Prenatal Diagnosis最新文献

Objective: To explore the experiences of people having cfDNA screening to detect unbalanced translocations, and to understand motivations for choosing this option.

Methods: We used a qualitative approach with in-depth semi-structured interviews with reciprocal translocation carriers and their partners. People who underwent cfDNA screening with translocation analysis through Victorian Clinical Genetics Services between 2015 and 2019 were invited to take part. Purposive sampling based on the participant's geographic location, requesting practitioner specialty and cfDNA screening result was used to capture a range of experiences. Interview transcripts were analysed using thematic analysis.

Results: Participants (n = 13) had complex reproductive journeys associated with the translocation and opted for cfDNA screening rather than prenatal diagnosis to avoid risk to their pregnancy. Participants benefited from having a result early in pregnancy and had sufficient confidence in the result to decline a diagnostic testing procedure.

Conclusion: Participants' experiences with cfDNA screening were intertwined with the experience of being a carrier of a reciprocal translocation. cfDNA screening with translocation analysis was perceived as an acceptable alternative to prenatal diagnosis and should be made more accessible to balanced translocation carriers. Access to specialist genetic counselling services is needed to ensure couples are provided with information about all prenatal testing options, including the benefits and limitations associated with cfDNA screening with translocation analysis.

This systematic review aims at presenting the ethical debate on the artificial placenta (AP) by identifying, distinguishing, and organizing the different ethical arguments described in the literature. Articles were selected based on predefined inclusion criteria: discussing ethical arguments, on AP, written in English. QUAGOL methodology was used for analysis. Forty-five articles were included. We identified three themes. First, foundational-ethical issues. There is disagreement on whether the AP subject should be considered an infant or a new moral entity. While physiologically it stays in the fetus, it sits outside the womb. Second, reproductive ethics issues. Few authors believed that the AP would increase reproductive choices. The majority warned that the AP could limit reproductive choices by creating pressure to use it in healthy pregnancies or as an alternative to abortion. Third, research ethics issues. Publications mostly focused on the selection of the in-human trial participants. We concluded that AP ethical literature focuses mostly on the potential use of AP as an alternative to abortion or healthy pregnancies rather than on its intended use as a treatment after extremely premature birth. Therefore, we conclude that the current ethical literature on AP is imbalanced: it leans more toward science fiction than actual clinical and technological reality.

Chromosomal microarray analysis (CMA), methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), and trio-whole exome sequencing (WES) were performed in a female fetus with omphalocele. A de novo heterozygous 300-kb deletion in the Xq13.1 region, which includes the MED12 gene, was identified. Follow-up ultrasound at 18⁺⁴ weeks of gestation revealed features consistent with Hardikar syndrome (HS), including a right-sided cleft lip and palate, an omphalocele with intestines, a diaphragmatic hernia with the stomach in the left thoracic cavity, and displacement of the heart to the right. Phenotypic evaluation confirmed the presence of a cleft lip and palate as well as umbilical hernia. These findings suggest that a heterozygous deletion of the entire MED12 gene may contribute to the HS phenotype. This case extends the possible damaging effects of haploinsufficiency of the MED12 gene in the pathogenesis of HS.

Objective: To describe postnatal outcome following the prenatal diagnosis of an abnormal fetal gallbladder.

Methods: We conducted a systematic review of studies from January 1980 to January 2023 that described FGB abnormalities, which included agenesis or non-visualisation, abnormal content presence of sludge, abnormal shape or size and abnormal position, and postnatal outcome to determine the association with pathology.

Results: In 51 studies, 842 fetuses had abnormal FGB. Non-visualisation of the FGB was the most common diagnosis (521 fetuses, mean gestational age 21.6 weeks, range 14-29). The FGB was subsequently visualised prenatally in 128 out of 521 cases (24.6%; 95% CI, 20.9%-28.3%). Of the 393 cases with persistent FGB non-visualisation (75.4%; 95% CI, 71.7-79.1), 48 cases (12.2%; 95% CI, 9.0-15.5) underwent termination of pregnancy (TOP) with FGB agenesis confirmed in 16 out of 26 fetuses that had a postmortem examination (61.5%; 95% CI, 42.8-80.2). After excluding cases with missing outcomes (n = 121), postnatal ultrasound was performed in 82.4% of cases with persistent non-visualised FGB (224/272; 95% CI, 77.8%-86.9%). The gallbladder was not visualised in 63.4% (142/224; 95% CI, 57.1-69.7), confirming GB agenesis. This was an isolated finding in 41.1% of cases (92/224; 95% CI, 34.6-47.5). Of 272 known outcomes, biliary atresia, cystic fibrosis, and structural or chromosomal abnormalities were diagnosed in 8.5% (n = 23), 12.5% (n = 34), 18.0% (n = 49) and 6.3% (n = 17) cases, respectively. The sensitivity (true positive rate) of ultrasound for GB agenesis in fetuses with persistently non-visualised FGB was 58.1% (158/272; 95% CI, 52.2%-64.0%). Fetal gallbladder stones/sludge were described in 100 fetuses mainly in the third trimester of pregnancy (mean gestational age 33.8 weeks). Resolution of postnatally followed up cases occurred in around one-third of the cases (37.3%) within 1 month after birth. There was a low reported association with severe conditions (2%).

Conclusions: This systematic review and meta-analysis found that when the fetal gallbladder was absent in mid-trimester, it was visualised in subsequent fetal ultrasound examinations in around 25% of cases. If persistently absent on prenatal ultrasound, the confirmed rate of GB agenesis was around 50%, with the neonates having biliary atresia, cystic fibrosis, or structural abnormalities. Because of the association with severe conditions, if persistent FGB agenesis is suspected, prenatal diagnosis should be offered. FGB abnormalities such as stones/sludge tended to resolve by 1 year of age with around half of all cases resolving by 1 month postnatal.

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: 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.

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.

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.