Two-step offer and return of multiple types of additional genomic findings to families after ultrarapid trio genomic testing in the acute care setting: a study protocol.

INTRODUCTION: As routine genomic testing expands, so too does the opportunity to look for additional health information unrelated to the original reason for testing, termed additional findings (AF). Analysis for many different types of AF may be available, particularly to families undergoing trio genomic testing. The optimal model for service delivery remains to be determined, especially when the original test occurs in the acute care setting. METHODS AND ANALYSIS: Families enrolled in a national study providing ultrarapid genomic testing to critically ill children will be offered analysis for three types of AF on their stored genomic data: paediatric-onset conditions in the child, adult-onset conditions in each parent and reproductive carrier screening for the parents as a couple. The offer will be made 3-6 months after diagnostic testing. Parents will have access to a modified version of the Genetics Adviser web-based decision support tool before attending a genetic counselling appointment to discuss consent for AF. Parental experiences will be evaluated using qualitative and quantitative methods on data collected through surveys, appointment recordings and interviews at multiple time points. Evaluation will focus on parental preferences, uptake, decision support use and understanding of AF. Genetic health professionals' perspectives on acceptability and feasibility of AF will also be captured through surveys and interviews. ETHICS AND DISSEMINATION: This project received ethics approval from the Melbourne Health Human Research Ethics Committee as part of the Australian Genomics Health Alliance protocol: HREC/16/MH/251. Findings will be disseminated through peer-review journal articles and at conferences nationally and internationally.

Family Communication about Diagnostic Genetic Testing for Younger-Onset Dementia.

Younger-onset dementia (YOD) refers to onset before 65 years of age and may be associated with a genetic cause. Family communication surrounding any genetic risk is complex, and this process may be further complicated in a YOD context due to its effects on cognition, behaviour, and associated psychosocial consequences. This study aimed to investigate how individuals experience family communication about potential genetic risk and testing for YOD. Thematic analysis was performed on verbatim transcripts of nine semi-structured interviews undertaken with family members who attended a neurogenetics clinic due to a relative diagnosed with YOD. The interviews explored the participants' experiences of learning that YOD might be inherited and the ensuing family communication about genetic testing. Four key themes emerged: (1) a clinical diagnostic odyssey was common and could be a motivator for genomic testing, (2) pre-existing family tension and/or disconnection was a common barrier, (3) family members' autonomy was considered, and (4) avoidant coping strategies influenced communication. Communication regarding potential YOD genetic risk is a complicated process and may be influenced by pre-existing family dynamics, individual coping mechanisms, and a desire to promote autonomy in relatives. To promote effective risk communication, genetic counsellors should pre-emptively address family tensions that may be exacerbated in the context of genetic testing for YOD, with awareness that family strain during a preceding period of diagnostic odyssey is common. Genetic counsellors can offer psychosocial support to facilitate coping with this tension in an adaptive way. The findings also indicated the importance of extending genetic counselling support to relatives.

Exploring approaches to facilitate family communication of genetic risk information after cystic fibrosis population carrier screening.

Population carrier screening for cystic fibrosis (CF) enables individuals with no known family history of the condition to ascertain their risk of having a child with CF. When an individual is identified as a carrier of CF, a life-shortening condition, they are encouraged to inform their relatives who are at increased risk of being a carrier. Research suggests that the uptake of CF carrier testing amongst relatives of carriers or people with CF is low. This study aimed to explore approaches to facilitate the process of family communication of genetic information after an individual is identified as a carrier of CF through population screening. Five key informants were interviewed to inform the development of a telephone survey which was administered to 21 individuals identified as carriers of CF through population carrier screening at Victorian Clinical Genetics Services. This study suggests that providing carriers with additional information and follow-up support would be appreciated by carriers and could result in more accurate information being disseminated more widely within families, which could lead to more at-risk relatives accessing testing. Suggested strategies to enhance current practice include mailing a fact sheet to carriers and a follow-up telephone call provided by a genetic counsellor to carriers to offer further support in communicating this information to their relatives.

Respiratory physicians and clinic coordinators' attitudes to population-based cystic fibrosis carrier screening.

