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This article, titled "Prenatal detection of Down syndrome based on second and third trimester ultrasound scan," examines the incidence of Down Syndrome suspected on late trimester scans. The study analyzed the medical records of pregnant women who gave birth to babies with confirmed Down Syndrome. Out of 126 mothers, 80 had at least one prenatal scan, and 50 of them had abnormal findings on the scans. 15 fetuses were suspected with Down Syndrome, and further genetic testing confirmed the diagnosis in some cases. The article suggests that early prenatal diagnosis through first trimester screening programs could be beneficial for counseling and support. [Extracted from the article]

This article, published in the journal Ultrasound in Obstetrics & Gynecology, discusses the challenges of prenatal diagnosis of genetic disorders through ultrasound. The study analyzed the prenatal ultrasound findings and genetic test results of neonates born without major congenital anomalies but later diagnosed with genetic disorders through Next-Generation Sequencing (NGS). The results showed that meaningful gene mutations were detected in 60.3% of the neonates, with 76.3% of them exhibiting soft markers or abnormalities in fetal size or amniotic fluid observed in prenatal ultrasound. The study concludes that when multiple ultrasound findings abnormalities are observed, an assessment for genetic disorders may be considered after birth. [Extracted from the article]

Summary: Clinician bias negatively impacts the healthcare received by marginalized communities. In this study, we explored factors that influence clinician and trainee bias against individuals with intellectual disabilities and its impact on clinical judgment in prenatal genetic testing settings. Specifically, we examined bias toward a fetus with a higher chance of developing a disability. We compared genetics specialists with their non-expert counterparts. This web-based study included clinical vignettes, implicit association tests (IATs), and an educational module. 595 participants were recruited via their institution or professional society. We conducted statistical analyses, including regression models controlling for key demographic characteristics, to analyze recommendation patterns and degree of change after the module. Genetics expertise strongly correlated with appropriate testing recommendation when the patient would not consider pregnancy termination (r = 1.784 pre-module, r = 1.502 post-module, p

Background: Obstetric complications (OCs) are key contributors to psychosis risk. However, it is unclear whether they increase psychosis vulnerability independently of genetic risk, in interaction with it, or are a manifestation of psychosis proneness. We examined the role of distinct types of OCs in terms of psychosis risk and tested whether they interact differently with genetic vulnerability, whilst accounting for other known environmental risk factors. Study Design: 405 participants (219 first episode psychosis patients and 186 healthy volunteers) underwent a comprehensive assessment of OCs, measured using the Lewis‐Murray scale and divided into complications of pregnancy, abnormalities of foetal growth and development, and complications of delivery. Participants were compared in terms of history of OCs, polygenic risk score for schizophrenia (PRS‐SZ) and interactions between these. Results: Both complications of pregnancy and abnormalities of foetal growth were significantly associated with case–control status (p = 0.02 and 0.03, respectively), whereas complications of delivery were not. PRS‐SZ showed a significant association with psychosis (p = 0.04), but there were no significant interactions between genetic risk for schizophrenia and OCs, either when these were considered globally or separated based on their timeframe. Conclusions: We observed no significant interaction between genetic and obstetric vulnerability, yet distinct types of OCs may have a different impact on psychosis risk, based on their nature and timeframe. Examining their differential role might clarify their relative contributions to this risk. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the prenatal characteristics of double aortic arch (DAA), assess the relative size of the arches and their growth during pregnancy, describe associated cardiac, extracardiac and chromosomal/genetic abnormalities and review postnatal presentation and clinical outcome. Methods: This was a retrospective cohort study of all fetuses with a confirmed diagnosis of DAA seen in five specialized referral centers in London, UK, between October 2012 and November 2019. Cases were identified from the hospitals' fetal databases. Fetal echocardiographic findings, intracardiac and extracardiac abnormalities, genetic defects, computed tomography (CT) findings and postnatal clinical presentation and outcome were evaluated. Results: A total of 79 fetuses with DAA were included. Of those assessed postnatally, 48.6% had an atretic left aortic arch (LAA), while 5.1% had an atretic LAA at the first fetal scan and were misdiagnosed antenatally with right aortic arch (RAA). The LAA was atretic in 55.8% of those who underwent CT. DAA was an isolated abnormality in 91.1% of cases; 8.9% of patients had an additional intracardiac abnormality and 2.5% had both intra‐ and extracardiac abnormalities. Among the 52 cases that underwent genetic testing, 11.5% had genetic abnormalities and, specifically, the 22q11 microdeletion was identified in 3.8% of patients. At a median follow‐up of 993.5 days, 42.5% of patients had developed symptoms of tracheoesophageal compression (5.5% during the first month after birth) and 56.2% had undergone intervention. Statistical analysis using the χ‐square test showed no significant relationship between morphology of DAA (patency of both aortic arches vs atretic LAA) and the need for intervention (P = 0.134), development of vascular ring symptoms (P = 0.350) or evidence of airway compression on CT (P = 0.193). Conclusions: Most cases of DAA can be diagnosed easily at midgestation, as typically both arches are patent with a dominant RAA at this stage. However, we found that the LAA had become atretic in approximately half of the cases postnatally, supporting the theory of differential growth of the arches during pregnancy. DAA is usually an isolated abnormality; however, thorough assessment is required to exclude associated intra‐ and extracardiac anomalies and to determine the need for invasive prenatal genetic testing. Postnatally, early clinical assessment is needed and CT scan should be considered, irrespective of the presence of symptoms. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

There is no gene for fate: Kostas Kampourakis: Understanding genes. According to Kampourakis, this approach helps us to realize that organisms are not direct I products i of their genetic makeup, since genes are rather default I resources i for cells and other respective levels, which are then co-responsible for a particular development within a particular environment. The fifth and penultimate chapter, "What Genes Do", focuses on the positive account of the functional role of genes, i.e., this chapter examines what genes really do with respect to other levels of biological organization (protein, molecular, cellular, etc.). [Extracted from the article]

(1) Background: The aim of our study is to evaluate whether cell-free DNA testing can overlap the genetic testing of miscarriage tissue in women with early pregnancy loss (EPL) and length of recurrent pregnancy loss (RPL); (2) Methods: We conducted a prospective cohort study at the Pregnancy Loss Unit of the Fondazione Policlinico Universitario A. Gemelli (IRCCS), Rome, Italy between May 2021 and March 2022. We included women with EPL and length of RPL. Gestational age was >9 weeks + 2 days and <12 weeks + 0 days of gestation corresponding to a crown rump length measurement of >25 and <54 mm. Women underwent both dilation and curettage for the collection of miscarriage tissue and for blood sample collection. Chromosomal microarray analysis (CMA) on miscarriage tissues was performed by oligo-nucleotide- and single nucleotide polymorphisms (SNP)-based comparative genomic hybridization (CGH+SNP). Maternal blood samples were analyzed by Illumina VeriSeq non-invasive prenatal testing (NIPT) to evaluate the cell-free fetal DNA (cfDNA) and the corresponding fetal fraction and the presence of genetic abnormalities; (3) Results: CMA on miscarriage tissues revealed chromosome aneuploidies in 6/10 cases (60%), consisting of trisomy 21 (5 cases) and monosomy X (one case). cfDNA analysis was able to identify all cases of trisomy 21. It failed to detect monosomy X. A large 7p14.1p12.2 deletion concomitant to trisomy 21 was, in one case, detected by cfDNA analysis but it was not confirmed by CMA on miscarriage tissue. (4) Conclusions: cfDNA largely reproduces the chromosomal abnormalities underlying spontaneous miscarriages. However, diagnostic sensitivity of cfDNA analysis is lower with respect to the CMA of miscarriage tissues. In considering the limitations when obtaining biological samples from aborted fetuses suitable for CMA or standard chromosome analysis, cfDNA analysis is a useful, although not exhaustive, tool for the chromosome diagnosis of both early and recurrent pregnancy loss. [ABSTRACT FROM AUTHOR]

