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A couple of Ashkenazi Jewish descent was referred for an early anatomy scan at 14 + 2 weeks of gestation following a previous pregnancy termination due to posterior encephalocele and enlarged kidneys. The index pregnancy was also positive for several fetal abnormalities, including enlarged kidneys with cystic dysplasia and abnormal cerebellar morphology highly suggestive of Joubert syndrome.Trio exome sequencing revealed compound heterozygosity for variants in the TMEM67 gene: a known pathogenic maternally inherited variant found in trans with a paternal intronic variant of unknown significance. RNA analysis revealed that the intronic variant creates a cryptic acceptor splice site in intron 12, leading to the insertion of 22 bp and causing a frameshift with a premature stop codon. This analysis enabled the reclassification of the intronic variant to likely pathogenic.This information empowered the couple to make informed reproductive choices and opt for preimplantation genetic testing (PGT) for future pregnancies.

Prenatal trio exome sequencing (ES) has become integrated into the care for pregnant women when the fetus has structural anomalies. Details regarding optimizing indications for prenatal exome sequencing, its detection rates with different categories of fetal anomalies, and principles of interpretation of pathogenicity of sequence variants are still under investigation. However, there is now growing consensus about its benefits for finding the cause of fetal structural anomalies. What is not established, is whether exome or genome sequencing (GS) has a place in the care of all pregnant women. This report is a summary of the debate on this topic at the 26th International Conference on Prenatal Diagnosis and Therapy. Both expert debaters considered the advantages and disadvantages. Advantages include the ability to diagnose serious childhood conditions without a prenatally observable phenotype, which creates the potential of early treatments. Disadvantages include difficulties with variant classification, counseling complexities, healthcare cost, and the burden on healthcare systems and families, in particular with the discovery of adult-onset disorders or variants of uncertain significance. Although both debaters weighed the balance of these conflicting arguments differently, they agreed that more research is needed to further explore the clinical utility and ethical aspects of GS for all pregnant women.

Hamartomatous polyposis syndromes (HPS) are rare cancer-predisposing disorders including Juvenile polyposis (JPS), Peutz–Jeghers (PJS) and PTEN hamartomatous syndromes (PHS). Penetrant mutations in corresponding genes (SMAD4, BMPR1A, STK11, PTEN and AKT1), are usually diagnosed via a next-generation-sequencing gene panel (NGS-GP) for tailored surveillance and preimplantation testing for monogenic disorders (PGT-M). Five probands with HPS phenotype, with no genetic diagnosis per genetic workup, underwent whole-genome sequencing (WGS) that identified structural genetic alterations: two novel inversions in BMPRA1 and STK11, two BMPR1A-deletions, known as founders among Bukharan Jews, and BMPR1A microdeletion. BMPR1A inversion was validated by “junction fragment” amplification and direct testing. PGT-M was performed via multiplex-PCR and enabled successful birth of a non-carrier baby. WGS may be considered for HPS patients with no NGS-GP findings to exclude structural alterations.

PURPOSE To evaluate whether ethnicity affects the risk of full mutation expansion among females heterozygous for FMR1 premutation. METHODS Women who carry the FMR1 premutation alelle of Jewish origin who underwent fragile X prenatal diagnosis between 2011 and 2018 in two medical centers in Israel were included. The heterozygote women and fetuses were analyzed for the number of CGG repeats and AGG interruptions. RESULTS Seven hundred sixty-six subjects were included. Parental ethnicity was fully concordant in 592 cases (Jewish, Ashkenazi, and non-Ashkenazi). Ashkenazi compared with non-Ashkenazi heterozygotes have a significantly higher mean number of CGG repeats (68 ± 8.7, 64 ± 6.4 respectively, P = 0.03) and a lower mean number of AGG interruptions (0.89 ± 0.83, 1.60 ± 1.18 respectively, p = 0.0001). Overall, 56/198 (28.2%) fetuses of Ashkenazi heterozygotes had an expansion to a full mutation compared with 6/98 among the non-Ashkenazi (6.1%) (p = 0.001). Multivariate analysis demonstrated that, in addition to CGG repeats and AGG interruptions (which contributed 68.3% of variance), ethnicity is an independent risk factor for a full mutation expansion (odds ratio [OR] = 2.04, p

