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STUDY QUESTION: What is the frequency of major chromosome abnormalities in a population-based diagnostic data set of genomic tests performed on miscarriage, fetal and infant samples in a state with >73 000 annual births? SUMMARY ANSWER: The overall frequency of major chromosome abnormalities in the entire cohort was 28.2% (2493/8826), with a significant decrease in the detection of major chromosome abnormalities with later developmental stage, from 50.9% to 21.3% to 15.6% of tests in the miscarriage, prenatal and postnatal cohorts, respectively. WHAT IS KNOWN ALREADY: Over the past decade, technological advances have revolutionized genomic testing at every stage of reproduction. Chromosomal microarrays (CMAs) are now the gold standard of chromosome assessment in prenatal diagnosis and pediatrics. STUDY DESIGN, SIZE, DURATION: A population-based cohort study including all chromosome analysis was performed in the Australian state of Victoria during a 24-month period from January 2015 to December 2016. All samples obtained via invasive prenatal diagnosis and postnatal samples from pregnancy tissue and infants <=12 months of age were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: A research collaboration of screening and diagnostic units in the Australian state of Victoria was formed (the Perinatal Record Linkage collaboration), capturing all instances of prenatal and postnatal chromosome testing performed in the state. Victoria has over 73 000 births per annum and a median maternal age of 31.5 years. We analyzed our population-based diagnostic data set for (i) chromosome assessment of miscarriage, prenatal diagnosis and postnatal samples; (ii) testing indications and diagnostic yields for each of these cohorts; (iii) and the combined prenatal/infant prevalence of 22q11.2 deletion syndrome (DS) as a proportion of all births >=20 weeks gestation. MAIN RESULTS AND THE ROLE OF CHANCE: During the 24-month study period, a total of 8826 chromosomal analyses were performe

Introduction: This study aimed to ascertain the real-world utilisation and performance of various prenatal screening pathways, and to report the numbers of major chromosome abnormalities detected after a low-risk screening result. Method(s): Retrospective study of women resident in Victoria, Australia, undergoing screening or prenatal diagnosis in 2015. Patient-funded cell-free (cf) DNA referrals were merged with statewide results for combined frst-trimester screening (CFTS), second-trimester serum screening (STSS) and invasive diagnostic procedures. Postnatal cytogenetic were used to ascertain cases of false-negative screening results. Individual record linkage was performed with LinkageWizTM. Result(s): In 2015, 66146 women accessed at least one form of aneuploidy screening. Of the 61810 (94.6%) women with complete linkage data, 20.1% used cfDNA as their primary screen; 73.2% used CFTS alone; 5.3% had STSS, and 1.3% used both CFTS and cfDNA. CFTS had a combined sensitivity for trisomies 21/13/18 of 85.29% (95% CI 77.15-90.88) for a screen-positive rate (SPR) of 2.94%; cfDNA screening had 100% (95% CI 93.47-100.0) sensitivity and a 1.21% SPR for trisomies 21/13/18. The risk of any major chromosome abnormality after a low risk screening result was 1 in 1188 for CFTS and 1 in 717 for cfDNA (p = 0.08). Discussion(s): In 2015, 1 in 5 Victorian women chose self-funded cfDNA as a frst-line test. While the sensitivity of cfDNA for trisomies 21/18/13 was superior to CFTS, there was no statistically signifcant diference in the risk of any major chromosome abnormality after low-risk CFTS or cfDNA result.

Objectives: To perform individual record-linkage of women undergoing prenatal screening and/or prenatal and postnatal diagnosis to analyse the performance of different screening strategies, and report the residual risks of any major chromosome abnormality following a low risk result. Method(s): Retrospective study of women resident in Victoria, Australia, undergoing screening or prenatal diagnosis in 2015. Patientfunded cell-free (cf) DNA referrals from multiple providers were merged with statewide results for combined first trimester screening (CFTS), second trimester serum screening (STSS) and invasive diagnostic procedures. Postnatal cytogenetic results from products of conception and infants up to 12 months of age were used to ascertain cases of false negative screening results. Individual record-linkage was performed with LinkageWizTM and statistical analyses with STATA v14.0. Result(s): In 2015, 66,146 women (83.6% total births) accessed at least one form of aneuploidy screening. Of the 61,810 (94.6%) women with complete linkage data, 20.1% used cfDNA as their primary screen; 73.2% used CFTS alone; 5.3% had STSS, and 1.3% used both CFTS and cfDNA. Of women with a high risk CFTS result (>1 in 300), 11.6% (178) had additional screening with cfDNA and of these, 10 had fetal aneuploidy confirmed on prenatal diagnosis. CFTS had a combined sensitivity for trisomies 21/13/18 of 87.95% (95% CI 79.22-93.32) for a screen positive rate (SPR) of 2.94%; cfDNA screening had 100% (95% CI 93.47-100.0) sensitivity and a 1.21% SPR for trisomies 21/13/18. When high risk cfDNA results for any chromosome abnormality and failed cfDNA tests were treated as screen positives, the SPR increased to 2.42%. The risk of any major chromosome abnormality after a low risk screening result was 1 in 1188 for CFTS and 1 in 717 for cfDNA (p = 0.08). Conclusion(s): In a population with primary screening with government-subsidized CFTS or self-funded cfDNA available, approximately 1 in 5 women chos

