The Australian Reproductive Genetic Carrier Screening Project (Mackenzie's Mission): Design and Implementation.

Reproductive genetic carrier screening (RGCS) provides people with information about their chance of having children with autosomal recessive or X-linked genetic conditions, enabling informed reproductive decision-making. RGCS is recommended to be offered to all couples during preconception or in early pregnancy. However, cost and a lack of awareness may prevent access. To address this, the Australian Government funded Mackenzie's Mission­the Australian Reproductive Genetic Carrier Screening Project. Mackenzie's Mission aims to assess the acceptability and feasibility of an easily accessible RGCS program, provided free of charge to the participant. In study Phase 1, implementation needs were mapped, and key study elements were developed. In Phase 2, RGCS is being offered by healthcare providers educated by the study team. Reproductive couples who provide consent are screened for over 1200 genes associated with >750 serious, childhood-onset genetic conditions. Those with an increased chance result are provided comprehensive genetic counseling support. Reproductive couples, recruiting healthcare providers, and study team members are also invited to complete surveys and/or interviews. In Phase 3, a mixed-methods analysis will be undertaken to assess the program outcomes, psychosocial implications and implementation considerations alongside an ongoing bioethical analysis and a health economic evaluation. Findings will inform the implementation of an ethically robust RGCS program.

Prenatal and preimplantation genetic diagnosis for single gene disorders: A population-based study from 1977 to 2016.

OBJECTIVE: To examine the statewide utilisation of prenatal diagnosis (PNDx) and preimplantation genetic diagnosis (PGT-M) for single gene disorders. METHODS: Population-based study of all women utilising PNDx in the Australian state of Victoria from 1977 to 2016. Single gene disorders were categorised using a systematic approach that aimed to reflect aspects of the PNDx decision-making process. Data on PGT-M for single gene disorders from 2005 to 2016 were similarly examined for comparison. Statistical significance testing was performed with χ2 test. RESULTS: Following an initial uptake period, annual PNDx rates for single gene disorders stabilised between 1.3 and 2.2 per 1000 births after the year 2000. The majority of PNDx (72%) was performed for disorders that primarily impair physical ability, while PNDx for adult onset conditions was rare (3%). PGT-M for single gene disorders has seen rapid growth since its introduction, and annual numbers now equal that of PNDx. In contrast to PNDx, one quarter of PGT-M tests were performed for adult onset conditions. CONCLUSIONS: Our population-wide analysis has demonstrated a steady demand for PNDx for single gene disorders over the past decade, in contrast to the rapidly increasing utilisation of PGT-M. PGT-M appears to be the preferred testing modality for adult onset disorders.

Offering pregnant women different levels of genetic information from prenatal chromosome microarray: a prospective study.

This study aimed to examine the choice pregnant women make about the amount of fetal genetic information they want from chromosome microarray. Women having invasive prenatal testing in the absence of fetal structural abnormality were recruited in Victoria, Australia. A decision aid for women described 'targeted' analysis as reporting only copy number variants implicated in a highly penetrant and well-described phenotype and 'extended' as additionally reporting variants of uncertain or unknown significance. Participant's choice and demographics were collected by survey before chorionic villus sampling or amniocentesis; psychological data were also collected then and again about 10 days after receiving results. High-resolution single-nucleotide polymorphism array analysis was performed, and a clinical review committee assessed variants for reporting before returning results to participants. Sixty-six participants (59.5%) chose extended analysis and 45 (40.5%) targeted. Choosing extended information was associated with (1) indication for prenatal diagnosis: maternal age alone (adjusted odds ratio (adjOR) 9.6, 95% confidence interval (CI): 1.4-66.0, p= 0.02), or 'other' indication (adjOR 7.1, 95% CI: 1.5-33.1, p= 0.01)); (2) >12 months to conceive (adjOR 4.1, 95% CI: 1.0-17.7, p= 0.05); and (3) Asian background (adjOR 4.67, 95% CI: 1.0-21.0, p= 0.04). No adverse psychological impact occurred in either group. We conclude that offering pregnant women different levels of fetal genetic analysis is warranted, alongside decision support.

