Human Genetics Society of Australasia Position Statement: Online DNA Testing.

Increasingly, consumers have been able to seek DNA testing online to explore their personal genetic information. This increased access to a range of genomic tests has raised concerns among health professionals tasked with providing guidance and support to patients requiring genetic/genomic testing. Individuals will seek genomic testing for a range of purposes; equally, the medical marketplace offers a range of different test types. The Human Genetics Society of Australasia (HGSA) published their first statement on Direct to Consumer Genetic Testing (2012 PS02). This is a revised statement, which considers developments in the field of online DNA testing, including rapid technological changes, diversity of applications and decreasing costs of testing. It draws from the first empirical nationwide study (Genioz - Genomics: National Insights of Australians) and insights from consumers with experience of this technology. The rapid adoption of these tests and the broad range of potential consequences have informed perspectives within this statement. It is the position of the HGSA that both individuals/consumers and health care professionals/providers should be supported to make informed choices about online DNA testing. This means adequate and ongoing education and resources should be available for individuals/consumers and health care professionals/providers before, during and after testing. Health care professionals/providers should be appropriately trained, have relevant experience and should be able to demonstrate (or provide evidence of) a current certification in their field of practice. This statement was ratified at the 2018 HGSA Council Meeting and was recently reviewed in 2019 for consistency with other HGSA position statements.

FMR1 allele size distribution in 35,000 males and females: a comparison of developmental delay and general population cohorts.

PURPOSE: Developmental delay phenotypes have been associated with FMR1 premutation (PM: 55-200 CGG repeats) and "gray zone" (GZ: 45-54 CGG repeats) alleles. However, these associations have not been confirmed by larger studies to be useful in pediatric diagnostic or screening settings. METHODS: This study determined the prevalence of PM and GZ alleles in two independent cohorts of 19,076 pediatric referrals to developmental delay diagnostic testing through Victorian Clinical Genetics Service (cohort 1: N = 10,235; cohort 2: N = 8841), compared with two independent general population cohorts (newborn screening N = 1997; carrier screening by the Victorian Clinical Genetics Service prepair program N = 14,249). RESULTS: PM and GZ prevalence rates were not significantly increased (p > 0.05) in either developmental delay cohort (male PM: 0.12-0.22%; female PM: 0.26-0.33%; male GZ: 0.68-0.69%; female GZ: 1.59-2.13-%) compared with general population cohorts (male PM: 0.20%; female PM: 0.27-0.82%; male GZ: 0.79%; female GZ: 1.43-2.51%). Furthermore, CGG size distributions were comparable across datasets, with each having a modal value of 29 or 30 and ~1/3 females and ~1/5 males having at least one allele with ≤26 CGG repeats. CONCLUSION: These data do not support the causative link between PM and GZ expansions and developmental-delay phenotypes in pediatric settings.

Informed decision making and psychosocial outcomes in pregnant and nonpregnant women offered population fragile X carrier screening.

PurposePopulation-based carrier screening for fragile X syndrome (FXS) is still not universally endorsed by professional organizations due to concerns around genetic counseling for complex information and potential for psychosocial harms.MethodsWe determined uptake levels, decision making, and psychosocial impact in a prospective study of pregnant and nonpregnant Australian women offered FXS carrier screening in clinical settings. Women received pretest genetic counseling, and completed questionnaires when deciding and one month later.ResultsOf 1,156 women recruited, 83.1% returned the first questionnaire with 70.6% nonpregnant and 58.8% pregnant women choosing testing (χ2=16.98, P<0.001). Overall, informed choice was high in both nonpregnant (77.4%) and pregnant (72.9%) women (χ2=0.21, P=0.644), and more tested (76.0%) than not-tested (66.7%) women (χ2=6.35, P=0.012) made an informed choice. Measures of depression, stress, and anxiety were similar to population norms for ~85% of women. Decisional conflict and regret were generally low; however, decisional uncertainty and regret were greater in pregnant than nonpregnant women, and not-tested than tested women (uncertainty: χ2=18.51, P<0.001 and χ2=43.11, P<0.001, respectively; regret: χ2=6.61, P<0.037 and χ2=35.54, P<0.001, respectively).ConclusionWe provide evidence to inform guidelines that population FXS carrier screening can be implemented with minimal psychosocial harms following appropriate information and prescreening genetic counseling.