BACKGROUND: Attitudes of Australian CF healthcare professionals toward population-based cystic fibrosis (CF) carrier screening were examined. METHOD: A purpose-designed questionnaire was distributed to 111 respiratory physicians and 30 CF clinic coordinators throughout Australia. RESULTS: Seventy-one questionnaires (52 physicians and 19 coordinators (46.8%, 63.3% respectively)) were returned. Forty respondents (56.3%) supported population-based carrier screening for CF. Support for screening was associated with rating the factors: carrier risk being 1 in 25 (OR 1.72 (1.12, 2.65)), reassurance when both partners test negative (OR 1.67 (1.12, 2.46)) and the daily treatment regimen for CF patients (OR 1.59 (1.05, 2.42)) as important. Opposition to screening was associated with identifying potential discrimination against carriers as a disadvantage (OR 0.3 (0.12, 0.88)), and limitations of predicting clinical outcomes as a barrier (OR 0.46 (0.25, 0.83)). CONCLUSIONS: There is moderate support for population-based carrier screening for CF by Australian CF healthcare professionals. Perceived barriers to implementation are surmountable.

An audit of clinical service examining the uptake of genetic testing by at-risk family members.

PURPOSE: The aim of this study was to investigate the uptake of genetic testing by at-risk family members for four genetic conditions: chromosomal translocations, fragile X syndrome, Huntington disease, and spinal muscular atrophy. METHODS: A clinical audit was undertaken using genetics files from Genetic Health Services Victoria. Data were extracted from the files regarding the number of at-risk family members and the proportion tested. Information was also collected about whether discussion of at-risk family members and family communication during the genetic consultation was recorded. RESULTS: The proportion of at-risk family members who had genetic testing ranged from 11% to 18%. First-degree family members were most frequently tested and the proportion of testing decreased by degree of relatedness to the proband. Smaller families were significantly more likely to have genetic testing for all conditions except Huntington disease. Female at-risk family members were significantly more likely to have testing for fragile X syndrome. CONCLUSION: The majority of at-risk family members do not have genetic testing. Family communication is likely to influence the uptake of genetic testing by at-risk family members and therefore it is important that families are supported while communicating to ensure that at-risk family members are able to make informed decisions about genetic testing.

Lessons learned from 20 years of newborn screening for cystic fibrosis.

OBJECTIVE: To compare three cystic fibrosis (CF) newborn screening strategies used in Victoria since 1989. DESIGN, SETTING AND PARTICIPANTS: Retrospective review of newborn screening and clinical records for people with CF born in Victoria between 1989 and 2008 to compare screening strategies: repeat immunoreactive trypsinogen (IRT) testing (IRT/IRT, 1989-1990), IRT and p.F508del mutation analysis (IRT/p.F508del, 1991-2006) and IRT with analysis of 12 CFTR mutations (IRT/12 mutations, 2007-2008). MAIN OUTCOME MEASURES: Total number of infants screened, people identified with CF (by screening or clinical diagnosis), number of CF-affected terminations of pregnancy, and number of carriers detected. RESULTS: There were 420 people born with CF (live-birth prevalence, 1/3139; 95% CI, 1/2853-1/3462) and 78 CF-affected pregnancy terminations (overall prevalence, 1/2647; 95% CI, 1/2425-1/2896). Of the babies born with CF, 283 (67.4%) were detected by newborn screening alone, 61 (14.5%) had meconium ileus, 33 (7.9%) had a family history of CF, nine (2.1%) were diagnosed antenatally, and 34 (8.1%) were missed by screening (17 missed because IRT level was < 99th percentile, two with repeat IRT level not elevated, 14 without a screened CFTR mutation, and one with missing data). The sensitivities of the protocols were 86.6% for IRT/IRT, 89.9% for IRT/p.F508del, and 95.8% for IRT/12 mutations. Including 12 mutations in the analysis detected one patient who would otherwise have been missed and, had this protocol been implemented from 1989, it would have detected four others. CONCLUSION: Most babies with CF without meconium ileus, a family history or antenatal diagnosis are detected by newborn screening. Despite improved sensitivity with the 12-mutation analysis, most infants detected would have been diagnosed using the IRT/p.F508del protocol.

Declining prevalence of cystic fibrosis since the introduction of newborn screening.

