Prenatal Diagnosis最新文献

Congenital cytomegalovirus (cCMV) is the most common congenital infection and a leading cause of non-genetic sensorineural hearing loss and neurodevelopmental disability in newborns. Despite its clinical burden, routine CMV screening in pregnancy has not been recommended so far due to the lack of effective treatment to prevent transplacental transmission. In December 2023, the Italian National Institute of Health, on behalf of the Ministry of Health, has issued a new recommendation supporting universal CMV serological screening during pregnancy. This recommendation is based on the results of a systematic review of the literature, including randomized controlled trials, observational studies, and systematic reviews. Recent high-quality evidence demonstrates that valacyclovir significantly reduces vertical transmission when administered during early primary maternal infection. In addition, cost-effectiveness analyses support universal screening in settings with moderate-to-high CMV seroprevalence among childbearing age women. Based on this evidence, the updated Italian guideline recommends CMV serological screening at the first antenatal visit within the first trimester, with monthly testing until 24 weeks in seronegative women, and targeted information on CMV prevention to all pregnant women. This article summarizes the evidence and decision-making process behind this new national recommendation and highlights its potential relevance to other countries currently considering the implementation of a similar screening policy.

Objectives: This research explored a cross-country comparison of qualitative and quantitative data assessing the experiences of prenatal genomic healthcare professionals (HCP) in Australia and the Netherlands.

Method: The interview script included open-ended questions on work experience, validated scales on compassion fatigue and stress, and demographic details. Content analysis with an inductive coding approach was used for the coding and analysis of qualitative data. Quantitative data were compared between professions and countries, using a one-way ANCOVA.

Results: Quantitative data were obtained from 93 participants and qualitative data from a subset of 63 participants, recruited from the departments of clinical genetics, maternal-fetal medicine and genomic laboratories. The following themes were constructed: (1) Advancements in prenatal genomics increase diagnostic rates but cause increased workloads; (2) Benefits and drawbacks of the current healthcare system; (3) The burden of equivocality: high stakes and ambiguous findings; and (4) Multidisciplinary teamwork, support and supervision may improve working conditions. There were no significant differences in compassion fatigue between professions, but Australian HCPs experienced significantly more symptoms of burnout and secondary traumatic stress than Dutch HCPs.

Conclusion: Although participants had overall positive views and experiences, with high levels of job satisfaction and low levels of compassion fatigue, additional resources are required to minimize professional burnout while dealing with increasing demands.

Objective: This study aimed to evaluate the perinatal outcome of fetal abdominal cysts based on the timing of prenatal diagnosis and identify prenatal characteristics associated with postnatal surgical intervention.

Methods: Fetuses with prenatally detected isolated abdominal cysts referred between January 2007 and December 2022 were included. Fetuses with multiple congenital anomalies or cysts suspected of renal or spinal origin were excluded.

Results: Among the 253 included cases, 67.6% (171/253) of the abdominal cysts regressed spontaneously either prenatally or postnatally. Persistent cysts were observed during postnatal follow-up in 28.9% (73/253) and in 3.6% (9/253) the suspected abdominal cyst was reclassified as another anomaly during postnatal follow-up. Two cases of a transient cyst diagnosed in the first trimester required surgical intervention postpartum. Surgical intervention was performed in 16.2%. Multivariate analysis showed that prenatal cysts > 40 mm were strongly associated with surgical intervention (OR 10.25, 95% CI 4.08-25.74). Diagnosis before 16 weeks (OR 5.03, 95% CI 1.04-24.42) and between 16 and 24 weeks (OR 6.42, 95% CI 2.49-16.51) was also linked to higher odds of surgery compared with diagnosis after 24 weeks, whereas gender showed no significant association.

Conclusion: Isolated fetal abdominal cysts have a good prognosis with a high rate of spontaneous regression (67.6%) and a low rate of surgical intervention (16.2%). However, especially first trimester cysts carry a significant risk of persistent lesions necessitating surgical intervention for which follow-up is recommended, even when prenatal regression is suspected.

Objective: Myotonic dystrophy type 1 (DM1) is an autosomal dominant neurodevelopmental disorder caused by CTG repeat expansion in the DMPK gene. Although the clinical classification of DM1 is determined by the CTG repeat length in DMPK, conventional sizing relies on Southern blotting, which is a suboptimal method in prenatal and PGD contexts as it requires large amounts of genomic DNA. We here evaluated the utility of nanopore long read sequencing (LRS) for DM1 diagnosis in these contexts.