Objectives: Explore health-care seeking behaviour among couples with pregnancies at-risk of monogenic disorders and compare time duration for obtaining Prenatal Genetic Test (PGT) results based on (i) amniocentesis and Chorionic Villus Sampling (CVS) (ii) in-house testing and out-sourced testing. Report the spectrum of monogenic disorders in our cohort. Methods: Medical records of women consulting prenatal genetic counselling clinic at Aga Khan University Hospital, Karachi from December-2015 to March-2021 with history of miscarriage or a monogenic disorder in previous children were reviewed. Results: Forty-three pregnancies in 40 couples were evaluated, 37(93%) were consanguineous. Twenty-five (63%) couples consulted before and 15(37%) after conception. Thirty-one (71%) pregnancies underwent CVS at the mean gestational age of 13-weeks and 6-days ± 1-week and 3-days and amniocentesis at 16-weeks and 2-days ± 1-week and 4-days. PGT for 30 (70%) pregnancies was outsourced. The mean number of days for in-house PGT was 16.92 ± 7.80 days whereas for outsourced was 25.45 ± 7.7 days. Mean duration from procedure to PGT result was 20.55 days after CVS compared to 28.75 days after amniocentesis. Eight (18%) fetuses were homozygous for disease-causing variant for whom couples opted for termination of pregnancy (TOP). Twenty-six monogenetic disorders were identified in 40 families. Conclusion: Proactive health-care seeking behaviour and TOP acceptance is present amongst couples who have experienced a genetic disorder. [ABSTRACT FROM AUTHOR]

Vascular rings, including right aortic arch with aberrant left subclavian artery (RAA-ALSCA), double aortic arch (DAA) and pulmonary artery sling (PAS), are congenital anomalies that may cause airway and oesophageal compression. As prenatal detection has improved, literature comparing clinical outcomes of antenatally versus postnatally diagnosed cases continues to emerge. The aim is to define a statewide tertiary paediatric institution's clinical profile and outcomes of prenatal versus postnatally diagnosed isolated vascular rings. A retrospective single-centre review of isolated RAA-ALSCA, DAA and PAS between 1 January 1999 and 31 December 2020 was conducted. Clinical characteristics, surgical and follow-up information were collected. Antenatal and postnatally diagnosed groups were compared. Out of 123 cases diagnosed with isolated vascular rings, 98 (79.7%) cases had RAA-ALSCA, 21 (17.1%) with DAA, 4 (3.3%) with PAS. The antenatal detection rate was 73.6% in the past decade; 20.3% had a genetic disorder, of which 48% had 22q11.21 microdeletion. Of prenatally diagnosed cases, 31.3% developed symptoms, commonly stridor and dysphagia, at a median age of 2.0 months (IQR 0.0–3.0), compared to a median age of diagnosis for the postnatal cohort of 9 months (IQR 1.0–40.7). Postnatally diagnosed cases were more likely to present with symptoms, primarily respiratory distress, than prenatally diagnosed cases (p=0.006). Fifty-nine (59) cases (50% antenatally diagnosed) required vascular ring division; 6.8% had residual symptoms following surgery. Antenatal diagnosis has improved and leads to better parental awareness and more timely, appropriate intervention. Postnatally diagnosed patients were older, more likely to be symptomatic, underwent more investigations and were commenced on more medications for symptom management prior to diagnosis. One in five cases of isolated vascular ring anomalies carried a genetic diagnosis, which has important implications on prenatal counselling and genetic testing. [ABSTRACT FROM AUTHOR]

To present the fetal features of Cornelia de Lange Syndrome (CdLS) with a molecular confirmation. This was a retrospective study of 13 cases with CdLS diagnosed by prenatal and postnatal genetic testing and physical examination. Clinical and laboratory data were collected and reviewed for these cases, including maternal demographics, prenatal sonographic findings, chromosomal microarray and exome sequencing (ES) results, and pregnancy outcomes. All of the 13 cases were detected to have a CdLS-causing variant, with 8 variants identified in the NIPBL gene, 3 in SMC1A , and 2 in HDAC8. Five had normal ultrasound scans during pregnancy; all were caused by variants of SMC1A or HDAC8. For the eight cases with NIPBL variants, all had prenatal ultrasound markers. Three had first trimester ultrasound markers including increased nuchal translucency in one and limb defects in three. Four presented with normal ultrasound in the first trimester, but abnormal ultrasound in the second trimester, including micrognathia in two, hypospadias in one and intrauterine growth retardation (IUGR) in one. IUGR as the isolated feature was identified in one case in the third trimester. The prenatal diagnosis of CdLS caused by NIPBL variants is possible. It seems to remain challenging to detect non-classic CdLS only relying on ultrasound examination. [ABSTRACT FROM AUTHOR]

PurposeExome sequencing (ES) has the potential to improve management of congenital anomalies and neurodevelopmental disorders in fetuses, infants, and children. US payers are key stakeholders in patient access to ES. We examined how payers view insurance coverage and clinical utility of pediatric and prenatal ES.MethodsWe employed the framework approach of qualitative research to conduct this study. The study cohort represented 14 payers collectively covering 170,000,000 enrollees.ResultsSeventy-one percent of payers covered pediatric ES despite perceived insufficient evidence because they saw merit in available interventions or in ending the diagnostic odyssey. None covered prenatal ES, because they saw no merit. For pediatric ES, 50% agreed with expanded aspects of clinical utility (e.g., information utility), and 21% considered them sufficient for coverage. For prenatal ES, payers saw little utility until in utero interventions become available.ConclusionThe perceived merit of ES is becoming a factor in payers' coverage for serious diseases with available interventions, even when evidence is perceived insufficient. Payers' views on ES's clinical utility are expanding to include informational utility, aligning with the views of patients and other stakeholders. Our findings inform clinical research, patient advocacy, and policy-making, allowing them to be more relevant to payers.

With a very large population and high birth rate, and consanguineous marriage favored in many communities, there is a high prevalence of genetic disorders in India. The cross-sectional study was carried out in people of the Kanyakumari District, Tamil Nadu community males and, females both married and single with a wide range of ages and educational backgrounds as well as covering a diverse number of generic diseases. The cross-sectional survey was conducted among people of the Kanyakumari District, Tamil Nadu (n = 201) to determine their practices toward reproductive decision-making. The main objective of the study is to analyze the participant's knowledge of the practices towards prenatal diagnosis (PND) and termination of pregnancy. Genetic testing has the maximum possible potential to reduce the prevalence of genetic disorders by early detection. Studies found that general knowledge of genetic diseases in Tamil Nadu lacks an understanding of the fundamental characteristics of genetic diseases. Primarily due to the occurrence of consanguineous marriages 20%. The practice towards PND (61%) was more favorable than TOP (39%). PND was found to be a good opportunity for early diagnosis and gives parents choice. In Kanyakumari District, most people will have an awareness of genetic disorders, Prenatal diagnosis, and Termination of pregnancy. Mercy (22.60%), religious belief (12.8%), and sin (12.2%) is the main influence on the participant's practices concerning Prenatal diagnosis and Termination of pregnancy. The fetus was diagnosed with a genetic disorder before 120 days of pregnancy, they have undergone abortion favored by 61.2%, and unfavored by 48% of the people. 62% of members responded to the diagnosis of a fetus with genetic diseases before delivery, and 38% were not accepted in prenatal diagnosis. 50.8% of members not knowing the causes of a family history of genetic diseases. But 49.2% know the causes of a family history of genetic diseases. The reason for rejecting the above question was religious belief (12.8%), Ethics (10.4%), culture (9.8%) Mercy (22.6%), sin (12.2%), Others reason (32.3%). For accepting abortion before 120 days of pregnancy (50.2%) members for getting a healthy child (68.9%), to avoid the affected child (31.1%). The current challenge of the research is a comprehensive effort to revisit consanguineous marriages and their effects with more recent using statistical methods to assess the prevalence and effect of consanguineous marriages on pregnancy. [ABSTRACT FROM AUTHOR]

Whole exome sequencing (WES) has become part of the postnatal diagnostic work-up of both pediatric and adult patients with a range of disorders. In the last years, WES is slowly being implemented in the prenatal setting as well, although some hurdles remain, such as quantity and quality of input material, minimizing turn-around times, and ensuring consistent interpretation and reporting of variants. We present the results of 1 year of prenatal WES in a single genetic center. Twenty-eight fetus-parent trios were analyzed, of which seven (25%) showed a pathogenic or likely pathogenic variant that explained the fetal phenotype. Autosomal recessive (4), de novo (2) and dominantly inherited (1) mutations were detected. Prenatal rapid WES allows for a timely decision-making in the current pregnancy, adequate counseling with the possibility of preimplantation or prenatal genetic testing in future pregnancies and screening of the extended family. With a diagnostic yield in selected cases of 25% and a turn-around time under 4 weeks, rapid WES shows promise for becoming part of pregnancy care in fetuses with ultrasound anomalies in whom chromosomal microarray did not uncover the cause. [ABSTRACT FROM AUTHOR]