Objectives: To explore the association between timing of diagnosis of common autosomal trisomies, maternal age and socioeconomic status (SES). Method(s): Retrospective study of all prenatal and postnatal cytogenetic diagnoses of trisomy 21 (T21), trisomy 18 (T18) and trisomy 13 (T13) in Victoria, Australia, in 2015-16, stratified by timing of diagnosis (prenatal <17 weeks gestation, prenatal > 17 weeks gestation, postnatal <12 months of age), maternal age and SES region (as assigned by postcode). Utilisation of prenatal testing following a liveborn T21 infant was ascertained via record linkage. Result(s): There were 160,230 total births and 817 diagnoses of T21 (n = 571), T18 (n = 139) and T13 (n = 107). The overall and livebirth prevalences of T21 were 3.56 and 0.47 per 1000 births, respectively. Compared with women from disadvantaged SES regions, women from advantaged SES regions were more likely to have a prenatal diagnosis of a trisomy before 17 weeks than after 17 weeks (p < 0.01) and less likely to have a liveborn T21 infant than a prenatal diagnosis (p < 0.01). There was a significant trend to higher livebirth rates of T21 with lower SES (p = 0.004). The majority (68.5%) of women who gave birth to a live infant with T21 did not utilise any prenatal screening or diagnostic testing. Conclusion(s): There is a significant relationship between lower SES, later prenatal diagnosis of trisomy, and higher livebirth rate of T21 in Victoria, Australia. The majority of livebirths with T21 were not preceded by any prenatal screening, suggesting significant disparities in utilization according to maternal SES.

Objectives: To explore the association between timing of diagnosis of common autosomal trisomies, maternal age, and socio-economic status (SES). Design(s): Retrospective study of cytogenetic diagnoses of trisomy 21 (T21), trisomy 18 (T18), and trisomy 13 (T13) in Victoria, Australia, in 2015 to 2016, stratified by timing (prenatal less than 17 weeks gestation, prenatal including or greater than or 17 weeks gestation, and postnatal before 12 months of age), maternal age, and SES region. Utilisation of prenatal testing following a live-born T21 infant was ascertained via record linkage. Result(s): Among 160 230 total births were 571 diagnoses of T21 and 246 of T18/T13. The overall and live birth prevalences of T21 were 3.56 and 0.47 per 1000 births, respectively. Compared with women from disadvantaged SES regions, women from high SES regions were more likely to have a prenatal diagnosis of a trisomy before 17 weeks than after (P <.01) and less likely to have a live-born T21 infant than a prenatal diagnosis (P <.01). There was a significant trend to higher live birth rates of T21 with lower SES (P =.004). The majority (68.5%) of women who gave birth to a live infant with T21 did not utilise prenatal testing. Conclusion(s): There is a significant relationship between lower SES, later prenatal diagnosis of trisomy, and higher live birth rate of T21 in Victoria.Copyright © 2019 John Wiley & Sons, Ltd.