Objective We have previously demonstrated that maternal‐plasma cell‐free DNA (cfDNA)‐testing can detect chromosomal anomalies in recurrent pregnancy loss (RPL) with 81.8% sensitivity and 90.3% specificity. Here we assess whether this is cost effective in guiding further workup in RPLs. Method A decision‐analytic model was developed to compare the cost of various RPL management pathways: (1) current American Society for Reproductive Medicine (ASRM) RPL workup; (2) microarray or karyotyping analysis of products of conception (POCs) and RPL workup only for euploid cases; and (3) cfDNA testing and RPL workup only for euploid cases. Sample accessibility, failure rates, and sensitivity were specified for each test. Costs of sample collection, genetic tests, and RPL workup were considered. Analysis outcomes included detection rate of chromosomal anomaly and cost per patient tested. Results In comparison to existing cytogenetic testing on POCs, cfDNA testing pathway allowed for better sample accessibility with a lower cost per patient. In addition, using cfDNA to guide further workup significantly increases the number of causative fetal chromosome anomalies detected, reducing the number of patients undergoing unnecessary workup resulting in an overall cost savings. Conclusion Our study showed that inclusion of cfDNA testing is a cost‐effective approach to guide RPL workup., Key points What is already known about this topic? Chromosomal anomalies account for 50%–70% of early pregnancy loss (EPL) and even in recurrent pregnancy loss (RPL) random aneuploidy is the single most common etiology, accounting for >50% of cases.In a previous study we have shown that maternal‐plasma genome‐wide cell‐free DNA (cfDNA)‐based testing can reliably detect chromosomal anomalies in random EPL and RPL with a sensitivity of 81.8% and a specificity of 90.3%.We therefore suggested cfDNA‐based testing serve to guide further management in cases of RPL: if cfDNA in the second and subsequent RPL demonstrates aneuploidy, no further action is taken; if an unbalanced rearrangement is found, parental karyotyping is recommended; if no abnormality is detected, the recommended RPL workup is performed. What does this study add? In this study we demonstrate that using cfDNA to guide further workup in RPL is a cost‐effective approach.We share our algorithm to facilitate local cost‐effectiveness analysis based on prevailing billing schemes, either based on national health systems or private payor systems.

BACKGROUND: HNF1B deletion/intragenic mutations are the most commonly identified genetic cause of congenital anomalies of the kidney and urinary tract (CAKUT) suggested by fetal ultrasound findings such as: parenchymal hyperechogenicity, overt cystic changes or gross morphological urinary system (UT) abnormalities. The postnatal evolution of these 17q12 deletions encompassing the HNF1B gene-associated findings has not been assessed in depth. METHODS: In this observational study, we present postnatal follow-up findings in 5 of 6 cases (one pregnancy was terminated on parental request) of fetal-onset cystic/hyperechogenic kidneys eventually diagnosed with 17q12 microdeletion encompassing the HNF1B gene between 2009 and 2017. RESULTS: Complete normalization of kidney parenchymal abnormalities and of depressed neonatal renal function was observed in 4/5 and 5/5 patients within 2–4.9 years and 1.5–8 months, respectively. All 5 patients had preserved normal renal function at 3–11 years of follow-up. The evolving later-onset renal features included: hypomagnesemia, hyperuricemia, urinary tract infection (UTI), and bilateral grade 3–4 vesicoureteral reflux and bladder diverticula in 3, 3, 2, and 1 patient, respectively. HNF1B gene deletion-associated extra-renal manifestations with delayed presentation were global developmental delay/autistic spectrum disorder (ASD), rolandic-type seizures, overweight, and borderline fasting hyperglycemia observed in 1–2 patients each. Family history was positive for small-size or asymptomatic cystic kidneys with normal function, diabetes mellitus, seizures, and mental/psychiatric problems in 3/6 cases. CONCLUSIONS: Fetal-onset HNF1B deletion-associated kidneys’ parenchymal abnormalities confirmed postnatally with initially depressed renal function might undergo complete resolution within several years and few months, respectively. However, later-onset urinary tract, metabolic, and neurodevelopmental features of this mutation might appear over years. Therefore, genetic molecular evaluation/diagnosis and continuous follow-up for evolving features are mandatory in affected children.