Non-invasive prenatal testing (NIPT) using cell-free DNA can detect fetal chromosomal anomalies with high clinical sensitivity and specificity. In approximately 0.1% of clinical cases, the NIPT result and a subsequent diagnostic karyotype are discordant. Here we report a case of a 32-year-old pregnant patient with a 44.1 Mb duplication on the short arm of chromosome 4 detected by NIPT at 12 weeks' gestation. Amniocentesis was carried out at 18 weeks' gestation, followed by conventional and molecular cytogenetic analysis on cells from the amniotic fluid. SNP array analysis found a de novo deletion of 1.2 Mb at chromosome 4, and this deletion was found to be near the critical region of the Wolf-Hirschhorn syndrome. A normal 46,XY karyotype was identified by G-banding analysis. The patient underwent an elective termination and molecular investigations on tissues from the fetus, and the placenta confirmed the presence of type VI true fetal mosaicism. It is important that a patient receives counselling following a high-risk call on NIPT, with appropriate diagnostic analysis advised before any decisions regarding the pregnancy are taken. This case highlights the importance of genetic counselling following a high-risk call on NIPT, especially in light of the increasing capabilities of NIPT detection of sub-chromosomal deletions and duplications. [ABSTRACT FROM AUTHOR]

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by the arrest of fetal lung formation, resulting in neonatal death due to acute respiratory failure and pulmonary arterial hypertension. Heterozygous single-nucleotide variants or copy-number variant (CNV) deletions involving the FOXF1 gene and/or its lung-specific enhancer are found in the vast majority of ACDMPV patients. ACDMPV is often accompanied by extrapulmonary malformations, including the gastrointestinal, cardiac, or genitourinary systems. Thus far, most of the described ACDMPV patients have been diagnosed post mortem, based on histologic evaluation of the lung tissue and/or genetic testing. Here, we report a case of a prenatally detected de novo CNV deletion (~0.74 Mb) involving the FOXF1 gene in a fetus with ACDMPV and hydronephrosis. Since ACDMPV is challenging to detect by ultrasound examination, the more widespread implementation of prenatal genetic testing can facilitate early diagnosis, improve appropriate genetic counselling, and further management. [ABSTRACT FROM AUTHOR]

Background : Treatment of psychotic disorders in pregnancy is often ethically and clinically challenging, especially when psychotic symptoms impair decision-making capacity. There are several competing ethical obligations to consider: the ethical obligation to maternal autonomy, the maternal and fetal beneficence-based obligations to treat peripartum psychosis, and the fetal beneficence-based obligation to minimize teratogenic exposure. Objective : This article outlines an ethical framework for clinical decision-making for the management of chronic psychosis in pregnancy, with an emphasis on special considerations in the previable and periviable period. Case Presentation : A 31-year-old gravida 2, para 1 with intrauterine pregnancy at 12 weeks and 4 days gestation was brought to the emergency department by her husband seven months after delivering her first child, due to sudden onset of behavioral changes that included self-isolation, not eating, and not taking care of her child. Her past medical history included hypothyroidism and inflammatory bowel disease, but no prior psychiatric illness. After being admitted to the psychiatric hospital, she continued to have poor oral intake and weight loss despite initial inpatient treatment with antipsychotics, levothyroxine, and discontinuation of corticosteroids. Her pregnancy was also complicated by the diagnosis of multiple fetal anomalies at 20 weeks gestation, when the fetus was periviable. Conclusions : For previable or periviable pregnancies, the patient and/or surrogate should decide whether to pursue prenatal genetic screening and invasive diagnostic testing, as well as whether to continue or terminate the pregnancy. When the choice is made to continue the pregnancy, initiation of long-term psychiatric treatment (including medications with potential adverse fetal effects) should be based on shared decision-making between the physician and the patient and/or surrogate. Although some pharmacologic interventions may have potential adverse effects on the developing fetus, the use of psychotropic medications can be ethically justified, even if the patient herself does not have the capacity to consent and requires a surrogate, when the goal is to restore maternal autonomy and minimize the risks of maternal and fetal harm from untreated psychiatric illness. [ABSTRACT FROM AUTHOR]

The article focuses on the emerging challenge for doctors in informing pregnant patients about genetic carrier screening and testing, so they can make an informed decision. Topics include understand the implications of genetic carrier screening with medicolegal issues of informed consent and autonomy, the importance of providing patients with enough information to make an informed decision; and the challenges involved in explaining the implications of genetic carrier screening.

Prenatal genetic screening and diagnostic testing options vary greatly by gestational age, and practice patterns will be affected by gestational age–based abortion restrictions post- Roe. Prenatal genetic screening and diagnostic testing should be offered to every pregnant individual, with methods varying based on gestational age. Since Roe v Wade was overturned in June 2022, many states have implemented gestational age–based abortion restrictions. It is critical that reproductive health care professionals be aware of the interaction between the timing of genetic screening and diagnostic testing and the availability of legal abortion services in their state. We examined individual state abortion restrictions per publicly available data from The New York Times and the Guttmacher Institute and reviewed which genetic screening and diagnostic tests could be performed to provide results in time for individuals to decide whether to terminate their pregnancies legally in each state. As of December 11, 2022, 14 states have restrictions in which no diagnostic testing could be completed before gestational age–based cutoffs. Gestational age–based abortion restrictions may also influence a patient to favor chorionic villous sampling (CVS) over amniocentesis. There are two states, Florida and Arizona, where CVS would be feasible before the state's gestational age limit on abortion but amniocentesis would not. Both CVS and amniocentesis are feasible in 35 states, with legal challenges pending in 8 of the 35. Seven states specifically prohibit abortion for fetuses with genetic abnormalities. Clinicians may be placed in the suboptimal position of counseling patients with screening results alone before the gestational age–based ban in their state. There are several potential downstream consequences of gestational age–based termination restrictions for current genetic screening and testing paradigms, from adjustments to counseling options to potentially higher CVS procedure rates. Clinicians should be prepared for practice patterns to change to best serve patients in this evolving legal context. [ABSTRACT FROM AUTHOR]

Background: Hypochondroplasia (HCH) is a common nonlethal skeletal dysplasia caused by pathogenic variations in the fibroblast growth factor receptor 3 (FGFR3) gene, and HCH has similar clinical manifestations with achondroplasia (ACH), which can be screened during the fetal period by prenatal ultrasound testing and diagnosed by genetic testing. Case presentation: we report the special case of a patient with obvious growth retardation and rhizomelic disproportionate short stature, accompanied by other manifestations, including an enlarged head and short hands at 1 year old. However, several multiple color ultrasound exams identified shortened limbs (< 3rd percentile), an increased biparietal diameter (> 95th percentile) and a low nasal bridge in the fetal period. Due to the high incidence rate of ACH, genetic testing for the hotspot FGFR3 gene c.1138 g > A pathogenic variations was performed immediately in the third trimester. Unfortunately, the definitive diagnosis could not be made before birth due to the negative result of hotspot gene exam. Whole exome sequencing (WES) was performed at 1 year identified FGFR3 gene c.1620C > A variations positivity, and the patient was finally diagnosed as HCH. Conclusion: Our report extends the understanding of the limitations of prenatal genetic diagnostic testing, especially the hot spot pathogenic variations test should be not the only clinical diagnostic basis. Moreover, this case also emphasizes that further gene analysis for patients with significant conflict between the clinical manifestation and the prenatal genetic panel examination findings should be reconducted timely to spare the family from a delayed diagnosis or a misdiagnosis. [ABSTRACT FROM AUTHOR]

X-linked myopia 26 (Myopia 26, MIM #301010), which is caused by the variants of ARR3 (MIM *301770), is characterized by female-limited early-onset high myopia (eo-HM). Clinical characteristics include a tigroid appearance in the fundus and a temporal crescent of the optic nerve head. At present, the limited literature on eo-HM caused by ARR3 mutations shows that its inheritance mode is complex, which brings certain difficulties to pre-pregnancy genetic counseling, pre-implantation genetic diagnosis, and prenatal diagnosis. Here, we investigated the genetic underpinning of a Chinese family with eo-HM. Whole exome sequencing of the proband revealed a novel frameshift mutation in ARR3 (NM_004312, exon10, c.666delC, p. Asn222LysfsTer22). Although the mode of inheritance of the eo-HM family fits the X-linked pattern of ARR3, the phenotypes of three patients deviate from the typical early-onset high myopia. Through X-chromosome inactivation experiments, the patient's different phenotypes can be precisely explained. In addition, this study not only enhanced the correlation between ARR3 and early-onset high myopia but also provided explanations for different phenotypes, which may inspire follow-up studies. Our results enrich the knowledge of the variant spectrum in ARR3 and provide critical information for preimplantation and prenatal genetic testing, diagnosis, and counseling. [ABSTRACT FROM AUTHOR]