Clinical audit of genetic testing and referral patterns for fragile X and associated conditions.

An audit was conducted of laboratory/clinical databases of genetic tests performed between January 2003 and December 2009, and for 2014, as well as referrals to the clinical service and a specialist multidisciplinary clinic, to determine genetic testing request patterns for fragile X syndrome and associated conditions and referrals for genetic counseling/multidisciplinary management in Victoria, Australia. An expanded allele (full mutation, premutation or intermediate) was found in 3.7% of tests. Pediatricians requested ∼70% of test samples, although fewer general practitioners and more obstetricians/gynecologists ordered tests in 2014. Median age at testing for individuals with a full mutation seeking a diagnosis without a fragile X family history was 4.3 years (males) and 9.4 years (females); these ages were lower when pediatricians ordered the tests (2.1 years and 6.1 years, respectively). Individuals with a premutation were generally tested at a later age (median age: males, 33.2 years; females, 36.4 years). Logistic regression showed that a family history of ID (OR 3.28 P = 0.005, CI 1.77-5.98) was the only indication to independently increase the likelihood of a test-positive (FM or PM) result. Following testing, ∼25% of full mutation or premutation individuals may not have attended clinical services providing genetic counseling or multidisciplinary management for these families. The apparent delay in fragile X syndrome diagnosis and lack of appropriate referrals for some may result in less than optimal management for these families. These findings suggest continued need for awareness and education of health professionals around diagnosis and familial implications of fragile X syndrome and associated conditions. © 2016 Wiley Periodicals, Inc.

Detection of skewed X-chromosome inactivation in Fragile X syndrome and X chromosome aneuploidy using quantitative melt analysis.

Methylation of the fragile X mental retardation 1 (FMR1) exon 1/intron 1 boundary positioned fragile X related epigenetic element 2 (FREE2), reveals skewed X-chromosome inactivation (XCI) in fragile X syndrome full mutation (FM: CGG > 200) females. XCI skewing has been also linked to abnormal X-linked gene expression with the broader clinical impact for sex chromosome aneuploidies (SCAs). In this study, 10 FREE2 CpG sites were targeted using methylation specific quantitative melt analysis (MS-QMA), including 3 sites that could not be analysed with previously used EpiTYPER system. The method was applied for detection of skewed XCI in FM females and in different types of SCA. We tested venous blood and saliva DNA collected from 107 controls (CGG < 40), and 148 FM and 90 SCA individuals. MS-QMA identified: (i) most SCAs if combined with a Y chromosome test; (ii) locus-specific XCI skewing towards the hypomethylated state in FM females; and (iii) skewed XCI towards the hypermethylated state in SCA with 3 or more X chromosomes, and in 5% of the 47,XXY individuals. MS-QMA output also showed significant correlation with the EpiTYPER reference method in FM males and females (P < 0.0001) and SCAs (P < 0.05). In conclusion, we demonstrate use of MS-QMA to quantify skewed XCI in two applications with diagnostic utility.

Development of a fragile X syndrome (FXS) knowledge scale: towards a modified multidimensional measure of informed choice for FXS population carrier screening.

BACKGROUND: Genetic carrier screening is increasingly possible for many conditions, but it is important to ensure decisions are informed. The multidimensional measure of informed choice (MMIC) is a quantitative instrument developed to evaluate informed choice in prenatal screening for Down syndrome, measuring knowledge, attitudes and uptake. To apply the MMIC in other screening settings, the knowledge scale must be modified. OBJECTIVE: To develop and validate a modified MMIC knowledge scale for use with women undergoing carrier screening for fragile X syndrome (FXS). SETTING AND PARTICIPANTS: Responses to MMIC items were collected through questionnaires as part of a FXS carrier screening pilot study in a preconception setting in Melbourne, Australia. DESIGN: Ten knowledge scale items were developed using a modified Delphi technique. Cronbach's alpha and factor analysis were used to validate the new FXS knowledge scale. We summarized the knowledge, attitudes and informed choice status based on the modified MMIC. RESULTS: Two hundred and eighty-five women were recruited, 241 eligible questionnaires were complete for analysis. The FXS knowledge scale items measured one salient construct and were internally consistent (alpha = 0.70). 71% (172/241) of participants were classified as having good knowledge, 70% (169/241) had positive attitudes and 27% (65/241) made an informed choice to accept or decline screening. DISCUSSION AND CONCLUSIONS: We present the development of a knowledge scale as part of a MMIC to evaluate informed choice in population carrier screening for FXS. This can be used as a template by other researchers to develop knowledge scales for other conditions for use in the MMIC.