This research sought to understand IVF-physicians’ knowledge of, experience with, and attitudes toward fertility preservation for cancer patients. A 35-question, self-report survey request was emailed to IVF providers who were registered on the IVF-Worldwide.com network (3826 clinics). Physicians submitted responses on the IVF-Worldwide.com website. Survey results were reported as a proportion of the responding clinics. Survey responses were completed by 321 (8.4%) globally distributed IVF clinics, representing 299,800 IVF cycles. Of these clinics, 86.6% (278) performed fertility preservation, treating approximately 6300 patients annually. However, 18.4% of the centers reported that patients sought advice independently, without an oncologist’s referral. Ovarian tissue cryopreservation was performed by 37.7% of the clinics, yet 52.6% considered the procedure experimental. IVM was performed by 16.5% of responding clinics. A majority (63.6%) of the clinics selected treatment protocols based on each patient’s malignancy. Most respondents (76.3%) disagreed that fertility preservation was not yet successful enough to make it an available option. However, 44.2% believed that pregnancy rates following oocyte cryopreservation could not be determined because not enough oocyte cryopreservation patients had completed embryo transfer. Most clinics performed fertility preservation, tailoring protocols to each patient’s disease and condition. Almost 20% of patients sought advice independently, indicating that more effort is needed to encourage oncologists to refer patients. Most survey respondents believed that data was not yet available on either live birth outcomes or the best protocol for each disease. Therefore, long-term study must continue, with the establishment of interim milestones and an outcome-tracking registry.

To evaluate whether ethnicity affects the risk of full mutation expansion among females heterozygous for FMR1 premutation.Women who carry the FMR1 premutation alelle of Jewish origin who underwent fragile X prenatal diagnosis between 2011 and 2018 in two medical centers in Israel were included. The heterozygote women and fetuses were analyzed for the number of CGG repeats and AGG interruptions.Seven hundred sixty-six subjects were included. Parental ethnicity was fully concordant in 592 cases (Jewish, Ashkenazi, and non-Ashkenazi). Ashkenazi compared with non-Ashkenazi heterozygotes have a significantly higher mean number of CGG repeats (68 ± 8.7, 64 ± 6.4 respectively, P = 0.03) and a lower mean number of AGG interruptions (0.89 ± 0.83, 1.60 ± 1.18 respectively, p = 0.0001). Overall, 56/198 (28.2%) fetuses of Ashkenazi heterozygotes had an expansion to a full mutation compared with 6/98 among the non-Ashkenazi (6.1%) (p = 0.001). Multivariate analysis demonstrated that, in addition to CGG repeats and AGG interruptions (which contributed 68.3% of variance), ethnicity is an independent risk factor for a full mutation expansion (odds ratio [OR] = 2.04, p 0.001) and accounted for 9% of the variation of a full mutation expansion.Apart from significant differences regarding the number of CGG repeats and AGG interruptions between Ashkenazi and non-Ashkenazi heterozygotes, ethnicity independently affects the risk of a full mutation.