Germline pathogenic variants mutations) in the BRCA1 and BRCA2 genes cause an increased risk of breast cancer and ovarian cancer. Mainstream cancer genetic testing (MCG) was introduced for breast cancer patients in our unit in 2013. Non-geneticist clinicians have been trained to offer genetic testing during initial treatment planning. We assessed the impact of timely test results on surgical decision-making. Women who had undergone mainstream genetic testing for breast cancer between September 2013 and September 2018 were identified from a prospective database. Surgical data were collected retrospectively. 580 eligible women had mainstream genetic testing. For 474 this was their first breast cancer diagnosis. The median age was 46 years (interquartile range (IQR) 38–57). The indications were: age ≤45 years for 233 (49%); triple negative disease for 192 women (40.5%); bilateral breast cancer age <60 for 39 (8%) and other for 72 (14%) women. The median time for test initiation to result was 18 days (IQR 15-21). 302 (64% received results before surgery. 88% of those found to have a BRCA mutation before surgery opted for bilateral mastectomy (compared to 5% with BRCA wild type). An additional 106 patients had a new diagnosis on a background of previous treatment. Of these all with a pathogenic variant chose bilateral mastectomy. Timely BRCA gene testing influences surgeons' and patients' choice of surgery. It reassures women with a negative result and allows those with a positive result to take an active decision about the management of their future risk. • Early access to rapid genetic testing for high risk women allows results to contribute to surgical decision-making. • Median time to receiving results was 29 calendar days9% had a pathogenic mutation. • Women with mutations were more likely to have bilateral mastectomy as their primary surgery if results were available before surgery. Those for whom results were available after surgery often chose additional risk-reducing surgery. • Only 4% of women without a mutation had bilateral mastectomy. [ABSTRACT FROM AUTHOR]

Establishing the diagnosis of a fetal genetic disease in utero expands decision-making opportunities for individuals during pregnancy and enables providers to tailor prenatal care and surveillance to disease-specific risks. The selection of prenatal genetic tests is guided by key details from fetal imaging, family and obstetrical history, suspected diagnoses and mechanisms of disease, an accurate understanding of what abnormalities each test is designed to detect, and, at times, the gestational age at which testing is initiated. Pre- and posttest counseling, by or in conjunction with providers trained in genetics, ensure an accurate understanding of genetic tests, their potential results and limitations, estimated turnaround time for results, and the clinical implications of their findings. As prenatal diagnosis and testing options continue to expand rapidly, it is increasingly important for obstetrical providers to understand how to choose appropriate genetic testing and contextualize the clinical implications of their results. [ABSTRACT FROM AUTHOR]

This article discusses a case of prenatal diagnosis of congenital eyelid eversion in a fetus with trisomy 21. A 27-year-old pregnant woman underwent genetic screening for trisomy 21 and a subsequent ultrasound at 39 weeks and 6 days revealed a soft tissue mass below the right eye of the fetus. The male infant was delivered via cesarean section and was found to have congenital bilateral upper eyelid eversion. The article emphasizes the importance of prompt identification and treatment of congenital eyelid eversion, particularly in cases of trisomy 21, as delays can lead to complications including vision loss. The authors suggest that clinicians should consider the diagnosis of eyelid eversion in fetuses with eyelid masses on ultrasound. [Extracted from the article]

Background: Prenatal invasive genetic testing is commonly recommended to pregnancies of early-onset FGR or FGR combined with a structural defect. Our study aimed to explore the genetic findings for FGR without structural malformations according to cytogenetic karyotyping and single nucleotide polymorphism array (SNP array) technology over a 10-year period. Methods: A total of 488 pregnancies diagnosed with FGR without structural malformation were retrospectively reviewed. Cytogenetic karyotyping was performed on all the subjects, and SNP array was available from 272 of them. Based on the gestational age at onset, the cohort was classified into four groups: ≤ 24, 25–28, 29–32, and > 32 weeks of gestation. According to the ultrasound findings, they were grouped into isolated FGR, FGR with soft markers, and FGR with non-structural anomalies. In pregnancies of young maternal age, based on the results of maternal serum screening (MSS), they were categorized into high-risk and low-risk MSS groups. Results: Nineteen (3.9%) cases of chromosomal abnormalities were detected by cytogenetic karyotyping, including 11 cases of numerical abnormalities, 5 cases of structural abnormalities, and 3 cases of mosaicism. Trisomy 21 was the most frequent abnormality. Abnormal karyotypes were more frequently observed in cases diagnosed at ≤ 24 weeks (7.2%) than those in any other group. Among pregnancies with normal karyotype, an incremental yield of 4.2% were revealed by SNP array technology regarding clinically relevant aberrations. The additional detection rates by SNP array in cases diagnosed at ≤ 24 weeks (6.5%), cases with soft markers (9.5%), and cases with high-risk MSS (12.0%) were higher than those in other groups within each classification. All the cases with abnormal karyotypes and 7 out of 11 pregnancies with clinically relevant anomalies revealed by SNP array alone resulted in pregnancy terminations. Conclusion: Chromosome abnormality is an important etiology for FGR with no associated structural malformations, and plays a crucial role in pregnancies decision-making. SNP array improves the detection of genetic anomalies especially in FGR diagnosed at ≤ 24 weeks, FGR combined with soft makers, and FGR combined with high-risk MSS. [ABSTRACT FROM AUTHOR]

Background: Dandy-Walker syndrome (DWS) is a rare congenital malformation of the central nervous system (CNS), characterized by underdevelopment or dysplasia of the cerebellar vermis, expansion of the fourth ventricle and posterior fossa cistern. The incidence is aboutapproximately 1/25000–1/35000. At present, the etiology and pathogenesis of DWS are not completely clear. It is mostly considered to be a multifactorial genetic disease that is related to both genetic factors and environmental factors. There is no large sample size analysis of the chromosomal profile of DWS up to now. This study aims to provide clinical reference for prenatal diagnosis via summarizing the clinical features and pregnancy outcomes of Dandy-Walker syndrome. Methods: A total of 76 cases of foetal Dandy-Walker syndrome out of 19,506 pregnant women underwent cordocentesis or amniocentesis for genetic detection. Rapid prenatal karyotyping, single nucleotide polymorphism array (SNP-array) and BACs-on-Beads™ (BoBs) were performed for prenatal genetic diagnosis. The results of ultrasonography, genetic analysis and pregnancy outcome were recorded. Results: Of the 76 cases, 19 were isolated DWS, while 57 cases were accompanied by other ultrasound-visible abnormalities. Ultrasound abnormalities of the CNS were most frequently observed, accompanied by DWS. Twenty-five out of 76 cases had chromosomal abnormalities, and the rate of chromosomal abnormalities increased in pregnant women of advanced maternal age or in combination with other ultrasound abnormalities. Of the 19 cases in the isolated DWS group, nine pregnant women chose to terminate the pregnancy, while seven cases continued the pregnancy and all infants were normal. Among the 57 pregnant women with pathological ultrasound manifestations other than foetal DWS, 44 chose to terminate the pregnancy, while 12 cases continued the pregnancy. Further follow-up revealed one newborn with postnatal neurodevelopmental delay. A female term neonate presented with very severe sensorineural deafness, and an infant died 7 days after birth with abnormal development of multiple organs. Conclusions: Pregnant women with DWS in foetal ultrasonic examination should be offered a careful and comprehensive foetal ultrasound scan and further prenatal genetic testing including karyotype analysis and SNP-array. The prognosis of the foetus without chromosomal aberration is good in isolated DWS pregnancies but poor in nonisolated DWS pregnancies. [ABSTRACT FROM AUTHOR]

Background: Prenatal information may be obtained through invasive diagnostic procedures and non-invasive screening procedures. Several psychological factors are involved in the decision to undergo a non-invasive prenatal testing (NIPT) but little is known about the decision-making strategies involved in choosing a specific level of in-depth NIPT, considering the increased availability and complexity of NIPT options. The main aim of this work is to assess the impact of psychological factors (anxiety about pregnancy, perception of risk in pregnancy, intolerance to uncertainty), and COVID-19 pandemic on the type of NIPT chosen, in terms of the number of conditions that are tested. Methods: A self-administered survey evaluated the decision-making process about NIPT. The final sample comprised 191 women (Mage = 35.53; SD = 4.79) who underwent a NIPT from one private Italian genetic company. Based on the test date, the sample of women was divided between "NIPT before COVID-19" and "NIPT during COVID-19". Results: Almost all of the participants reported being aware of the existence of different types of NIPT and more than half reported having been informed by their gynecologist. Results showed no significant association between the period in which women underwent NIPT (before COVID-19 or during COVID-19) and the preferences for more expanded screening panel. Furthermore, regarding psychological variables, results showed a significant difference between perceived risk for the fetus based on the NIPT type groups, revealing that pregnant women who underwent the more expanded panel had a significantly higher level of perceived risk for the fetus than that reported by pregnant women who underwent the basic one. There was no statistically significant difference between the other psychological variables and NIPT type. Conclusions: Our findings indicate the paramount role of gynecologist and other health care providers, such as geneticists and psychologists, is to support decision-making process in NIPT, in order to overcome people's deficits in genetic knowledge, promote awareness about their preferences, and control anxiety related to the unborn child. Decision-support strategies are critical during the onset of prenatal care, according to the advances in prenatal genomics and to parent's needs. [ABSTRACT FROM AUTHOR]