Population-based carrier screening for cystic fibrosis: a systematic review of 23 years of research.

Cystic fibrosis is the most common severe autosomal recessive disease, with a prevalence of 1 in 2,500-3,500 live births and a carrier frequency of 1 in 25 among Northern Europeans. Population-based carrier screening for cystic fibrosis has been possible since CFTR, the disease-causing gene, was identified in 1989. This review provides a systematic evaluation of the literature from the past 23 years on population-based carrier screening for cystic fibrosis, focusing on the following: uptake of testing; how to offer screening; attitudes, opinions, and knowledge; factors influencing decision making; and follow-up after screening. Recommendations are given for the implementation and evaluation of future carrier-screening programs.

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.

Exploring inhibitory deficits in female premutation carriers of fragile X syndrome: through eye movements.

There is evidence which demonstrates that a subset of males with a premutation CGG repeat expansion (between 55 and 200 repeats) of the fragile X mental retardation 1 gene exhibit subtle deficits of executive function that progressively deteriorate with increasing age and CGG repeat length. However, it remains unclear whether similar deficits, which may indicate the onset of more severe degeneration, are evident in female PM-carriers. In the present study we explore whether female PM-carriers exhibit deficits of executive function which parallel those of male PM-carriers. Fourteen female fragile X premutation carriers without fragile X-associated tremor/ataxia syndrome and fourteen age, sex, and IQ matched controls underwent ocular motor and neuropsychological tests of select executive processes, specifically of response inhibition and working memory. Group comparisons revealed poorer inhibitory control for female premutation carriers on ocular motor tasks, in addition to demonstrating some difficulties in behaviour self-regulation, when compared to controls. A negative correlation between CGG repeat length and antisaccade error rates for premutation carriers was also found. Our preliminary findings indicate that impaired inhibitory control may represent a phenotype characteristic which may be a sensitive risk biomarker within this female fragile X premutation population.

Prenatal ß-thalassemia carrier screening in Australia: healthcare professionals' perspectives of clinical practice.

OBJECTIVE: To gain a better understanding of healthcare professionals' practice and attitudes regarding prenatal ß-thalassemia carrier screening in Australia. METHOD: Qualitative study with semi-structured interviews of healthcare professionals (obstetricians, general practitioners, midwives, genetic counselors, and hematologists) involved in prenatal thalassemia carrier screening in public and private practice. RESULTS: Twenty-three healthcare providers were interviewed and several themes emerged. Participants described and acknowledged inconsistencies in the ß-thalassemia screening processes, such as variability in ordering the tests, communicating the diagnosis, and action taken after diagnosis. They indicated a preference for more structure and valued the importance of screening guidelines but many of those involved in ordering the screening test were unaware of their availability. These healthcare professionals recognized they lacked knowledge regarding the screening process, and many had not undertaken education activities in this area in recent times. There were mixed views about the consent process, particularly at which stage this should be obtained, and what information is provided. CONCLUSIONS: ß-thalassemia screening in Victoria occurs with apparent lack of awareness of guidelines and an acknowledged preference for a more systematic process and educational support. Informed consent was not considered an important component of this screening process.

Impaired response inhibition is associated with self-reported symptoms of depression, anxiety, and ADHD in female FMR1 premutation carriers.

Fragile X Mental Retardation 1 (FMR1) premutation carriers (PM-carriers) have a defective trinucleotide expansion on the FMR1 gene that is associated with continuum of neuropsychological and mental disorders. Currently, little is known about the distinct subcomponents of executive function potentially impaired in female PM-carriers, and there have been no investigations into associations between executive function and incidences of mental disorders. A total of 35 female PM-carriers confirmed by Asuragen triple primed PCR DNA testing and 35 age- and intelligence-matched controls completed tests of executive function (i.e., response inhibition and working memory) and self-reported on social anxiety, depression, and ADHD predominantly inattentive (ADHD-PI) symptoms. Compared to controls, PM-carriers were significantly elevated on self-reported social anxiety and ADHD-PI symptoms. Irrespective of mental symptoms, female PM-carries performed significantly worse than controls on a response inhibition test, and further investigations revealed significant correlations between executive function performance and self-reported symptoms of anxiety, depression and ADHD-PI. Critically, among PM-carriers with good executive function performance, no women exceeded threshold markers for probable caseness of mental disorder. However, rates of probable caseness were elevated in those with average performance (response inhibition: social anxiety: 41.7%; depression: 20%; ADHD: 44.4%; working memory: social anxiety: 27.3%; depression: 9.1%; ADHD: 18.2%) and highly elevated for those with poor executive function performance (response inhibition: social anxiety: 58.3%; depression: 80%; ADHD: 55.6%; working memory: social anxiety: 100%; depression: 50%; ADHD: 83.3%). These data suggest that subtle executive dysfunction may be a useful neuropsychological indicator for a range of mental disorders previously reported in female PM-carriers.