The aim of this study was to devise an evidence-based scoring system for prioritizing mosaic aneuploid embryos for transfer. A retrospective analysis was performed of all sequential cytogenetic and molecular results on chorionic villi samples (n = 72,472) and products of conception (n = 3806) analysed at a single centre. The likelihood that a mosaic aneuploidy detected in chorionic villi samples will involve the fetus, the incidence of clinically significant fetal uniparental disomy in the presence of a mosaic in chorionic villi and the chance of the mosaicism culminating in miscarriage were used to generate a scoring system for prioritizing mosaic aneuploid embryos detected by preimplantation genetic screening. A composite score was obtained for each individual mosaic aneuploidy after assignment of an individual risk score based on the incidence/likelihood of each adverse outcome. A final additional score was assigned to viable full or mosaic aneuploidies with a well-defined phenotype. The higher the composite score the lower the priority for embryo transfer. In conclusion, due to the paucity of prospective studies on the actual transfer of mosaic aneuploid embryos, we suggest using this evidence-based scoring system to provide a useful tool for clinicians, embryologists and patients.

Our objective was to evaluate and characterize the extent and patterns of worldwide usage of preimplantation genetic screening (PGS) among the assisted reproductive technique community. A prospective, web-based questionnaire with questions relating to practices of, and views on, PGS was directed to users and non-users of PGS. A total of 386 IVF units from 70 countries conducting 342,600 IVF cycles annually responded to the survey. A total of 77% of respondents routinely carry out PGS in their clinics for a variety of indications: advanced maternal age (27%), recurrent implantation failure (32%) and recurrent pregnancy loss (31%). Few (6%) offer PGS to all their patients. In most cycles (72%), trophectoderm biopsy is carried out and either array-comparative genomic hybridization (59%) or next-generation sequencing (16%) are used for genetic analysis. Only 30% of respondents regard PGS as clearly evidenced-based, and most (84%) believe that more randomized controlled trials are needed to support the use of PGS. Despite ongoing debate and lack of robust evidence, most respondents support the use of PGS, and believe that it may aid in transferring only euploid embryos, thereby reducing miscarriage rates and multiple pregnancies, increasing live birth rates and reducing the risk of aneuploid pregnancies and births.

Objectives to evaluate the incidence of chromosomal aberration (both microscopic and sub-microscopic) in fetuses with an aberrant right subclavian artery (ARSA) detected by ultrasonographic anomaly scan. Methods The study included 62 pregnant women whose fetuses were diagnosed with ARSA who were referred for genetic counseling. Of these, 55 patients underwent amniocentesis and 7 declined invasive testing. All 55 amniocentesis samples were tested by standard G-banding and chromosomal microarray (CMA), except for 2 samples for which only karyotype and FISH for 22q11.2 deletions were performed. Results Of the 55 women who underwent amniocentesis, 5 were detected with trisomy 21 (9.1%), all of whom had additional ultrasound findings. Among the 14 fetuses with ARSA and additional ultrasound findings, the incidence of trisomy 21 was 35.7%. In fetuses with isolated ARSA, no chromosomal aberrations were detected by standard cytogenetic analysis and only one (1.9%) deleterious copy number variants (CNV) was detected by CMA. Conclusion aberrant right subclavian artery (ARSA) with additional ultrasound findings constitute a strong predictor for aneuploidy. However, when ARSA is found in isolation, it confers no increased risk for aneuploidy or pathogenic CNVs.

Objective Performance of noninvasive prenatal screening (NIPS) methodologies when applied to low fetal fraction samples is not well established. The single-nucleotide polymorphism (SNP) method fails samples below a predetermined fetal fraction threshold, whereas some laboratories employing the whole-genome sequencing (WGS) method report aneuploidy calls for all samples. Here, the performance of the two methods was compared to determine which approach actually detects more fetal aneuploidies. Methods Computational models were parameterized with up-to-date published data and used to compare the performance of the two methods at calling common fetal trisomies (T21, T18, T13) at low fetal fractions. Furthermore, clinical experience data were reviewed to determine aneuploidy detection rates based on compliance with recent invasive screening recommendations. Results The SNP method's performance is dependent on the origin of the trisomy, and is lowest for the most common trisomies (maternal M1 nondisjunction). Consequently, the SNP method cannot maintain acceptable performance at fetal fractions below ~3%. In contrast, the WGS method maintains high specificity independent of fetal fraction and has >80% sensitivity for trisomies in low fetal fraction samples. Conclusion The WGS method will detect more aneuploidies below the fetal fraction threshold at which many labs issue a no-call result, avoiding unnecessary invasive procedures. © 2017 Counsyl Inc. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