Early identification of fetal sex is possible due to both improved ultrasound resolution and the incorporation of cell-free DNA testing into routine prenatal screening services. While ultrasound assessment of the external genitalia generally suffices, there are instances where identification of the internal genitalia becomes vital to allow accurate prenatal diagnosis and comprehensive counseling. This manuscript outlines the methodology and clinical utility of assessing fetal genitalia beyond conventional sonography from the second trimester onward and is the first to describe direct visualization of the fetal vagina. [ABSTRACT FROM AUTHOR]

Study Question: Are chromosome abnormalities detected at Day 3 post-fertilization predominantly retained in structures of the blastocyst other than the inner cell mass (ICM), where chromosomally normal cells are preferentially retained?Summary Answer: In human embryos, aneuploid cells are sequestered away from the ICM, partly to the trophectoderm (TE) but more significantly to the blastocoel fluid within the blastocoel cavity (Bc) and to peripheral cells (PCs) surrounding the blastocyst during Day 3 to Day 5 progression.What Is Known Already: A commonly held dogma in all diploid eukaryotes is that two gametes, each with 'n' chromosomes (23 in humans), fuse to form a '2n' zygote (46 in humans); a state that remains in perpetuity for all somatic cell divisions. Human embryos, however, display high levels of chromosomal aneuploidy in early stages that reportedly declines from Day 3 (cleavage stage) to Day 5 (blastocyst) post-fertilization. While this observation may be partly because of aneuploid embryonic arrest before blastulation, it could also be due to embryo 'normalization' to a euploid state during blastulation. If and how this normalization occurs requires further investigation.Study Design, Size, Duration: A total of 964 cleavage-stage (Day 3) embryos underwent single-cell biopsy and diagnosis for chromosome constitution. All were maintained in culture, assessing blastulation rate, both for those assessed euploid and aneuploid. Pregnancy rate was assessed for those determined euploid, blastulated and subsequently transferred. For those determined aneuploid and blastulated (174 embryos), ICM (all 174 embryos), TE (all 174), Bc (47 embryos) and PC (38 embryos) were analyzed for chromosome constitution. Specifically, concordance with the original Day 3 diagnosis and determination if any 'normalized' to euploid karyotypes within all four structures was assessed.Participants/materials, Setting, Methods: All patients (144 couples) were undergoing routine preimplantation genetic testing for aneuploidy in three IVF clinical settings. Cleavage-stage biopsy preceded chromosome analysis by next-generation sequencing. All patients provided informed consent. Additional molecular testing was carried out on blastocyst embryos and was analyzed for up to four embryonic structures (ICM, TE, Bc and PC).Main Results and the Role Of Chance: Of 463/964 embryos (48%) diagnosed as euploid at Day 3, 70% blastulated (leading to a 59% pregnancy rate) and 30% degenerated. Conversely, of the 501 (52%) diagnosed as aneuploid, 65% degenerated and 35% (174) blastulated, a highly significant difference (P < 0.0001). Of the 174 that blastulated, the ratio of '(semi)concordant-aneuploid' versus 'normalized-euploid' versus 'other-aneuploid' embryos was, respectively, 39%/57%/3% in the ICM; 49%/48%/3% in the TE; 78%/21%/0% in the PC; and 83%/10%/5% in the Bc. The TE karyotype therefore has a positive predictive value of 86.7% in determining that of the ICM, albeit with marginally higher aneuploid rates of abnormalities (P = .071). Levels of abnormality in Bc/PC were significantly higher (P < 0.0001) versus the ploidy of the ICM and TE and nearly all chromosome abnormalities were (at least partially) concordant with Day 3 diagnoses.Limitations, Reasons For Caution: The results only pertain to human IVF embryos so extrapolation to the in vivo situation and to other species is not certain. We acknowledge (rather than lineage-specific survival, as we suggest here) the possibility of other mechanisms, such as lineage-specific movement of cells, during blastulation. Ethical considerations, however, make investigating this mechanism difficult on human embryos.Wider Implications Of the Findings: Mosaic human cleavage-stage embryos can differentiate into a euploid ICM where euploid cell populations predominate. Sequestering of aneuploid cells/nuclei to structures no longer involved in fetal development has important implications for preimplantation and prenatal genetic testing. These results also challenge previous fundamental understandings of mitotic fidelity in early human development and indicate a complex and fluid nature of the human embryonic genome.Study Funding/competing Interest(s): This research was funded by Organon Pharmaceuticals and Merck Serono by grants to W.G.K. W.G.K. is also an employee of AdvaGenix, who could, potentially, indirectly benefit financially from publication of this manuscript. R.C.M. is supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R35GM133747. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. D.K.G. provides paid consultancy services for Care Fertility.Trial Registration Number: : N/A. [ABSTRACT FROM AUTHOR]

Health policies and insurance plans that exclude genetic testing for reproductive partners contradict ethical principles, potentially contributing to adverse perinatal outcomes. Despite evidence-based recommendations from the American College of Obstetricians and Gynecologists and the American College of Medical Genetics to offer prenatal genetic carrier screening for reproductive partners, partner carrier screening or genetic testing is inconsistently covered by pregnant patients' health insurance plans. Health policies that exclude reproductive partners from insurance coverage for prenatal carrier screening or genetic testing contradict multiple ethical principles and can even contribute to adverse maternal–child health outcomes. Incomplete or missing information regarding partner carrier status can lead to costly, invasive, and potentially risky interventions for the pregnant patient that can be avoided by a simple and less expensive blood test in the reproductive partner. Lack of information regarding carrier status also harms the neonate by obviating an opportunity for early detection and treatment of potential medical complications. Insurance policies that exclude coverage for paternal genetic testing perpetuate the disproportionate burdens of pregnancy care and risk shouldered by pregnant people. To rectify these ethical dilemmas, partner carrier screening and genetic testing should be considered and covered as routine components of obstetric health care that are covered by health insurance. [ABSTRACT FROM AUTHOR]

To highlight the current diagnostic pathway for children with Spinal Muscular Atrophy (SMA) in Ireland. We look to identify points along the diagnostic pathway that may impede a timely diagnosis, and argue that newborn screening for SMA is the single best measure to remediate these delays. Through retrospective chart review and an online questionnaire, we gathered SMA patient data outlining clinical characteristics and the route to diagnosis of the SMA cohort attending the National SMA Treatment centre at Children's Health Ireland. We found that 32 children were diagnosed with SMA in Ireland in the 15-years from 2007 to 2021, with twelve cases of SMA type I. Muscle weakness is the most commonly reported initial sign, and the GP is usually the first health provider to address parental concerns. Patients commonly experience delays in diagnosis due to factors such as varied SMA clinical phenotypes, and a lack of experience or awareness of SMA amongst community based health care practitioners. In spite of this, when patients do gain early access to tertiary diagnostics through prenatal or neonatal genetic testing, they then report rapid diagnosis and initiation of disease modifying therapy in the crucial pre-symptomatic window. We conclude that delays to diagnosis inherent within the current Irish system are pervasive and arise prior to engagement with tertiary services. All of these delays are remediable through the establishment of a dedicated SMA newborn screening programme. • Pre-symptomatic treatment is paramount when using novel gene therapies in spinal muscular atrophy. • Obstacles to pre-symptomatic diagnosis are not insurmountable. • Newborn screening offers the best route to early access to disease modifying treatments. [ABSTRACT FROM AUTHOR]

The options for prenatal genetic testing have evolved rapidly in the past decade, and advances in sequencing technology now allow genetic diagnoses to be made down to the single-base-pair level, even before the birth of the child. This offers women the opportunity to obtain information regarding the foetus, thereby empowering them to make informed decisions about their pregnancy. As genetic testing becomes increasingly available to women, clinician knowledge and awareness of the options available to women is of great importance. Additionally, comprehensive pretest and posttest genetic counselling about the advantages, pitfalls and limitations of genetic testing should be provided to all women. This review article aims to cover the range of genetic tests currently available in prenatal screening and diagnosis, their current applications and limitations in clinical practice as well as what the future holds for prenatal genetics. [ABSTRACT FROM AUTHOR]