Prenatal diagnosis and socioeconomic status in the non-invasive prenatal testing era: A population-based study.

BACKGROUND: Advances in technology can bring great benefits to human health, but their implementation may be influenced by socioeconomic factors, particularly in the field of prenatal screening for Down syndrome. AIM: To analyse screening test indications for, and diagnostic yield of, invasive prenatal diagnostic testing (PNDx) according to socioeconomic status. METHODS: Retrospective analysis of population-based data on PNDx and karyotype results for 2014-2015 in the Australian state of Victoria. Women having PNDx < 25 weeks due to combined first trimester screening (CFTS), second trimester serum screening (STSS), or noninvasive prenatal testing (NIPT) results were included. PNDx data were analysed by indication and maternal Index of Relative Socio-economic Advantage and Disadvantage (IRSAD), the latter determined by postcode. RESULTS: There were 145 206 births in 2014-2015; 1906 women underwent PNDx for the indication of CFTS (70.1%), NIPT (17.8%) or STSS (12.0%). Covariates positively associated with NIPT-indicated PNDx, compared with CFTS-indicated testing, were residence in a region of socioeconomic advantage, metropolitan status and maternal age. Women from the most advantaged regions had higher adjusted odds ratios (aOR) of NIPT-indicated testing compared with women from disadvantaged regions (aOR 5.72, 95% CI: 2.95-11.09). The diagnostic yield of PNDx increased with socioeconomic region, from 14% in the lowest IRSAD quintile to 31.2% in the highest (P < 0.0001). CONCLUSION: Population-based data reveal significant disparities in screening indications for PNDx and hence, in diagnostic yield, according to socioeconomic region. This finding may have ethical and policy implications for prenatal screening in Australia.

Alcohol consumption in a general antenatal population and child neurodevelopment at 2 years.

BACKGROUND: Prenatal alcohol exposure (PAE) is a community health problem with up to 50% of pregnant women drinking alcohol. The relationship between low or sporadic binge PAE and adverse child outcomes is not clear. This study examines the association between PAE in the general antenatal population and child neurodevelopment at 2 years, accounting for relevant contributing factors. METHODS: This prospective population-based cohort recruited 1570 pregnant women, providing sociodemographic, psychological and lifestyle information and alcohol use for five time periods. PAE categories were 'low', 'moderate/high', 'binge', in trimester 1 or throughout pregnancy. Measures of cognitive, language and motor development (Bayley Scales of Infant and Toddler Development) were available for 554 children, while measures of sensory processing (Infant/Toddler Sensory Profile) and social-emotional development (Brief Infant Toddler Social Emotional Assessment) were available for 948. RESULTS: A positive association in univariate analysis with low-level PAE throughout pregnancy and cognition (ß=4.1, 95% CI -0.02 to 8.22, p=0.05) was attenuated by adjusting for environmental/social deprivation risk factors (ß=3.06 (-1.19 to 7.30), p=0.16). Early binge drinking, plus continued PAE at lower levels, was associated with the child being more likely to score low in sensation avoidance (adjusted OR 1.88 (1.03 to 3.41), p=0.04). CONCLUSION: Early binge exposure, followed by lower-level PAE, demonstrated an increase in sensation-avoiding behaviour. There were, however, no significant associations between PAE and neurodevelopment following adjustment for important confounders and modifiers. Follow-up is paramount to investigate subtle or later onset problems.

A protocol for whole-exome sequencing in newborns with congenital deafness: a prospective population-based cohort.