Method: LRS was performed with adaptive sampling or CRISPR/Cas9-mediated enrichment targeting DMPK. The use of whole genome amplified DNA (WGA-DNA) prepared with RepliG was also assessed.

Results: Adaptive sampling and Cas9-based LRS enabled detection of both the normal and expanded alleles. Further, LRS with CRISPR/Cas9-mediated enrichment improved efficiency and enabled accurate sizing of expanded CTG repeats exceeding 1000 units. In contrast, the use of whole genome amplified DNA prepared with RepliG did not permit reliable CTG repeat sizing, even when combined with adaptive sampling or CRISPR/Cas9.

Conclusion: Nanopore sequencing can potentially replace Southern blotting for prenatal DM1 diagnosis, including repeat sizing. However, further improvement is needed for PGD using WGA-DNA.

Objective: To develop a consensus-based framework to support individualized prenatal counselling for congenital diaphragmatic hernia.

Method: A RAND-modified Delphi study was conducted with an expert panel of parents (n = 10) and healthcare professionals (n = 17) working in Dutch or Flemish CDH European Reference Network (ERN) centres. In three consensus rounds, a preliminary list of recommendations (n = 101) from literature and previous studies was refined to a final list of recommendations.

Results: The process yielded 40 recommendations across four domains: (a) organization and logistics of the counselling, (b) information provision, (c) decision-making and (d) preconditions. For (a), counselling should take place in CDH ERN centres, involving a multidisciplinary team familiar with the severity assessment and management of foetuses and infants with CDH. For (b), both medical and psychosocial aspects should be discussed. For (c), options for pregnancy continuation, antenatal management where applicable, or termination must be clearly explained, ensuring parental understanding, autonomy, and value clarification. For (d), high-quality, personalized information, decision-making support, and care for mental health are essential.

Conclusion: A framework for prenatal counselling for CDH was developed, combining evidence-based extraction of recommendations with expert consensus. It incorporates the needs, experiences, perceptions, and perspectives of both parents and healthcare providers.

Objective: To characterize prenatal phenotypes and genetic basis of ciliopathies identified by prenatal exome sequencing (pES) in fetuses with ultrasound abnormalities.

Method: Singleton pregnancies who underwent pES due to fetal ultrasound abnormalities were retrospectively reviewed between 2020 and 2023. Cases affected by ciliopathies were included if diagnostic variants were identified in 959 ciliopathy-associated gene entries in the manually curated SCGSv2 and integrated database CilioGenics (top 500). Phenotype-genotype correlations were analyzed.

Results: A total of 41 cases were diagnosed as ciliopathies by pES with a detection rate of 7.4% (41/555). DYNC2H1 and FGFR3 were the most common genes associated with first-order and second-order skeletal ciliopathies, while PKD1 was the major causative gene of renal ciliopathies. Consistent with genetic diagnoses, skeletal (53.7%, 22/41) and kidney (34.1%, 14/41) abnormalities were frequent features by ultrasound. Kidney abnormalities (59.1%, 13/22) were more prominent in first-order ciliopathies, especially hyperechogenic kidneys. By contrast, skeletal findings (78.9%, 15/19) were the leading ultrasound sign in second-order ciliopathies, usually manifesting as short limbs.

Conclusions: Ciliopathies prenatally present with variable ultrasound features, with kidney and skeletal systems frequently affected in first-order and second-order ciliopathies. Characterization of the genetic etiology and phenotypes of prenatal ciliopathies will increase our understanding of fetal genetic disorders.

Objectives: To report the outcome of isolated rare anomalies of the cavum septi pellucidum (CSP) and corpus callosum (CC), including obliterated CSP, septal agenesis, hypoplasia of the CC, pericallosal lipoma, thin and thick CC and wide and narrow CSP.

Methods: Medline, Embase and Cochrane databases were searched. Inclusion criteria were studies reporting the outcome. The outcomes observed were genetic anomalies, associated anomalies detected exclusively at follow-up ultrasound, fetal MRI or post-natal imaging, and adverse neurodevelopmental outcomes. Random-effect meta-analyses of proportions were used to combine data.