Objective: There is no consensus for the method of aneuploidy screening in pregnancy. Cell free DNA (cfDNA) is the most sensitive screen for trisomies 21, 13, and 18, however the first trimester screen (FTS) is a marker for other adverse outcomes, such as structural anomalies, growth restriction, and preeclampsia. In 2019, we offered FTS (nuchal translucency (NT) and analytes) with or without cfDNA. The purpose of this study was to assess clinical relevance of abnormal FTS in women with normal cfDNA. Methods: We retrospectively reviewed women undergoing screening in our Fetal Evaluation Unit in 2019. Women included had normal cfDNA and abnormal FTS; consisting of NT >95%, PAPP-A < 0.4 MoM, beta-HCG >2.5 MoM, or overall increased risk of trisomies. Results: 195 patients had abnormal FTS and normal cfDNA. 41 (21%) had adverse maternal outcomes including hypertension, abnormal placentation, and placental abruption. 34 (17%) had adverse fetal outcomes including growth restriction, structural anomalies, fetal demise, polyhydramnios, previable PPROM, necrotizing enterocolitis after a preterm birth, and a balanced translocation. Conclusion: Abnormal FTS predicts adverse outcomes in 33% of women with normal cfDNA. Our data suggests that offering universal FTS with cfDNA may have clinical benefit. [ABSTRACT FROM AUTHOR]

Objective To evaluate maternal and neonatal outcomes of low-risk singleton pregnancies, without underlying maternal medical conditions or genetic and fetal anomalies associated with fetal growth restriction, that were diagnosed with fetal growth restriction (FGR) (EFW < 10th %) in the mid-second trimester (between 17 and 22 weeks and 6 days’ gestation). Methods A retrospective cohort study of all women who underwent a routine fetal anatomy ultrasound between 17 and 22 weeks and 6 days’ gestation at a community-based academic hospital was performed to identify subjects with an EFW <10th%. Pregnancies with inadequate dating, multiple gestations, preexisting maternal vascular disease (chronic hypertension and pregestational diabetes), lethal fetal anomalies, and abnormal prenatal genetic screening were excluded. Descriptive statistics were computed to describe the study population. Subjects were stratified into two groups, estimated fetal weight (EFW) <5th% and EFW 5th–9th%. The primary outcome was a small for gestational age neonate (SGA) at delivery. Secondary outcomes included a composite adverse neonatal outcome, perinatal death, hypertensive disorders of pregnancy, medically indicated delivery, and mode of delivery. A comparison of the two groups, EFW <5th% and EFW 5th–9th %, was performed. Continuous variables were compared utilizing Wilcoxon Rank Sum tests and categorical variables were compared using Fisher’s exact test or Chi-squared tests, and a dichotomous composite variable for adverse neonatal outcomes was also calculated. Results In total, 3,868 unique patient records were screened. Thirty-two patient records (0.8% of the total screened records) were eligible for inclusion. The primary outcome, SGA at delivery, occurred in 13/32 (41%) of the subjects. The secondary outcomes of the composite neonatal morbidity occurred in 9/32 (28%), hypertensive disorders of pregnancy in 10/32 (31%), and medically indicated delivery at <28 weeks gestation in 7/32 (22%) of the subjects. When comparing EFW <5th% and EFW 5th–9th%, EFW <5th% had a larger percentage of SGA newborns (66% vs. 25%, p = .02, OR = 8.0 95% CI 1.5–42.5). EFW <5th% was also significantly associated with a greater composite adverse neonatal outcome when compared to EFW 5th–9th% (54% vs. 10%, p = .015). The subgroup with an EFW <5th% also had higher rates of adverse outcomes including preeclampsia (42% vs. 10%, p = .073), abnormal umbilical artery Doppler studies (50% vs. 15%, p = .049), and medically indicated delivery <28 weeks (42% vs. 10%, p = .07). Conclusions Early onset FGR is a associated with high rates of SGA at delivery, as well as several adverse maternal and neonatal outcomes which include hypertensive disorders of pregnancy, a greater composite neonatal morbidity, perinatal death, and medically indicated preterm delivery. EFW <5th% was associated with worse outcomes when compared to those with an EFW 5th%–9th%. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the success and reliability of QF-PCR analysis in detecting chromosomal abnormalities and to determine its advantages and limitations. Methods: Patients who underwent karyotype and QF-PCR analysis as a prenatal invasive diagnostic test in a tertiary center were retrospectively analyzed. Invasive genetic test indications, ultrasonographic fetal screening reports, karyotype and QF-PCR analysis results of the patients were obtained from the electronic data system. Karyotypes were classified as normal, common aneuploidies (trisomies 21, 18, 13, and sex chromosome aneuploidies) and other aneuploidies. QF-PCR analysis and karyotype results were compared for inconsistency. Results: A total of 426 cases (41 [9.6%] chorionic villus sampling, 339 [79.6%] amniocentesis and 46 [10.8%] cordocentesis) were included in the study. The most common indication for prenatal invasive diagnostic testing was fetal structural anomalies (36.7%). Aneuploidy was detected in 61 (14.3%) of the fetuses. Fifty-nine (96.7%) of 61 fetuses with aneuploidy were common aneuploidies. The sensitivity and specificity of the QF-PCR analysis in detecting common aneuploidies was 100%. QF-PCR analysis was indicative if not diagnostic in all fetuses with mosaic trisomy or sex chromosome aneuploidies. Conclusion: QF-PCR analysis is a rapid, robust, and reliable test for the prenatal detection of common aneuploidies. Although QF-PCR analysis has high sensitivity and specificity in detecting common aneuploidies, it should be used for rapid preliminary information and the result of karyotype analysis should be awaited for important clinical decisions. [ABSTRACT FROM AUTHOR]

To explore the application of third-generation sequencing (TGS) for genetic diagnosis and prenatal genetic screening of thalassemia genes. Two groups of subjects were enrolled in this study. The first group included 176 subjects with positive hematological phenotypes for thalassemia. Thalassemia-associated genes were detected simultaneously in each sample using both the PacBio TGS platform based on single-molecule real-time (SMRT) technology and the conventional PCR-reverse dot blot (PCR-RDB). Sanger sequencing was used for validation when results were discordant between the two methods. The second group included 53 couples with at least one partner having a positive thalassemia hematological phenotype, and they were screened for homotypic thalassemia variants by TGS, and the risk of pregnancies with babies presenting with severe thalassemia, was assessed. Of the 176 subjects, 175 had concordant genotypes between the two methods, including 63 normal subjects and 112 α- and/or β-thalassemia gene carriers, with a concordance rate of 99.43%. TGS detected a rare β-thalassemia gene variant −50 (G > A) that was not detected by conventional PCR-RDB. TGS identified seven of the 53 couples as homotypic thalassemia gene carriers, five of whom were at risk of pregnancies with severe thalassemia. TGS could effectively detect common and rare thalassemia variants with high accuracy and efficiency. This approach would be suitable for prenatal thalassemia genetic screening in areas with high incidence of thalassemia. [ABSTRACT FROM AUTHOR]