Cascade carrier testing after a child is diagnosed with cystic fibrosis through newborn screening: investigating why most relatives do not have testing.

PURPOSE: Newborn screening for cystic fibrosis is increasingly available, but cascade testing following the diagnosis in a child has received little attention. We previously reported low levels of cascade testing over time, and this study investigated motivators as well as barriers to testing. METHODS: Parents were interviewed about communicating the genetic information and also asked to recruit their relatives to receive a specifically developed questionnaire. RESULTS: Thirty parents were interviewed and addresses of 284 relatives were provided; completed questionnaires were received from 225 (79%). A relative's relationship to the child, as well as knowledge, is associated with having had carrier testing. Relatives' reasons for testing included curiosity and wanting information for other relatives and for reproductive planning. Reasons for not testing were perceived irrelevance, lacking awareness, and viewing it as something to do in the future. Parents communicated the genetic information to relatives in various ways, which contributed to whether relatives accessed carrier testing. CONCLUSION: Newborn screening programs should provide support to parents to aid communication of genetic information to relatives. (Ir)relevance of testing is often linked to life stage; ongoing support and communication may allow relatives to learn of their risk and then seek testing, if they wish, at a time perceived to be most relevant to them.

Fragile X-related element 2 methylation analysis may provide a suitable option for inclusion of fragile X syndrome and/or sex chromosome aneuploidy into newborn screening: a technical validation study.

PURPOSE: We show that a novel fragile X-related epigenetic element 2 FMR1 methylation test can be used along with a test for sex-determining region Y (SRY) to provide the option of combined fragile X syndrome and sex chromosome aneuploidy newborn screening. METHODS: Fragile X-related epigenetic element 2, SRY, and FMR1 CGG repeat analyses were performed on blood and saliva DNA, and in adult and newborn blood spots. The cohort consisted of 159 controls (CGG <40), 187 premutation (CGG 56-170), and 242 full-mutation (CGG ~200-2,000) males and females, 106 sex chromosome aneuploidy individuals, and 151 cytogenetically normal controls. RESULTS: At the 0.435 threshold, fragile X-related epigenetic element 2 analysis in males was robust on both blood DNA and newborn blood spots, with specificity and sensitivity of ~100% for full-mutation genotype. In females, the specificity was 99%, whereas half of full-mutation females were above the 0.435 threshold in both blood DNA and newborn blood spots. Furthermore, at this threshold, the test could not differentiate individuals with Klinefelter syndrome from female controls without using the SRY marker. When combined with SRY analysis, the test was consistent with most results for sex chromosome aneuploidies from karyotyping. CONCLUSION: Setting specific thresholds for fragile X-related epigenetic element 2 analysis and including the SRY marker provides the option to either include or exclude detection of sex chromosome aneuploidies as part of fragile X syndrome newborn screening.

"It's about having the choice": stakeholder perceptions of population-based genetic carrier screening for fragile X syndrome.

This project explored, the views of key stakeholders regarding population-based genetic carrier screening for fragile X syndrome (FXS). Interviews and focus groups were conducted with healthcare providers, relatives of individuals with FXS and members of the general population. Data were transcribed verbatim and coded into themes. 188 individuals took part in this study. Perceived benefits of carrier screening included: learning the risk of having a child with FXS; learning the risk of fragile X-associated primary ovarian insufficiency; and the opportunity for carriers to access reproductive options. Concerns included: the emotional impact of screening and receiving a carrier result; the predictive testing nature of the carrier test with respect to fragile X-associated tremor/ataxia syndrome; potential confusion created by receiving an intermediate result; and implications of genetic screening for society. Overall, population-based genetic carrier screening was perceived to be acceptable provided it is optional and offered at an appropriate stage of life. With the support of the participants to promote individual choice by offering a population-based carrier screening program for FXS, it is essential to carefully consider how screening might be offered in order to ensure broad accessibility and facilitation of decision-making.