Chromosomal aberrations are a common cause for miscarriage. The purpose of this study was to evaluate factors that influence the frequency of chromosomal abnormalities in miscarriages and provide clinicians with a guideline for management of such cases.The study included 170 women who experienced pregnancy loss between the 2004 and 2014. Cytogenetic analysis of products of conception (POC) was routinely performed.Successful cytogenetic analysis was achieved in 144 cases (84%). Of these, 78 cases (54%) had a chromosomal aberration. The incidence of chromosomal aberrations was not statistically significant among patients with 1, 2, 3, 4 or ≥5 previous miscarriages (33.3%, 57.4%, 48.6%, 65.2%, and 59.1%, respectively, p = 0.227). The F/M ratio was similar in normal and abnormal POC karyotypes (1.2:1 and 1.3:1, respectively, p = 0.7).Contrary to previous assumptions we did not find correlation between number of previous spontaneous miscarriages a women experienced and chromosomal aberration in her current miscarriage.

Preimplantation genetic screening (PGS) has been one of the most promising advancements in reproductive medicine. Current PGS practice employs comprehensive chromosomal screening. This progressive technique, particularly next-generation sequencing (NGS), has revealed the phenomenon of embryonic mosaic aneuploidy, the presence of cell lineages with different chromosomal constitutions. Two Web-based PGS surveys conducted about reproductive medicine practitioners assessed, among other topics, attitudes and opinions regarding mosaicism in PGS. Published survey results highlighted a number of distinct differences between practitioners in facilities that performed PGS and those that did not. There were also gaps in consensus on the objectives of PGS, how often mosaicism was encountered and reported, whether NGS was required to detect mosaicism, and what the maximum aneuploid cell percentage should be employed for performing embryo transfers. These discrepancies ultimately lead to differences in opinion regarding whether PGS should be performed if mosaicism decision-making guidelines are not yet available.

We describe a case of Beckwith-Wiedemann syndrome (BWS) demonstrating pre- and post-natal intra-familial variability. Our first encounter with the family occurred in the 1990s following the birth of 3 affected offspring. The first two pregnancies presented with exomphalos and elevated second trimester maternal serum alpha-fetoprotein (msAFP, 3.43 and 4.01 MOM, respectively) as well as elevated maternal human chorionic gonadotrophin (mhCG, 4.33 and 8.8 MOM, respectively). The diagnosis of BWS was confirmed postnatally in both cases. The third ongoing pregnancy presented only with elevated mhCG (7.09 MOM) and no malformation. Nonetheless BWS was suspected. The diagnosis was confirmed postnatally with clinical manifestations including macroglossia and cleft palate. Two affected female siblings were also diagnosed with Mullerian agenesis in adulthood. Suspecting a common genetic etiology, sequencing of the CDKN1C gene revealed a maternally inherited, likely pathogenic variant (NM_000076.2: c.367_385del; p.(Ala123Serfs*143)) causative of BWS. Chromosomal microarray and whole exome sequencing did not reveal any other pathogenic variant that would explain the Mullerian agenesis. One of the affected females underwent successful preimplantation genetic testing (PGT) with a surrogate and gave birth to a healthy female. To the best of our knowledge, this is the first report of Mullerian agenesis as a possible rare expansion of the BWS phenotype. In addition, this case highlights the potential role of abnormal second trimester biochemical markers (msAFP, mHCG) as possible indicators of BWS, especially in familial cases.