National guidelines recommend cancer genetic risk assessment (CGRA) (i.e. genetic counseling prior to genetic testing) for women at increased risk for hereditary breast and ovarian cancer (HBOC). Less than one-half of eligible women obtain CGRA, leaving thousands of women and their family members without access to potentially life-saving cancer prevention interventions. The Genetic Risk Assessment for Cancer Education and Empowerment Project (GRACE) addressed this translational gap, testing the efficacy of a tailored counseling and navigation (TCN) intervention vs. a targeted print brochure vs. usual care on CGRA intentions. Selected behavioral variables were theorized to mediate CGRA intentions. Breast and ovarian cancer survivors meeting criteria for guideline-based CGRA were recruited from three state cancer registries (N = 654), completed a baseline survey, and were randomized. TCN and targeted print arms received the brochure; TCN also participated in a tailored, telephone-based decision coaching and navigation session grounded in the Extended Parallel Process Model and Ottawa Decision Support Framework. Participants completed a one-month assessment. Logistic regression was used to compare the rate of CGRA intentions. CGRA intentions and theorized mediator scores (continuous level variables) were calculated using mixed model analysis. CGRA intentions increased for TCN (53.2%) vs. targeted print (26.7%) (OR = 3.129; 95% CI: 2.028, 4.827, p <.0001) and TCN vs. usual care (23.1%) (OR = 3.778, CI: 2.422, 5.894, p <.0001). Perceived risk (p = 0.023) and self-efficacy (p = 0.035) mediated CGRA intentions in TCN. Improvements in CGRA intentions and theorized mediators support the use of a tailored communication intervention among women at increased HBOC risk. (Clinicaltrials.gov: NCT03326713.) Trial registration: ClinicalTrials.gov identifier: NCT03326713. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic brought significant changes in health care, specifically the accelerated use of telehealth. Given the unique aspects of prenatal care, it is important to understand the impact of telehealth on health care communication and quality, and patient satisfaction. This mixed methods study examined the challenges associated with the rapid and broad implementation of telehealth for prenatal care delivery during the pandemic. Objective: In this study, we examined patients’ perspectives, preferences, and experiences during the COVID-19 pandemic, with the aim of supporting the development of successful models to serve the needs of pregnant patients, obstetric providers, and health care systems during this time. Methods: Pregnant patients who received outpatient prenatal care in Cleveland, Ohio participated in in-depth interviews and completed the Coronavirus Perinatal Experiences-Impact Survey (COPE-IS) between January and December 2021. Transcripts were coded using NVivo 12, and qualitative analysis was used, an approach consistent with the grounded theory. Quantitative data were summarized and integrated during analysis. Results: Thematic saturation was achieved with 60 interviews. We learned that 58% (35/60) of women had telehealth experience prior to their current pregnancy. However, only 8% (5/60) of women had used both in-person and virtual visits during this pregnancy, while the majority (54/60, 90%) of women participated in only in-person visits. Among 59 women who responded to the COPE-IS, 59 (100%) felt very well supported by their provider, 31 (53%) were moderately to highly concerned about their child’s health, and 17 (29%) reported that the single greatest stress of COVID-19 was its impact on their child. Lead themes focused on establishing patient-provider relationships that supported shared decision-making, accessing the information needed for shared decision-making, and using technology effectively to foster discussions during the COVID-19 pandemic. Key findings indicated that participants felt in-person visits were more personal, established greater rapport, and built better trust in the patient-provider relationship as compared to telehealth visits. Further, participants felt they could achieve a greater dialogue and ask more questions regarding time-sensitive information, including prenatal genetic testing information, through an in-person visit. Finally, privacy concerns arose if prenatal genetic testing or general pregnancy conversations were to take place outside of the health care facility. Conclusions: While telehealth was recognized as an option to ensure timely access to prenatal care during the COVID-19 pandemic, it also came with multiple challenges for the patient-provider relationship. These findings highlighted the barriers and opportunities to achieve effective and patient-centered communication with the continued integration of telehealth in prenatal care delivery. It is important to address the unique needs of this population during the pandemic and as health care increasingly adopts a telehealth model. [ABSTRACT FROM AUTHOR]

The introduction of next generation sequencing (NGS) technologies has revolutionized the practice of Medical Genetics, and despite initial reticence in its application to prenatal genetics (PG), it is becoming gradually routine, subject to availability. Guidance for the clinical implementation of NGS in PG, in particular whole exome sequencing (ES), has been provided by several professional societies with multiple clinical studies quoting a wide range of testing yields. ES was introduced in our tertiary care center in 2017; however, its use in relation to prenatally assessed cases has been limited to the postnatal period. In this study, we review our approach to prenatal testing including the use of microarray (CMA), and NGS technology (gene panels, ES) over a period of three years. The overall diagnostic yield was 30.4%, with 43.2% of those diagnoses being obtained through CMA, and the majority by using NGS technology (42% through gene panels and 16.6% by ES testing, respectively). Of these, 43.4% of the diagnoses were obtained during ongoing pregnancies. Seventy percent of the abnormal pregnancies tested went undiagnosed. We are providing a contemporary, one tertiary care center retrospective view of a real-life PG practice in the context of an evolving use of NGS within a Canadian public health care system that may apply to many similar jurisdictions around the world. [ABSTRACT FROM AUTHOR]

This article discusses clinical genetic approaches to managing patients with myotonic dystrophy type 1 (DM1) and their families. DM1 is an autosomal dominant multisystem disorder caused by a CTG repeat expansion in the DMPK gene. Early diagnosis is important for initiating disease-modifying therapies and preventing complications. Genetic counseling and testing can provide standard medical care and enable family planning strategies for patients with DM1. The article also highlights the need for increased awareness and self-management of healthcare among individuals with mild DM1 symptoms. The development of disease-modifying therapies for DM1 is expected to improve patient outcomes and promote widespread acceptance of genetic counseling and medical management. [Extracted from the article]

Increased access to and utilization of genetic testing for diagnostic and family planning purposes have led to more children or fetuses incidentally identified to be at risk for dystrophinopathy. We present 3 unrelated cases of a likely benign non-tandem in-frame duplication of exons 45-51 of the DMD gene, inserted into chromosome 17 at q21 (chr17:40,203,142‐40,204,487; GRCh38/UCSC hg38). In case 1, a mother undergoing in vitro fertilization is informed she is a carrier for dystrophinopathy and wishes to proceed with testing of male embryos. Subsequent familial testing to create probes through sequencing with a genome backbone revealed a non-tandem DMD duplication. Case 2 is a 1-day-old male infant with multiple congenital anomalies and Case 3 is a 3-year-old female with developmental delay; both underwent a chromosomal microarray with subsequent FISH analysis showing the same non-tandem DMD duplication. Genome sequencing identified the breakpoints and resolved the genomic structure. In both patients, the duplication was paternally inherited. The father of Case 2 is unaffected, and the father of Case 3 has developmental delay without muscle symptoms. These unrelated families with the same partial DMD duplication are not at risk for dystrophinopathy, as the males have an intact copy of DMD and lack of dystrophinopathy symptoms. Instead, they have an identical complex structural rearrangement, likely a benign variant. As DMD gene duplications occur in ∼10% of dystrophinopathy, this information is vital for future patients with the same exons 45-51 duplication. In the era of advancing dystrophinopathy treatments and increased prenatal genetic testing, accurate classification of in-frame DMD duplications is essential, especially when found in asymptomatic individuals. Without further analysis of such duplications, the significant financial burden of preimplantation genetic testing and potential misguidance in medical management and family planning decisions based on assumed dystrophinopathy risk may occur. [ABSTRACT FROM AUTHOR]

This article discusses a study conducted in Barcelona on the association between isolated aberrant right subclavian artery (ARSA) and genetic abnormalities in fetuses. The study found that out of 154 fetuses diagnosed with ARSA, 116 were isolated cases and 38 were associated with other structural anomalies. Genetic abnormalities were detected in 4 fetuses, all of which had associated structural defects. However, no genetic disorders or postnatal compressive symptoms were found in the isolated ARSA group. The study concludes that isolated ARSA does not appear to be a risk factor for genetic disorders. [Extracted from the article]

This article discusses a study conducted in a Chinese prenatal cohort to explore the genetic causes of conotruncal defects (CTDs) in fetuses and assess the pregnancy outcomes of fetuses with CTD. The study analyzed the results of different genetic tests, including chromosomal microarray analysis (CMA), karyotype analysis, and whole-exome sequencing (WES). The results showed that the chromosome abnormality rate in fetuses with CTD was 22.6%, and the detection rate of abnormal chromosomes in CMA and karyotype was 15.8%. WES identified pathogenic variants, likely pathogenic variants, and variants of uncertain significance. The study recommends invasive prenatal genetic testing and CMA as first-line tests for all patients with CTD, especially those with an interrupted aortic arch (IAA), and suggests considering WES when necessary. [Extracted from the article]

This article discusses a case report of a rare congenital disorder called congenital disorders of glycosylation type Id (CDG-Id). CDG-Id is characterized by a deficiency in alpha-1,3-mannosyltransferase caused by a variant in the ALG3 gene. The article describes a pregnant woman who had a previous pregnancy with fetal malformations and genetic testing revealed the ALG3 gene variant. Subsequent pregnancies also showed fetal malformations consistent with CDG-Id. The article emphasizes the importance of prenatal ultrasound and genetic testing in identifying CDG-Id and providing valuable information for clinical management. [Extracted from the article]

BACKGROUND: Genetic screening and testing are technologies historically underutilized in Black populations despite predicting diseases like sickle cell disease (SCD), which is predominantly found in Blacks. We surveyed prenatal patients to understand choices, beliefs and experiences surrounding genetic screening and testing, specifically for SCD. METHODS: In this cross-sectional study, we surveyed 322 women during prenatal visits. Responses were analyzed to identify barriers to care and education about testing and screening for SCD. Patients rated whether they agreed or disagreed with statements regarding sickle cell health behaviors. We used χ2 tests to compare categorical variables by self-reported race. Binary logistic regression was used to determine the odds ratios and confidence intervals for each outcome. RESULTS: Women were a mean (SD) age of 33.3 (6.1). 42.9% of patients self-identified as White while 41.3% of patients self- identified as Black. Screening questions were adjusted for differences in race, insurance, and education levels to show significant differences in responses between Blacks and Whites for screening for SCD (p = 0.047, OR 95% CI = 0.455 [0.210–0.989]) and plans to meet with genetic counselors (p = 0.049, OR 95% CI = 0.299 [0.090–0.993]). The statements "if sickle cell is not in their family, then it is likely not in themselves or their children," was significantly different between Black and White populations (p = 0.011, OR 95% CI = 0.207 [0.081–0.526]). CONCLUSION: Our findings suggest gaps in screening, testing, education, and pregnancy management choices between Black and White patients. Research should focus on decreasing these healthcare gaps and improving education that address concerns about SCD for relevant populations. [ABSTRACT FROM AUTHOR]