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.

"Taking its toll": the challenges of working in fetal medicine.

BACKGROUND: Advances in genetic technologies have resulted in the diagnosis during pregnancy of increasing numbers of fetal abnormalities. A few published personal commentaries have indicated that health professionals' interactions with couples at risk of a fetal abnormality can be emotionally and ethically challenging, highlighting the need for empirical research in this area. This study sought to explore whether working in the fetal medicine setting has an effect on health professionals and to ascertain any supports used to manage these effects. METHODS: In-depth interviews were conducted with 40 medical and allied health professionals working in fetal medicine settings in Melbourne, Australia. Qualitative analysis of the interview data was performed using thematic analysis. RESULTS: Participants discussed at length the emotional impact of working with patients who were experiencing adverse pregnancy outcomes. All participants reported that working in fetal medicine had an impact on their daily lives, and many spoke about dreaming about or losing sleep over patient outcomes. Participants described working in this setting as being particularly difficult when they were pregnant themselves. Most spoke about feeling largely unsupported in their work and felt that these effects resulted in burnout and staff turnover. CONCLUSIONS: This study explored several work force concerns in fetal medicine. Health professionals working with couples at risk of a fetal abnormality are vulnerable to the phenomena of compassion fatigue and burnout. The need for formal support and self-care management is suggested.

A systematic review of population screening for fragile X syndrome.

PURPOSE: To conduct a systematic review of literature regarding population-based screening for fragile X syndrome in newborns and women of reproductive age, either before or during pregnancy. METHODS: Seven electronic databases were searched for English language studies published between January 1991 and November 2009. Data extraction was performed for all included studies. Results were synthesized using a narrative approach. RESULTS: One article that examined offering newborn screening for fragile X syndrome and 10 that examined the offer of fragile X syndrome screening to women of reproductive age were identified. Two of these articles also addressed psychosocial aspects of population screening for fragile X syndrome such as attitudes to screening and experiences of screening, and a further nine addressed these issues alone. Studies exploring psychosocial issues demonstrated challenges for counseling arising from a lack of awareness or personal experience with fragile X syndrome in the general population. CONCLUSIONS: Targeted counseling and educational strategies will be essential to support women from the general population. It is crucial that future studies offering screening for fragile X syndrome explore a range of psychosocial aspects in addition to looking at uptake of testing and mutation frequency.

"It's challenging on a personal level"--exploring the 'lived experience' of Australian and Canadian prenatal genetic counselors.

Prenatal genetic counselors work with clients who are at risk of having a child with a fetal anomaly, or who have been diagnosed with a fetal anomaly. This can raise challenging ethical, moral and legal issues for both clients and counselors. Few studies have explored whether this type of work impacts on genetic counselors themselves. Interviews were conducted with 15 prenatal genetic counselors, five from Toronto, Canada and ten from Melbourne, Australia. A qualitative approach was used to allow for an in-depth exploration of the experiences of genetic counselors working in the prenatal setting. While participants reported that working in a prenatal setting affected them in several ways, this paper focuses on one particular unanticipated finding--that of the impact experienced by counselors from both countries while working when pregnant.

"Testing times, challenging choices": an Australian study of prenatal genetic counseling.

In many countries pregnant women deemed to be at increased risk for fetal anomaly following a screening test may attend a genetic counseling session to receive information and support in decision-making about subsequent diagnostic testing. This paper presents findings from an Australian study that explored 21 prenatal genetic counseling sessions conducted by five different genetic counselors. All were attended by pregnant women who had received an increased risk result from a maternal serum screening (MSS) test and who were offered a diagnostic test. Qualitative methods were used to analyze the content and structure of sessions and explore the counseling interactions. Findings from this cohort demonstrate that, within these prenatal genetic counseling sessions, counselor dialogue predominated. Overall the sessions were characterized by: a) an emphasis on information-giving b) a lack of dialogue about relevant sensitive topics such as disability and abortion. Arguably, this resulted in missed opportunities for client deliberation and informed decision-making. These findings have implications for the training and practice of genetic counselors and all healthcare professionals who communicate with women about prenatal testing.