INTRODUCTION: The aetiology of congenital hearing loss is heterogeneous, and in many infants a genetic cause is suspected. Parents face a diagnostic odyssey when searching for a cause of their infant's hearing loss. Through the Melbourne Genomics Health Alliance, a prospective cohort of infants will be offered whole-exome sequencing (WES) with targeted analysis in conjunction with chromosome microarray to determine the genetic causes of congenital hearing loss. Parents will also be offered the opportunity to receive additional results from their infant's WES. METHODS: Eligible infants will be identified through the Victorian Infant Hearing Screening Program and offered an appointment in a paediatrician-run clinic, a genetics assessment and enrolment in the Victorian Childhood Hearing Impairment Longitudinal Databank. If parents consent to WES, genes causing deafness will be analysed and they can choose to obtain additional findings. For the additional results component, a modified laboratory protocol has been designed for reporting of results in the absence of a relevant phenotype. Parents' experience of being offered WES will be evaluated using surveys. DISCUSSION: This project will provide descriptive analysis of the genetic aetiology of congenital hearing loss in this cohort and may provide data on genotype-phenotype correlations. Additionally, choices regarding additional findings will be analysed. Participants will represent a diverse cross section of the population, increasing the ability to generalise results beyond the study group. Evaluation surveys will allow analysis of preferences around counselling, usefulness of a decision aid and adequacy of information provision.

Improving family communication after a new genetic diagnosis: a randomised controlled trial of a genetic counselling intervention.

BACKGROUND: Genetic information given to an individual newly diagnosed with a genetic condition is likely to have important health implications for other family members. The task of communicating with these relatives commonly falls to the newly diagnosed person. Talking to relatives about genetic information can be challenging and is influenced by many factors including family dynamics. Research shows that many relatives remain unaware of relevant genetic information and the possible impact on their own health. This study aims to evaluate whether a specific genetic counselling intervention for people newly diagnosed with a genetic condition, implemented over the telephone on a number of occasions, could increase the number of at-risk relatives who make contact with genetics services after a new genetic diagnosis within a family. METHODS: This is a prospective, multi-centre randomised controlled trial being conducted at genetics clinics at five public hospitals in Victoria, Australia. A complex genetic counselling intervention has been developed specifically for this trial. Probands (the first person in a family to present with a diagnosis of a genetic condition) are being recruited and randomised into one of two arms - the telephone genetic counselling intervention arm and the control arm receiving usual care. The number of at-risk relatives for each proband will be estimated from a family pedigree collected at the time of diagnosis. The primary outcome will be measured by comparing the proportion of at-risk relatives in each arm of the trial who make subsequent contact with genetics services. DISCUSSION: This study, the first randomised controlled trial of a complex genetic counselling intervention to enhance family communication, will provide evidence about how best to assist probands to communicate important new genetic information to their at-risk relatives. This will inform genetic counselling practice in the context of future genomic testing. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ANZCTRN12608000642381.

Availability of treatment drives decisions of genetic health professionals about disclosure of incidental findings.

Contrasting opinions exist regarding the disclosure of incidental findings detected through clinical genomic testing. This study used a discrete choice experiment to investigate genetic health professionals' preferences for the disclosure of incidental findings in an Australian paediatric setting. Four attributes of conditions relating to incidental findings were investigated: availability of prevention and treatment, chance of symptoms ever developing, age of onset and severity. Questionnaires from 59 Australian genetic health professionals were analysed. Results show that when evaluating incidental findings for disclosure, these professionals value the availability of prevention and treatment for the condition above all other characteristics included in the study. The framework of this discrete choice experiment can be used to investigate the preferences of other stakeholders such as paediatricians and parents about disclosure of incidental findings. The results of this study may be considered when assessing which categories of incidental findings are most suitable for disclosure in clinical practice.

Key informants' perspectives of implementing chromosomal microarrays into clinical practice in Australia.

High-resolution genomic tests have the potential to revolutionize healthcare by vastly improving mutation detection. The use of chromosomal microarray (CMA) represents one of the earliest examples of these new genomic tests being introduced and disseminated in the clinic. While CMA has clear advantages over traditional karyotyping in terms of mutation detection, little research has investigated the process by which CMA was implemented in clinical settings. Fifteen key informants, six clinicians, and nine laboratory scientists from four Australian states were interviewed about their experiences during and in the time since CMA was adopted for clinical use. Participants discussed challenges such as result interpretation and communication. Strengths were also highlighted, including the collaborative approaches of some centers. Clinical experiences and opinions can inform larger studies with a range of stakeholders, including patients. The historical perspectives from this retrospective study can be helpful in guiding the implementation of future genomic technologies such as whole exome/genome sequencing.