Objectives: To create and analyse a population-based dataset of genomic tests performed on miscarriage, fetal, and infant samples in a state with >73,000 annual births. Method(s): Analysis of state-wide chromosome testing from Jan 2015 to Dec 2016, including all prenatal and postnatal samples including infants up to 12 months of age, was performed for: (i) the numbers and types of chromosome abnormalities present in miscarriage, prenatal diagnosis, and postnatal specimens; (ii) trends in chromosome abnormalities with advancing development; and (iii) the state-wide prevalence of the 22q11.2 deletion syndrome. Result(s): 8827 chromosomal analyses on 2573 miscarriage, 3661 prenatal, and 2593 postnatal samples were obtained. The majority (91.1%) were performed with whole genome SNP microarrays. The overall frequency of major chromosome abnormalities in the entire cohort was 28.4%. There was a significant decreasing trend in the percentage of chromosome abnormalities with later developmental stage from 51.0% to 21.3% to 16.2% in the miscarriage, prenatal and postnatal cohorts respectively (chi2 trend = 768.1, p < 0.0001). The total frequency of abnormalities in the live infant subgroup was 14.1%. The frequencies of pathogenic CNVs detected via CMA for the miscarriage and prenatal and postnatal cohorts were 2.8%, 2.3%, and 6.2%, respectively. There was a significant increasing trend in the frequency of pathogenic CNVs with later developmental stage (chi2 trend = 41.75, p < 0.0001). For the subgroup of live infants, the pathogenic CNV frequency on CMA analysis was 7.1%. There were 39 cases of 22q11.2 DS detected, including 1 miscarriage and 15 prenatal and 23 postnatal cases. After accounting for two cases of duplicate testing, and excluding the miscarriage case, the estimated prevalence of 22q11 DS was 1 in 4301 Victorian births. More than one third of diagnoses were confirmed during pregnancy. Conclusion(s): Our study marks a complete transition in genomic testing from t

Structural abnormalities involving the Y chromosome include deletions, inversions, isochromosomes, ring chromosomes and translocations. Phenotypes associated with these rearrangements can vary greatly from normal male with/without fertility issues to ambiguous genitalia to females resembling testicular feminization or displaying features of Turner syndrome. In addition to the nature of the rearrangement, the clinical consequences will be effected by the presence of other cell lines such as 45,X, and the tissue distribution and proportions of abnormal cell lines when observed in mosaic form. A combination of conventional chromosomal and molecular testing may be required to elucidate the morphology and extent of loss/gain of an abnormal Y chromosome. Certain anomalies such as satellited Yqh and pericentric inversions tend to be familial variants. A retrospect review of 76 cases with structurally abnormal Y chromosome identified pre- and postnatally over the last two decades at Monash Pathology was undertaken. Proportions of the more common abnormalities were found to correlate with other published data.

OBJECTIVES: To perform individual record linkage of women undergoing screening with cell-free DNA (cfDNA), combined first-trimester screening (CFTS), second-trimester serum screening (STSS), and/or prenatal and postnatal cytogenetic testing with the aim to (1) obtain population-based estimates of utilization of prenatal screening and invasive diagnosis, (2) analyze the performance of different prenatal screening strategies, and (3) report the residual risk of any major chromosomal abnormality following a low-risk aneuploidy screening result. METHOD(S): This was a retrospective study of women residing in the state of Victoria, Australia, who underwent prenatal screening or invasive prenatal diagnosis in 2015. Patient-funded cfDNA referrals from multiple providers were merged with state-wide results for government-subsidized CFTS, STSS and invasive diagnostic procedures. Postnatal cytogenetic results from products of conception and infants up to 12months of age were obtained to ascertain cases of false-negative screening results and atypical chromosomal abnormalities. Individual record linkage was performed using LinkageWizTM . RESULT(S): During the study period, there were 79140 births and 66166 (83.6%) women underwent at least one form of aneuploidy screening. Linkage data were complete for 93.5% (n=61877) of women who underwent screening, and of these, 73.2% (n=45275) had CFTS alone, 20.2% (n=12486) had cfDNA alone; 5.3% (n=3268) had STSS alone, 1.3% (n=813) had both CFTS and cfDNA, and <0.1% (n=35) had both STSS and cfDNA. CFTS had a combined sensitivity for trisomies 21 (T21), 18 (T18) and 13 (T13) of 89.57% (95%CI, 82.64-93.93%) for a screen-positive rate (SPR) of 2.94%. There were 12 false-negative results in the CFTS pathway, comprising 10 cases of T21, one of T18 and one of T13. cfDNA had a combined sensitivity for T21, T18 and T13 of 100% (95%CI, 95.00-100%) for a SPR of 1.21%. When high-risk cfDNA results for any chromosome (including the sex chromosomes) a

OBJECTIVES: To explore the association between timing of diagnosis of common autosomal trisomies, maternal age, and socio-economic status (SES). DESIGN: Retrospective study of cytogenetic diagnoses of trisomy 21 (T21), trisomy 18 (T18), and trisomy 13 (T13) in Victoria, Australia, in 2015 to 2016, stratified by timing (prenatal less than 17 weeks gestation, prenatal including or greater than or 17 weeks gestation, and postnatal before 12 months of age), maternal age, and SES region. Utilisation of prenatal testing following a live-born T21 infant was ascertained via record linkage. RESULTS: Among 160 230 total births were 571 diagnoses of T21 and 246 of T18/T13. The overall and live birth prevalences of T21 were 3.56 and 0.47 per 1000 births, respectively. Compared with women from disadvantaged SES regions, women from high SES regions were more likely to have a prenatal diagnosis of a trisomy before 17 weeks than after (P < .01) and less likely to have a live-born T21 infant than a prenatal diagnosis (P < .01). There was a significant trend to higher live birth rates of T21 with lower SES (P = .004). The majority (68.5%) of women who gave birth to a live infant with T21 did not utilise prenatal testing. CONCLUSION: There is a significant relationship between lower SES, later prenatal diagnosis of trisomy, and higher live birth rate of T21 in Victoria.