Results: Thirty-three studies (604 fetuses) were included; an isolated anomaly was reported at the time of the initial diagnosis in 394 fetuses. There was no abnormal karyotype in any of the anomalies explored in the present systematic review. Abnormal neurodevelopmental outcome was reported in 9.7% of children with obliterated CSP, 15.4% of those with isolated septal agenesis, 24.9% of those with hypoplastic CC, 33% of those with thin CC, 8.7% of those with wide CSP, and none of the cases with isolated pericallosal lipoma and tick CC.

Conclusion: The outcome is generally favorable in cases of isolated obliterated CSP, pericallosal lipoma, wide CSP and tick CC, while the small number of included cases does not allow drawing a robust conclusion of fetuses presenting with thin CSP and narrow CSP.

Objective: Current inclusion criteria for fetal surgery at most centers include the absence of multiple major anomalies and a normal chromosome analysis or fluorescence in situ hybridization (FISH) for aneuploidy. We evaluated the concordance of FISH with non-invasive screening methodologies to determine if invasive genetic testing provides additional information on fetal surgery candidacy.

Methods: A retrospective chart review was performed on 963 pregnancies evaluated for fetal surgery at the Cincinnati Children's Hospital Fetal Care Center between July 1, 2018 and July 31, 2023 for genetic testing results, fetal imaging, and surgical candidacy.

Results: FISH was concordant with screening results in 100% of pregnancies whose imaging and cell-free fetal DNA screening suggested a fetus at low risk for trisomy 21, trisomy 18, trisomy 13, and sex chromosome aneuploidies. Pregnancies with multiple congenital anomalies were significantly more likely to have abnormal genetic testing compared to pregnancies with isolated anomalies (52% vs. 17%, P = 0.0009).

Conclusions: In this study cohort, FISH did not provide additional information for the risk-benefit analysis of fetal surgery and introduced additional risk to the pregnancy due to the need for invasive fetal DNA collection.

Objective: This study aimed to evaluate the clinical value of integrating optical genome mapping (OGM) with conventional genetic methods in the diagnosis of families with spontaneous abortion or offspring abnormalities.

Method: Herein, 24 families were included. Genetic testing was first applied in fetuses and children according to indications if samples were available. A parental study was then conducted using OGM with or without conventional methods.

Results: In total, 76 samples (28 samples of fetuses and children from 20 families and 48 samples of all 24 parents) were investigated. Clinically reported variants were identified in 21 (21/28, 75.0%) fetuses and children from 17 (17/20, 85.0%) families. OGM with or without conventional methods detected 16 (16/24, 66.7%) clinically reported variants in either parent, including five submicroscopic balanced translocations, two microscopic balanced translocations, four complex chromosomal rearrangements, two D4Z4 repeat contraction disorders, and three variants of uncertain significance (VOUS). Additionally, variations detected in fetuses and children from three (3/24, 12.5%) families were determined to be de novo by OGM. OGM identified structural variations (SVs) out of the detection range of conventional methods and provided structure and breakpoint information to improve clinical interpretation.

Conclusion: This study illustrates that integrating OGM with conventional methods is a feasible and powerful strategy in families with spontaneous abortion or offspring abnormalities.

Objective: Comprehensive prenatal screening (CPS) (carrier screening and cfDNA for aneuploidy, 22q11.2 deletion syndrome, CNVs > 7Mb, and single gene disorders) can non-invasively identify genetic conditions in fetuses with congenital heart defects (CHD). We calculated the theoretical performance of CPS for CHDs with underlying genetic diagnoses. Secondarily, we compared theoretical performances across CHD subtypes and by the presence of extracardiac anomalies.

Methods: We retrospectively examined cases of fetal cardiac anomalies with known causative genetic diagnoses from January 2020 to October 2024. We calculated theoretical CPS performance by determining which genetic diagnoses were identifiable by CPS modalities.

Results: We extracted 153 fetuses with CHD and a known causative genetic diagnosis. Diagnoses included aneuploidies (37%), single gene disorders (22%), CNVs (18%), 22q11.2 deletion syndrome (17%), multiple diagnoses (6%), and uniparental disomy (1%). Of the 153 cases, 117 were identifiable by CPS, corresponding to a theoretical performance of 76%. Theoretical performances did not differ significantly across CHD categories or by the presence of extracardiac anomalies.

Conclusions: Antenatal diagnostic testing remains the standard of care for fetal anomalies. Among individuals who decline diagnostic testing, our findings suggest that, in cases where a CHD has an underlying genetic cause, an optimal combination of currently available screening tests could theoretically identify up to 76% of genetic causes. However, actual performance will be lower in clinical practice.