An exploration of genetic health professionals' experience with direct-to-consumer genetic testing in their clinical practice.

Direct-to-consumer genetic testing (DTC-GT) allows individuals to obtain genetic tests directly from companies without necessarily involving health professionals. This study explores genetic health professionals' opinions of health-related DTC-GT and the reported frequency of individuals presenting to clinical genetics services after undertaking testing. Genetic counsellors and clinical geneticists, members of the Human Genetics Society of Australasia, completed an online survey in mid 2011. The 130 genetic counsellors (estimated response fraction=43%) and 38 clinical geneticists (estimated response fraction=46%) had mixed opinions regarding DTC-GT, with only 7% confident in accurately interpreting and explaining DTC-GT results. Nineteen respondents (11%) reported one or more client(s) referred to them after undertaking DTC-GT. Descriptions of 25 clients were extracted from responses, and respondents reported that all clients were concerned for the health of either themselves or family members. Most clients presented to genetic clinics specifically as a result of their DTC-GT (96%) and were self or GP referred (92%). Respondents perceived that their clients typically undertook DTC-GT because they wanted to identify monogenic conditions, including carrier testing and/or know their susceptibility or predisposition for complex conditions (88%). The majority of clients needed help interpreting DTC-GT results (80%), however in general were not questioning the validity of their DTC-GT results (92%) nor seeking further genetic testing (84%). Currently, DTC-GT is not a major reason for referral to clinical genetics services in Australia and New Zealand and the majority of genetic health professionals lack confidence in being able to accurately interpret and explain DTC-GT results.

Outcomes of singleton births after blastocyst versus nonblastocyst transfer in assisted reproductive technology.

OBJECTIVE: To compare obstetric and perinatal outcomes of singleton births after assisted reproductive technology (ART) with blastocyst transfer (days 5 to 6) versus nonblastocyst transfer (days 2 to 4). DESIGN: Retrospective cohort study. SETTING: Monash IVF. PATIENT(S): 4,202 women who conceived using in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) between 2004 and 2009. INTERVENTION(S): Records analysis of fresh and frozen-thawed embryo transfers resulting in singleton births of at least 20 weeks' gestation. MAIN OUTCOME MEASURE(S): Perinatal outcomes: preterm birth, low birthweight, very low birthweight, small for gestational age, large for gestational age, preeclampsia, antepartum hemorrhage, placental abruption, placenta previa, and postpartum hemorrhage; and covariates: maternal age, year of birth of the baby, private health insurance status, maternal body mass index, smoking status, parity, gender of baby, and variations in treatment procedures. RESULT(S): Multivariate analysis found no statistically significant difference between transfers on days 5 and 6 and days 2 and 4 for all maternal and perinatal outcomes. There were modest increases in the adjusted odds ratios for preeclampsia (adjusted odds ratio 1.72, 99% confidence interval 0.93-3.20) and placenta previa (1.65, 0.92-2.98). CONCLUSION(S): Obstetric and perinatal outcomes after blastocyst transfer on days 5 to 6 are similar when compared with embryo cleavage-stage transfers on days 2 to 4.

The psychosocial impact of Klinefelter syndrome and factors influencing quality of life.