9p tetrasomy is a rare chromosomal imbalance defined by the presence of a supernumerary isochromosome involving the short arm of chromosome 9, or isodicentric chromosome that additionally includes 9q material. Prenatal diagnosis of mosaic or non-mosaic tetrasomy 9p is uncommon. Here we present a prenatal case of mosaic tetrasomy 9p in a fetus with multiple abnormalities using CGH microarray where conventional karyotyping assisted in elucidating the nature of the imbalance. While microarray provides a significant advantage in terms of resolution, it has limited capacity to ascertain the cytogenetic mechanism of copy number changes identified.

In Australia, microarray has replaced G-banded karyotyping as the first line of investigation in prenatal diagnosis. Hypothesis: Restricting prenatal microarray testing to structurally abnormal fetuses would constitute a service that is clinically efficient, costeffective, and in line with international guidelines. Method(s): The internationally recommended approach of restricting microarray testing to high-risk cases with abnormal ultrasound scan and/or nuchal translucency of more than 3.5 mm was implemented in September 2016. Result(s): Of 270 prenatal specimen received to date for various clinical indications and microarray was indicated and performed only on 52% of cases. Pathogenic copy number changes were detected in six cases and Variation of Unknown Significance (VoUS) were detected in 17 cases. Discussion(s): We review and compare indications and fetal outcome of these cases. Conclusion(s): The clinical and economic impact of the new approach with special emphasis in a public hospital setting will be summarized.

We report a case of an infant with congenital diaphragmatic hernia (CDH) and hydrops fetalis who died from hypoxic respiratory failure. Autopsy revealed type B interrupted aortic arch (IAA). Microarray revealed a female karyotype with deletion of chromosome 1p21.1p12. There may be an association between 1p microdeletion, CDH, and IAA.Copyright © 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.

Background: In the era of noninvasive prenatal testing (NIPT) the appropriate nuchal translucency (NT) threshold for offering diagnostic testing with chromosomal microarray (CMA) identification remains debated. Aim(s): To perform a population-based individual record-linkage study of women undergoing combined first trimester screening (CFTS) and prenatal or postnatal diagnosis in order to analyze the frequency and type of chromosome abnormalities according to NT measurement. Method(s): Retrospective study of women resident in Victoria, Australia, who underwent CFTS during 2015-16. CFTS results were matched to prenatal diagnostic procedures and postnatal cytogenetic results from products of conception and infants up to 12 months of age, using probabilistic record linkage. An atypical chromosome abnormality was defined as any major chromosome abnormality, other than whole chromosome aneuploidy involving chromosomes 21, 18, 13, X and Y. Result(s): Of the 81,244 singleton pregnancies undergoing CFTS, 534 (0.66%) had an NT 3.0-3.4 mm, and 491 (0.60%) had an NT > 3.5 mm. Of the 1779 pregnancies having diagnostic testing, 89.6% were performed by CMA and 93 atypical chromosome abnormalities were detected, two in fetuses with NT 3.0-3.4 mm. The frequency of an atypical chromosome abnormality with NT > 3.5 mm was 4.07% (95% CI [2.51, 6.22]), with 3.0-3.4 mm, was 0.37% (95% CI [0.05, 1.35]) and with <3.0 mm was 0.09% (95% CI [0.07, 0.11]). Conclusion(s): As expected, the risk of an atypical chromosome abnormality is highest in fetuses with enlarged NT > 3.5mm. For fetuses with NT 3.0-3.4mm, however, the 0.37% risk of an atypical chromosome abnormality (1 in 270) is within the traditional range for offering diagnostic testing.