Introduction Non-invasive prenatal testing (NIPT) using cell-free DNA in maternal blood is a relatively new screening modality for the common trisomies of chromosomes 21, 18 and 13 and sex chromosome aneuploidies. For some patients, however, results are not reported because of laboratory technical issues such as low fetal fraction and sequencing failures. In this review, the clinical implications of NIPT test failures are discussed. Methods A Medline search was performed for all studies on NIPT that include >1000 samples. The failure rates were assessed by technology. Results Methods based on massive parallel sequencing have been found to have the lowest failure rate (1.58%), while tests based on single-nucleotide polymorphism analysis have the highest failure rate (6.39%). Conclusions Recent publications suggest that patients who receive a ‘no call’ result are at increased risk of aneuploidy. Some professional societies have therefore recommended that these patients undergo genetic counseling and be offered invasive diagnostic testing. NIPT technology that has a high failure rate may increase the false positive rates, decrease the positive predictive value, and increase the procedure-related pregnancy loss. © 2016 John Wiley & Sons, Ltd.

Cell-free DNA-based noninvasive prenatal testing (cfDNA) is a relatively new screening tool that analyzes cfDNA circulating in maternal plasma to screen for aneuploidies. Since its introduction, cfDNA has been rapidly adopted by health care providers (HCPs). This rapid adoption, as well as progressive developments in the technology, requires professional societies to continuously update their guidelines to indicate the broadening scope both in terms of test indications and patient populations for whom it has become the appropriate primary test. CfDNA testing, initially applied to high-risk patients, is now largely considered an option for all patients. For HCPs, the rapid introduction of cfDNA into clinical practice has come with the requirement to stay up-to-date and accurately informed. We performed a survey to understand the current practices and views of European HCPs on the use of cfDNA. European HCPs were surveyed on several topics such as familiarity with cfDNA-based noninvasive prenatal testing (NIPT), current usage, patient counseling, test menu expansion, and future perspectives. The results of this survey demonstrate increasing usage and awareness of cfDNA-based NIPT in five European countries (UK, France, Germany, Spain and Italy). Major barriers to implementation include cost and a lack of physician education on NIPT.

We describe our experience with whole-exome sequencing (WES) in fetuses with central nervous system (CNS) abnormalities following a normal chromosomal microarray result. During the study period (2014–2017) 7 cases (9 fetuses) with prenatally diagnosed CNS abnormality, whose chromosomal microarray analysis was negative, were offered whole-exome sequencing analysis. A pathogenic or a likely pathogenic variant was found in 5 cases including a previously described, likely pathogenic de novo TUBA1A variant (Case #1); a previously described homozygous VRK1 variant (Case #2); an X-linked ARX variant (Case #3); a likely pathogenic heterozygous variant in the TUBB3 gene (Case #5). Finally, in two fetuses of the same couple (Case #6), a compound heterozygous state was detected, consisting of the NPHP1 gene deletion and a sequence variant of uncertain significance. Two additional cases had normal WES results. Whole-exome sequencing may improve prenatal diagnosis in fetuses with CNS abnormalities.

Item does not contain fulltext Introduction: Our objective was to evaluate the incidence of chromosomal aberration (both microscopic and submicroscopic) and the clinical outcome of fetuses with isolated muscular ventricular septal defect (VSD). Material and methods: The study included 40 pregnant women whose fetuses were diagnosed with isolated muscular ventricular septal defect (mVSD). Of these, 30 patients underwent amniocentesis and 10 declined. All samples were tested by chromosomal microarray analysis (CMA). Of the 40 women in the study, 32 gave birth and the clinical outcome of the children was retrieved from the patients' medical records. Results: Of the 30 patients who underwent amniocentesis, one was detected with mosaic Klinefelter syndrome and one was detected with a pathogenic copy number variant unrelated to the VSD. Clinical follow-up was performed on 26 children after birth. The first postnatal echocardiography did not detect a VSD in 13 (50%) of the followed-up children. Spontaneous closure occurred in another eight (30.8%) children during the postnatal follow-up period. In only five children (19.2%) VSD was still detected by echocardiography after the first year of life. Discussion: Isolated muscular VSD diagnosed prenatally does not appear to be a significant risk factor for chromosomal abnormalities and has a favorable clinical outcome.