Objectives. The objectives of this study were to identify global trends in research on cell-free deoxyribonucleic acid (cfDNA) from a bibliometric perspective and provide researchers with new research hotspots. Methods. In all, we extracted 5038 pieces of literature from PubMed and 527 articles from the Web of Science Core Collection (WoSCC) database related to cfDNA published from 1 January 2017 to 31 December 2021. For PubMed literature, we employed co-word, biclustering, and strategic diagram analysis to describe the trends in research on cfDNA in the said five years. Then, we used VOSviewer analysis for the WoSCC database to display the trends in research on cfDNA in obstetrics and gynecology during 2017–2021. Results. Strategy diagram analysis of 95 major Medical Subject Headings terms extracted from 5038 pieces of literature indicated that cfDNA sequence analysis for non-invasive prenatal and genetic testing and its application in the fields of neoplasm genetics and diagnosis is a newly emerging immature theme of cfDNA. VOSviewer analysis of 527 articles showed the global trends in research on cfDNA in obstetrics and gynecology, for example, in terms of most influential authors, institutions, countries, journals, and five research hotspots: (1) cfDNA application in prenatal screening and prenatal diagnosis, (2) cfDNA application in assisted reproductive technology, (3) cfDNA application in pre-eclampsia, DNA methylation, etc., (4) cfDNA application in placental dysfunction and fetal growth restriction, and (5) cfDNA application in fetal chromosomal abnormalities (fetal aneuploidy). Conclusions. Comprehensive visual analysis provides information regarding authors, organizations, countries/regions, journals, research hotspots, and emerging topics in the field of cfDNA for obstetrics and gynecology research. This comprehensive study could make it easier to find a partner for project development and build a network of knowledge on this emerging topic. [ABSTRACT FROM AUTHOR]

Several studies have shown that children from pregnancies with estimated first-trimester risk based on fetal nuchal translucency thickness and abnormal maternal serum pregnancy protein and hormone levels maintain a higher likelihood of adverse outcomes, even if initial testing for known genetic conditions is negative. We used the Finnish InTraUterine cohort (ITU), which is a comprehensively characterized perinatal cohort consisting of 943 mothers and their babies followed throughout pregnancy and 18 months postnatally, including mothers shortlisted for prenatal genetic testing but cleared for major aneuploidies (cases: n = 544, 57.7%) and control pregnancies (n = 399, 42.3%). Using genome-wide genotyping and RNA sequencing of first-trimester and term placental tissue, combined with medical information from registry data and maternal self-report data, we investigated potential negative medical outcomes and genetic susceptibility to disease and their correlates in placenta gene expression. Case mothers did not present with higher levels of depression, perceived stress, or anxiety during pregnancy. Case children were significantly diagnosed more often with congenital malformations of the circulatory system (4.12 (95% CI [1.22–13.93]) higher hazard) and presented with significantly more copy number duplications as compared to controls (burden analysis, based on all copy number variants (CNVs) with at most 10% frequency, 823 called duplications in 297 cases versus 626 called duplications in 277 controls, p = 0.01). Fifteen genes showed differential gene expression (FDR < 0.1) in association with congenital malformations in first-trimester but not term placenta. These were significantly enriched for genes associated with placental dysfunction. In spite of normal routine follow-up prenatal testing results in early pregnancy, case children presented with an increased likelihood of negative outcomes, which should prompt vigilance in follow-up during pregnancy and after birth. [ABSTRACT FROM AUTHOR]

This study aimed to compare the screening performance of genome-wide cfDNA testing for chromosomal abnormalities between two periods where additional findings were reported and not reported. Data were obtained from consecutive pregnant women with a singleton pregnancy at ≥10 weeks who requested cfDNA testing during 2015–2019. The performance of screening of the cfDNA test was determined by calculating the concordance rate, detection rate, and false-positive rate. Data from 3981 women were included. The no-result rates were similar between the two reporting periods (2.04% vs. 2.08%). Concordance rates for trisomy 21 and 18 were 100% and 100%, respectively. There were two cases tested high risk for trisomy 13, with a concordance rate of 0%. In total, 12 cases were high risk for any sex chromosome aneuploidy with an overall concordance of 75%, and 15 cases tested high risk for any rare autosomal trisomy, with a 13.3% concordance rate. The detection rates for trisomy 21 and 18 were 100% and 100%, respectively. For any SCA, the detection rate was 90%. For the two reporting periods, the combined false-positive rates were 0.93% and 0.17%, which were significantly different (p = 0.002). Restricting the reporting of additional findings from genome-wide cfDNA analysis has reduced the false-positive rate but without a reduction in the no-result rate. [ABSTRACT FROM AUTHOR]

A supernumerary marker chromosome (SMC) is a structurally abnormal chromosome that cannot be characterized by conventional banding cytogenetics. Marker chromosomes are present in 0.075% of prenatal cases. They are associated with variable phenotypes, ranging from normal to severely abnormal, and the prognosis is largely dependent on the results of further cytogenomic analysis. Here, we report the identification and characterization of a marker chromosome following prenatal screening in a 39-year-old pregnant patient. The patient had a normal first trimester ultrasound but was high-risk for fetal chromosome anomalies based on the results of maternal serum parameters. Chorionic villus sampling was performed, and analysis of chorionic villi revealed the presence of two identical marker chromosomes. In the interest of a rapid identification of the markers, we performed noninvasive prenatal testing (NIPT) together with chorionic villus sampling. A pericentromeric 29 Mb duplication of chromosome 20: dup (20) (p13q11.21) was identified and thereafter confirmed by targeted metaphasic FISH. Wholegenome sequencing-based NIPT was instrumental in rapid characterization of the SMCs and allowed us to obviate the need for multiple expensive and timeconsuming FISH analyses. [ABSTRACT FROM AUTHOR]

Introduction: Androgen insensitivity syndrome is a genetic disorder and a type of sexual development disorder. It is characterized by the evident feminization of the external genitalia at birth in an individual with the 46, XY genotype. Aim: To present the clinic, molecular studies, obstetric ultrasonography of the first trimester and ultrasound of the newborn with sexual differentiation disorder. Clinic case: 35-year-old female with third pregnancy, singleton fetus, with extended non-invasive prenatal genetic screening for chromosomal aneuploidies and fetal sex determination at week 11 of gestation with male genetic sex, ultrasound with genital tubercle angle less than 30° indicative of female phenotypic sex and postnatal ultrasound with male gonadal sex. Genetic molecular panel with a pathogenic variant for the AR gene, in hemi zygosis. Conclusion: Early detection of phenotype-genotype sexual discordance is important as it may indicate an underlying genetic, chromosomal, or biochemical condition, allowing timely critical counseling and postnatal treatment. [ABSTRACT FROM AUTHOR]

Background and Objective: Pediatric cardiomyopathies are clinically heterogeneous heart muscle disorders associated with significant morbidity and mortality for which substantial evidence for a genetic contribution was previously reported. We present a detailed molecular investigation of a cohort of 231 patients presenting with primary cardiomyopathy below the age of 18 years. Methods: Cases with pediatric cardiomyopathies were analyzed using a next-generation sequencing (NGS) workflow based on a virtual panel including 57 cardiomyopathy-related genes. Results: This molecular approach led to the identification of 69 cases (29.9% of the cohort) genotyped as a carrier of at least one pathogenic or likely pathogenic variant. Fourteen patients were carriers of two mutated alleles (homozygous or compound heterozygous) on the same cardiomyopathy-related gene, explaining the severe clinical disease with early-onset cardiomyopathy. Homozygous TNNI3 pathogenic variants were detected for five unrelated neonates (2.2% of the cohort), with four of them carrying the same truncating variant, i.e. p.Arg69Alafs*8. Conclusions: Our study confirmed the importance of genetic testing in pediatric cardiomyopathies. Discovery of novel pathogenic variations is crucial for clinical management of affected families, as a positive genetic result might be used by a prospective parent for prenatal genetic testing or in the process of pre-implantation genetic diagnosis. [ABSTRACT FROM AUTHOR]