Introduction: The American College of Obstetricians and Gynecologists recently recommended offering genetic counselling and diagnostic testing for enlarged nuchal translucency (NT) at >3.0 mm, regardless of prior negative screening with non-invasive prenatal testing (NIPT). Aim(s): To perform a population-based record-linkage study of women undergoing combined first-trimester screening (CFTS) and prenatal or post-natal diagnosis in order to analyse chromosome abnormalities according to NT in millimetres and multiples of the median (MoM). Method(s): Retrospective study of women resident in Victoria who underwent CFTS during 2015-16. CFTS results were linked to prenatal diagnostic procedures and post-natal cytogenetic results using probabilistic record linkage. An atypical chromosome abnormality was defined as any major chromosome abnormality, other than whole chromosome aneuploidy involving chromosomes 21, 18, 13, X and Y. Result(s): Of the 81,244 women undergoing CFTS, 491 had an NT > 3.5 mm and 534 had an NT 3.0-3.4 mm. There were 1,779 diagnostic tests: 89.6% were performed by microarray and 93 atypical chromosome abnormalities were detected. The risk of an atypical chromosome abnormality in fetuses with NT 3.0-3.4 mm was similar to previously reported risks without an ultrasound abnormality (1 in 270).The threshold of 1.9 MoM had better specificity than NT of 3.0 mm, capturing the same number of atypical abnormalities for 31% fewer 'false positives'. Discussion(s): If a NT threshold <3.5 mm prompts an offer of diagnostic testing with microarray after low-risk NIPT, an NT threshold of 1.9MoM is superior to a fixed threshold of 3.0 mm for the detection of atypical chromosome conditions.

Background: The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recently recommended offering genetic counseling and diagnostic testing for enlarged nuchal translucency at >=3.0 mm, regardless of previous negative screening with noninvasive prenatal testing. Objective(s): This study aimed to perform a population-based, individual record linkage study to determine the optimal definition of an enlarged nuchal translucency for the detection of atypical chromosome abnormalities. Study Design: This was a retrospective study of women resident in Victoria, Australia, undergoing combined first-trimester screening during the 24-month period from January 2015 to December 2016. Linkages between statewide results for combined first-trimester screening, prenatal diagnostic procedures, and postnatal cytogenetic results from products of conception and infants up to 12 months of age were used to ascertain the frequency and type of chromosome abnormality by gestation and nuchal translucency measurement. An atypical chromosome abnormality was defined as any major chromosome abnormality other than whole chromosome aneuploidy involving chromosomes 21, 18, 13, X, and Y. Result(s): Of the 81,244 singleton pregnancies undergoing combined first-trimester screening, 491 (0.60%) had a nuchal translucency of >=3.5 mm, 534 (0.66%) had a nuchal translucency of 3.0 to 3.4 mm, and 80,219 (98.74%) had a nuchal translucency of < 3.0 mm. When grouped by nuchal translucency multiples of the median (MoM), 192 (0.24%) had a nuchal translucency of >=3.0 MoM, 513 (0.63%) had a nuchal translucency of 1.9 to 2.9 MoM, and 80,539 (99.13%) had a nuchal translucency of <1.9 MoM. A total of 1779 pregnancies underwent prenatal or postnatal diagnostic testing, of which 89.60% were performed by whole-genome single-nucleotide polymorphism chromosomal microarray. The frequency of total major chromosome abnormalities was significantly higher in the group with a nuchal t

Introduction: The American College of Obstetricians and Gynecologists recently recommended offering genetic counselling and diagnostic testing for enlarged nuchal translucency (NT) at >3.0 mm, regardless of prior negative screening with non-invasive prenatal testing (NIPT). Aim(s): To perform a population-based record-linkage study of women undergoing combined first-trimester screening (CFTS) and prenatal or post-natal diagnosis in order to analyse chromosome abnormalities according to NT in millimetres and multiples of the median (MoM). Method(s): Retrospective study of women resident in Victoria who underwent CFTS during 2015-16. CFTS results were linked to prenatal diagnostic procedures and post-natal cytogenetic results using probabilistic record linkage. An atypical chromosome abnormality was defined as any major chromosome abnormality, other than whole chromosome aneuploidy involving chromosomes 21, 18, 13, X and Y. Result(s): Of the 81,244 women undergoing CFTS, 491 had an NT > 3.5 mm and 534 had an NT 3.0-3.4 mm. There were 1,779 diagnostic tests: 89.6% were performed by microarray and 93 atypical chromosome abnormalities were detected. The risk of an atypical chromosome abnormality in fetuses with NT 3.0-3.4 mm was similar to previously reported risks without an ultrasound abnormality (1 in 270).The threshold of 1.9 MoM had better specificity than NT of 3.0 mm, capturing the same number of atypical abnormalities for 31% fewer 'false positives'. Discussion(s): If a NT threshold <3.5 mm prompts an offer of diagnostic testing with microarray after low-risk NIPT, an NT threshold of 1.9MoM is superior to a fixed threshold of 3.0 mm for the detection of atypical chromosome conditions.