President President-Elect Past President Secretary Treasurer Lucas Otano MD, PhD (Argentina) Ignatia B. Van den Veyver MD (USA) Jan M.M. van Lith MD, PhD (Netherlands) Louise Wilkins-Haug MD (USA) Antoni Borrell MD, PhD (Spain) Directors Peter Benn PhD, DSc (USA) Lyn Chitty PhD (UK) Rossa Chiu (Hong Kong) Roland Devlieger MD, PhD (Belgium) Sylvie Langlois MD, CCMG (Canada) Anthony O. Odibo MD, MSCE (USA) R. Doug Wilson MD, Msc, FRCSC (Canada) Yuval Yaron MD (Israel) Diana W. Bianchi MD, ex officio (USA) Position Statement from the Chromosome Abnormality Screening Committee on Behalf of the Board of the International Society for Prenatal Diagnosis

The objective of this study is to evaluate the incidence of chromosomal aberration (both microscopic and sub-microscopic) in fetuses with an aberrant right subclavian artery (ARSA) detected by ultrasonographic anomaly scan.The study included 62 pregnant women whose fetuses were diagnosed with ARSA who were referred for genetic counseling. Of these, 55 patients underwent amniocentesis and 7 declined invasive testing. All 55 amniocentesis samples were tested by standard G-banding and chromosomal microarray, except for 2 samples for which only karyotype and fluorescence in situ hybridization for 22q11.2 deletions were performed.Of the 55 women who underwent amniocentesis, 5 were detected with trisomy 21 (9.1%), all of whom had additional ultrasound findings. Among the 14 fetuses with ARSA and additional ultrasound findings, the incidence of trisomy 21 was 35.7%. In fetuses with isolated ARSA, no chromosomal aberrations were detected by standard cytogenetic analysis and only one (1.9%) deleterious copy number variants (CNV) was detected by chromosomal microarray.Aberrant right subclavian artery with additional ultrasound findings constitute a strong predictor for aneuploidy. However, when ARSA is found in isolation, it confers no increased risk for aneuploidy or pathogenic CNVs. © 2017 John WileySons, Ltd.

Embryonic mosaicism, the presence of more than one distinct cell line within an embryo, has recently become the focus of growing attention and controversy in the context of preimplantation genetic screening (PGS). To evaluate the extent of mosaic aneuploidy in clinical practice and to gain insight on the practices and views regarding this issue, we conducted a survey using a prospective, 20-item Web-based questionnaire with questions related to practices and views regarding mosaicism in PGS. A total of 102 in vitro fertilization (IVF) units from 32 countries that performed 108,900 IVF cycles annually responded to the survey. More than half responded that embryonic mosaic aneuploidy is reported by the laboratory, but 31.9% stated that samples are reported as euploid or aneuploid only. If mosaic aneuploidy is reported, 46% stated that it was present in ≤10% of the embryos. More than two-thirds were of the opinion that next-generation sequencing is required to reliably detect mosaicism. Among centers performing PGS, 47.9% consider embryonic mosaicism when detected in >20% of the cells, and nearly two-thirds believe that mosaic aneuploid embryos should be stored for potential therapeutic use after extensive and appropriate counseling. In summary, mosaicism has always existed in preimplantation embryos, and new technologies can now detect its presence with higher resolution. More studies are needed before definite conclusions can be drawn.

