11-14 weeks ultrasound examinations.

Results: Among 919 pregnancies with gwNIPT and invasive testing, 338 had a single genetic abnormality. There were 9 false negative GwNIPT results and a further 26 undetectable abnormalities (18 MD, 8 triploidy) in this cohort. Twelve had a dual chromosomal abnormality, four of which returned a low-risk gwNIPT. Thirty-three "missed cases" also had a 13-week scan, to which the various NT threshold values (3.0 mm, 1.6 MoM, 3.5 mm, and 1.9 MoM) were applied. In only 3 (9%) cases did the NT exceed 3.0 mm with similar detection rates (DR) for all higher cut-offs. Static and MoM-based NT cut-offs had similar positive predictive values (PPV).

Conclusion: Enlarged NT measurement is a poor predictor of genetic abnormalities not identified by gwNIPT. When applied, the fixed NT cut-off of 3.5 mm provides a low FPR with a similar DR to lower cut-off thresholds, resulting in a higher PPV.

Objective: To explore decision makers' perspectives on the conditions for a responsible implementation of non-invasive prenatal testing (NIPT) as a first-tier test in Canadian provinces' healthcare systems.

Method: A qualitative study was conducted with 16 Canadian decision makers who were interviewed between February 2021 and July 2022. After anonymization and transcription, interviews were coded inductively using thematic analysis.

Results: Our interviews showed the complexity of the decision making environment regarding prenatal screening funding. Participants agreed that NIPT is superior to maternal serum screening as a first-tier test, but they also recognized that first-tier NIPT has limits and barriers. They described the following conditions for its responsible implementation: (1) need for time and evidence; (2) taking stakeholders' perspectives into account; (3) limit costs for the healthcare system; (4) ensure appropriate logistical conditions and harmonize the test offer; (5) ensure appropriate clinical services; (6) ensure informed consent; (7) ensure the test is presented as an individual choice to avoid eugenic concerns.

Conclusion: Multiple barriers and issues need to be addressed before moving NIPT from second- to first-tier. Decision makers' perspectives should be contrasted with those of other important stakeholders, including pregnant people, disability advocates and healthcare professionals.

Background: Congenital adrenal hyperplasia (CAH) is a common metabolic genetic disease. Early diagnosis and intervention are crucial to improve the prognosis. Noninvasive prenatal diagnosis (NIPD) is an early, safe, and accurate method. This study aimed to evaluate the NIPD of CAH while guiding individualized intrauterine treatment.

Methods: Twenty families with a 25% risk of having a baby with 21-hydroxylase deficiency (21-OHD) were included. Haplotypes were constructed based on targeted sequencing and family linkage analysis. Relative haplotype dosage (RHDO) combined with Bayes factor was used to infer fetal genotypes. Invasive prenatal diagnosis was performed to verify the reliability of NIPD. For affected-female fetuses, intrauterine treatment was applied until delivery.

Results: In 20 families, NIPD successfully identified one female-affected fetus, four male-affected fetuses, nine heterozygotes, and five normal fetuses. The first-pass success rate of NIPD was 90% (18/20), the reporting rate was 95% (19/20), and the accuracy was 100% (19/19). Individualized intrauterine treatment avoided 88.9% (8/9) of unnecessary treatment of unaffected female fetuses. Moreover, no significant virilization was observed in the newborn of CAH16, which underwent intrauterine treatment.

Conclusion: NIPD has far-reaching implications for the early treatment and clinical management of pregnancy in families with 21-OHD.

Objective: To evaluate the prevalence of chromosomal aberrations in fetuses with isolated PRUV in a nationwide cohort with 1st-trimester screening for aneuploidies.

Method: A retrospective study including all pregnancies in Denmark with a due date between 2010 and 2022. We retrieved all cases from patient files, where we searched for "PRUV" in the conclusion field. All retrieved cases were manually assessed to determine if PRUV was present, associated anomalies were present, and genetic tests were performed including results. Additional data on postnatal genetics were retrieved from the Danish Cytogenetic Central Registry.

Results: A total of 262 cases with PRUV were retrieved, of which 19 (7.3%) had associated malformations. Among the isolated cases, 119 (49.0%) had a prenatal invasive genetic test that consisted of CMA, and 5 cases had an NIPT (2.1%): All tests were normal or showed low risk for aneuploidies, respectively. None of the children born with PRUV had a postnatal genetic test performed.

Conclusion: We found no chromosomal aberrations in fetuses with isolated or non-isolated PRUVs. Isolated PRUV does not seem associated with a higher incidence of chromosomal aberrations, so parents can be reassured. However, since PRUV was associated with other malformations in 7% of cases, thorough scans are needed.