PURPOSE: There is considerable information regarding the medical and cognitive aspects of Klinefelter syndrome yet little research regarding its psychosocial impact. This study investigates the personal impact of Klinefelter syndrome and the influence of age at diagnosis, clinical, social, and demographic factors on adult quality of life outcomes. METHODS: Men from across Australia, diagnosed with KS at different ages, were recruited through multiple sources. Participants completed a questionnaire assessing subjective well-being, body image, self-esteem, mental health, social support, and general health. RESULTS: Eighty-seven individuals self-completed the questionnaire. All outcomes were much poorer for the study population than for the general male population. Individuals diagnosed later in life reported many of the same symptoms as those diagnosed at younger ages. Employment status, social support, and phenotypic features were the strongest predictors of psychosocial outcomes. Age at diagnosis was not as influential because it did not correlate with phenotypic severity score. CONCLUSION: This is the first quantitative study to show Klinefelter syndrome has a significant personal impact. Men diagnosed with Klinefelter syndrome later in life reported similar difficulties as those at younger ages, suggesting that they would benefit from early detection and intervention. Understanding factors influencing this can assist in providing adequate services to individuals with Klinefelter syndrome, their partners, families, and the health professionals caring for them.

The prevalence and diagnosis rates of Klinefelter syndrome: an Australian comparison.

OBJECTIVE: To determine the prevalence and diagnosis rates of Klinefelter syndrome (KS) in Victoria, Australia, and compare these to previous international findings. DESIGN, SETTING AND PARTICIPANTS: A Victorian population-based descriptive study of all cytogenetic examinations resulting in a diagnosis of KS, including prenatal diagnoses from 1986 to 2006 and postnatal diagnoses from 1991 to 2006. MAIN OUTCOME MEASURES: Birth prevalence and diagnosis rates of KS. RESULTS: The birth prevalence of KS in Victoria is estimated to be 223 per 100,000 males (95% CI, 195-254), with about 50% of cases remaining undiagnosed. CONCLUSIONS: KS may be occurring more frequently than has been reported previously, yet many cases remain undiagnosed. Our results highlight the need for increased awareness leading to timely detection.

Postnatal screening for Klinefelter syndrome: is there a rationale?

UNLABELLED: Diagnosis of Klinefelter syndrome (KS) allows for timely beneficial interventions across the lifespan. Most cases currently remain undiagnosed because of low awareness of KS amongst health professionals, the hesitancy of men to seek medical attention and its variable clinical presentation. Given these barriers, population-based genetic screening provides an approach to comprehensive and early detection. We examine current evidence regarding risks and benefits of diagnosing KS at different ages. CONCLUSION: There is a lack of evidence regarding the influence of age at diagnosis on adult outcomes that can only be obtained through a pilot screening programme.

Uptake of prenatal diagnostic testing and the effectiveness of prenatal screening for Down syndrome.

OBJECTIVES: To map prenatal screening and diagnostic testing pathways in Victorian pregnant women during 2003 to 2004; measure the impact of prenatal diagnostic testing uptake on the effectiveness of prenatal screening for Down syndrome; and assess factors influencing uptake of diagnostic testing following screening. METHODS: State-wide data collections of prenatal screening and diagnostic tests were linked to all Victorian births and pregnancy terminations for birth defects. RESULTS: Overall, 52% of women had a prenatal test (65 692/126 305); screening (44.9%), diagnostic testing (3.9%), or both (3.2%). Uptake of diagnostic testing was 71.4% (2390/3349) after an increased risk screen result, and 2.5% (1381/54 286) after a low risk result. Variation in uptake of diagnostic testing reduced the effectiveness of the screening program by 11.2%: from 87.4% (sensitivity - 125/143) to 76.2% (prenatal diagnoses of Down syndrome - 109/143). In both the increased and low risk groups, uptake was influenced by absolute numerical risk, as well as by the change in numerical risk from a priori risk. CONCLUSIONS: This comprehensive follow-up demonstrates clearly that numerical risk is being used to aid in decision making about confirmatory diagnostic testing. Collectively, these fundamental individual decisions will impact on the overall effectiveness of screening programmes for Down syndrome.

Adverse obstetric and perinatal outcomes in subfertile women conceiving without assisted reproductive technologies.