Objective Down syndrome screening programmes lead to the prenatal diagnosis of other chromosomal abnormalities, some of which would not be detected by the secondary use of cell-free (cf)DNA testing in screen positives. This study aims to assess the number of these incidental diagnoses. Method This study is a systematic review of the literature to identify large prospective screening studies that reported diagnoses other than trisomies 21 and 18. Results There were ten informative prospective studies in which a total of 1 500 999 women were screened, and there were 3689 aneuploidy cases detected in the screen positives. Trisomy 21 was estimated to comprise only 58% of detected aneuploidies, trisomies 21 and 18 comprised 72%, and the common trisomies – 21, 18 and 13 – comprised 76%. Common trisomies and sex chromosome abnormalities, now included in all commercial cfDNA tests, were estimated to comprise 87% of aneuploidies in the Down syndrome screen positives. All these proportions were higher for second trimester protocols compared with those carried out wholly or partly in the first trimester. Conclusion Secondary use of cfDNA testing will lead to about one-fifth reduction in diagnoses, taking account of both undetectable aneuploidies and false-negatives. This loss might be overcome by contingent cfDNA testing. © 2014 John Wiley & Sons, Ltd.

Objective A prenatal diagnosis of chromosome X short arm deletions may present a challenge in prenatal genetic counseling. We present clinical and molecular data of carriers of Xp distal deletions. Methods We assessed prenatal and postnatal phenotypes of individuals from three families with large Xp distal deletions and from a fourth family with a small Xp distal deletion. The work-up included karyotyping, chromosomal microarray analysis, and assessment of the X inactivation pattern. Results Five out of eight women with large deletions had a short stature (

Background: The purpose of this research was to calculate the minimum sample size needed to obtain reliable results from crowdsourced retrospective online surveys of IVF clinics, where the sample was IVF cycles

Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT, USA Prenatal Diagnosis Unit, Institute of Gynecology, Obstetrics and Neonatology, Hospital Clinic, Maternitat Campus, University of Barcelona Medical School, Catalonia, Spain Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY, USA Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, USA Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Department of Obstetrics and Gynecology, Albert Einstein College of Medicine, New York, NY, USA Department of Obstetrics and Gynecology, University of Calgary, Calgary, AB, Canada Department of Obstetrics and Gynecology, Assaf Harofe Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA Department of Obstetrics and Gynecology, Washington University in St Louis, St Louis, MO, USA Laboratory for Infectious Diseases and Perinatal Screening, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands Prenatal Screening Unit, Clinical Biochemistry Department, Barking Havering & Redbridge University Hospitals, King George Hospital, Goodmayes, UK Genetics Program, North York General Hospital, Toronto, ON, Canada Department of Mathematics and Statistics, University of Plymouth, Plymouth, UK Prenatal Diagnosis Unit, Genetic Institute, Sourasky Medical Center, Tel Aviv, Israel *Correspondence to: Peter Benn. E-mail: benn@nso1.uchc.edu This Statement replaces the January 2011 Statement (Prenatal Diagnosis 2011;31:519–522) and the Rapid Response Statement (Prenatal Diagnosis 2012;32:1–2).

ObjectivePerformance of noninvasive prenatal screening (NIPS) methodologies when applied to low fetal fraction samples is not well established. The single-nucleotide polymorphism (SNP) method fails samples below a predetermined fetal fraction threshold, whereas some laboratories employing the whole-genome sequencing (WGS) method report aneuploidy calls for all samples. Here, the performance of the two methods was compared to determine which approach actually detects more fetal aneuploidies.MethodsComputational models were parameterized with up-to-date published data and used to compare the performance of the two methods at calling common fetal trisomies (T21, T18, T13) at low fetal fractions. Furthermore, clinical experience data were reviewed to determine aneuploidy detection rates based on compliance with recent invasive screening recommendations.ResultsThe SNP method’s performance is dependent on the origin of the trisomy, and is lowest for the most common trisomies (maternal M1 nondisjunction). Consequently, the SNP method cannot maintain acceptable performance at fetal fractions below ~3%. In contrast, the WGS method maintains high specificity independent of fetal fraction and has >80% sensitivity for trisomies in low fetal fraction samples.ConclusionThe WGS method will detect more aneuploidies below the fetal fraction threshold at which many labs issue a no-call result, avoiding unnecessary invasive procedures.