OBJECTIVE: To determine whether adverse perinatal outcomes are increased in subfertile women. DESIGN: Cohort study. SETTING: Two tertiary assisted reproductive technologies (ART) centers; Victorian births register. PATIENT(S): Records of women who registered with the clinics (1991-2000), but did not have an infant using ART, were linked to the birth register (1991-2004) to identify singleton non-ART births within 5 years of registration (N = 2171). Controls, matched by maternal age and year of infant's birth, were selected randomly from birth records (N = 4363). INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): Adverse obstetric and perinatal outcomes. RESULT(S): After adjusting for confounders, compared with controls, subfertile women had increased odds of hypertension or preeclampsia (adjusted odds ratio [OR] 1.29, 1.02-1.61), antepartum hemorrhage (adjusted OR 1.41, 1.05-1.89), perinatal death (adjusted OR 2.19, 1.10-4.36), low birth weight (adjusted OR 1.44, 1.11-1.85), preterm birth <37 weeks (adjusted OR 1.32, 1.05-1.67) or <31 weeks (adjusted OR 2.37, 1.35-4.13), and cesarean delivery (adjusted OR 1.56, 1.37-1.77). There was weak evidence for increased birth defects (adjusted OR 1.30, 0.98-1.72) and gestational diabetes (adjusted OR 1.25, 0.96-1.63). No increased risk was found for prelabor rupture of membranes, small for gestational age, or postpartum hemorrhage. CONCLUSION(S): Subfertile women with singleton births are at increased risk of several adverse outcomes. These risks should be considered during their antenatal care and when analyzing adverse effects of ART.

Increased risk of blastogenesis birth defects, arising in the first 4 weeks of pregnancy, after assisted reproductive technologies.

BACKGROUND: The reasons for increased birth defect prevalence following in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) are largely unknown. Classification of birth defects by pathology rather than organ system, and examination of the role of embryo freezing and thawing may provide clues to the mechanisms involved. This study aimed to investigate these two factors. METHOD: Data on 6946 IVF or ICSI singleton pregnancies were linked to perinatal outcomes obtained from population-based data sets on births and birth defects occurring between 1991 and 2004 in Victoria, Australia. These were compared with 20,838 outcomes for singleton births in the same population, conceived without IVF or ICSI. Birth defects were classified according to pathogenesis. RESULTS: Overall, birth defects were increased after IVF or ICSI [adjusted odds ratio (OR) 1.36; 95% CI: 1.19-1.55] relative to controls. There was no strong evidence of risk differences between IVF and ICSI or between fresh and thawed embryo transfer. However, a specific group, blastogenesis birth defects, were markedly increased [adjusted OR 2.80, 95% CI: 1.63-4.81], with the increase relative to the controls being significant for fresh embryo transfer (adjusted OR 3.65; 95% CI: 2.02-6.59) but not for thawed embryo transfer (adjusted OR 1.60; 95% CI: 0.69-3.69). CONCLUSION: Our findings suggest that there is a specific risk of blastogenesis birth defects arising very early in pregnancy after IVF or ICSI and that this risk may be lower with use of frozen-thawed embryo transfer.

Preterm birth, ovarian endometriomata, and assisted reproduction technologies.

OBJECTIVE: To report preterm birth and small for gestational age (SGA) rates from assisted reproduction technologies (ART) patients with ovarian endometriomata compared with control groups. DESIGN: Retrospective cohort study. SETTING: Tertiary university affiliated ART center and Perinatal Data Collection Unit (PDCU). PATIENT(S): Every woman who had an ART singleton baby born between 1991 and 2004 had her database record assessed (N = 4382). Control groups included 1201 singleton babies from ART patients without endometriosis and 2400 randomly selected women from the PDCU database of 850,000 births. INTERVENTION(S): There were 95 singleton ART babies from patients with ovarian endometriomata and 535 ART singleton babies from patients who had endometriosis but no ovarian endometriomata. MAIN OUTCOME MEASURE(S): Preterm birth rates and SGA birth rates. RESULT(S): Preterm birth rate increased only in the ovarian endometriomata group when compared with community birth records (n = 850,000). Furthermore, ART patients with ovarian endometriomata had a statistically significantly increased likelihood of having a SGA baby when compared with other forms of endometriosis. CONCLUSION(S): Rates of preterm birth and SGA babies doubled in infertility patients with ovarian endometriomata who required ART.