OBJECTIVES: Newborn screening for cystic fibrosis (CF) facilitates early diagnosis and genetic counselling for parents of affected infants. Many parents elect to use prenatal testing for subsequent pregnancies, and this may affect the prevalence of CF. The aim of this study was to assess the evidence for changes in the live-birth prevalence of CF since the introduction of newborn screening for CF. METHODS: The authors reviewed the records of the Victorian newborn screening programme and the clinical records of the three centres caring for patients with CF in Victoria, Australia, in order to determine the live-birth prevalence of patients with CF; before (1979-1988) and after (1989-2006) the introduction of newborn screening. The authors reviewed the records of the Victorian Clinical Genetics Service to ascertain the number and outcome of prenatal tests for CF (1979-2006). Live births in Victoria were obtained from the state birth register. FINDINGS: Between 1979 and 1988, the live-birth prevalence of CF was 3.96 (95% CI 3.48 to 4.49) per 10 000 live births. Following the introduction of newborn screening (1989-2006) the live-birth prevalence of CF was 3.28 (95% CI 2.97 to 3.63) per 10 000 live births, representing a reduction of 17% (95% CI 2% to 29%, p=0.025). In the prescreening period, there were 10 prenatal tests, which identified three affected pregnancies, all of which were terminated. In the later period, there were 304 prenatal tests (mean 17/year), of which 76 were affected, and 70 of these pregnancies were terminated. CONCLUSION: The authors observed a modest reduction in the live-birth prevalence of CF since the introduction of newborn screening. This is principally due to at-risk couples detected by newborn screening electing to use prenatal testing on subsequent pregnancies.

Genetic health professionals and the communication of genetic information in families: Practice during and after a genetic consultation.

The communication of genetic information in families is an important process which can inform family members that they are at risk. However, evidence suggests that at-risk family members are often uninformed. Genetic health professionals have a role to assist consultands to communicate genetic information to their family members. Therefore, the aim of this study was to investigate genetic health professionals' practice with regard to the familial implications of a genetic diagnosis and subsequent family communication. An online survey resulted in 626 responses from genetic health professionals internationally. The results indicated that over 90% of genetic health professionals consistently counsel consultands about the familial implications of a genetic diagnosis during a consultation. Also there were no major differences in practice between clinical geneticists and genetic counselors. An average of 79% of genetic health professionals always send a summary letter to the consultand after a consultation. In contrast, 41% of genetic health professionals never write letters for at-risk family members. Other support is available to consultands after a consultation, but the availability of support relies on consultands and family members acting proactively and seeking out assistance from genetic health professionals for family communication. This may result in family members who are unaware that they are at risk of carrying and/or developing a genetic condition. This study is limited by the self-selection and self-reporting of the respondents' practice.

Population-based carrier screening for cystic fibrosis in Victoria: the first three years experience.

BACKGROUND: Cystic fibrosis (CF) is the most common inherited, life-shortening condition affecting Australian children. The carrier frequency is one per 25 and most babies with CF are born to parents with no family history. Carrier testing is possible before a couple has an affected infant. AIMS: To report the outcomes of a carrier screening program for CF. METHOD: Carrier screening was offered to women and couples planning a pregnancy, or in early pregnancy, through obstetricians and general practitioners in Victoria, Australia. Samples were collected by cheek swab and posted to the laboratory. Twelve CFTR gene mutations were tested. Carriers were offered genetic counselling and partner testing. Carrier couples were offered prenatal testing by chorionic villous sampling (CVS) if pregnant. The number of people tested, carriers detected and pregnancy outcomes were recorded from January 2006 to December 2008. RESULTS: A total of 3200 individuals were screened (3000 females). One hundred and six carriers were identified (one per 30, 95% confidence interval one per 25, one per 36). All carrier partners were screened, and nine carrier couples identified (total carriers 115). Ninety-six individuals (83%) were carriers of the p.508del mutation. Of the nine carrier couples, six were pregnant at the time of screening (five natural conception and one in vitro fertilisation) and all had CVS (mean gestation 12.5 weeks). Two fetuses were affected, three were carriers and one was not a carrier. Termination of pregnancy was undertaken for the affected fetuses. CONCLUSION: Carrier screening for CF by obstetricians and general practitioners by cheek swab sample can be successfully undertaken prior to pregnancy or in the early stages of pregnancy.

Health first, genetics second: exploring families' experiences of communicating genetic information.

Genetic information may have health and reproductive implications for the proband and their family members. The responsibility for communicating this information within families generally lies with the proband or consultand. Previous research has explored the barriers and facilitators to communication, particularly in families affected with familial cancer syndromes. This study is an exploration of families' experiences, which aims to elucidate the process of communicating genetic information in families affected with non-cancer genetic conditions. The methodology involved 12 semi-structured interviews with probands, consultands and their family members. There were six different genetic conditions present in the families: adrenoleukodystrophy (n=3), cystic fibrosis (n=3), fragile X syndrome (n=1), haemochromatosis (n=1), balanced reciprocal chromosomal translocation (n=3) and Robertsonian chromosomal translocation (n=1). The results presented arise from two key themes, (1) the diagnosis and (2) post diagnosis. The interview data illustrate that the time of the diagnosis is a traumatic experience for families and that communication stimulated by this event revolves around informing family members about the diagnosis, but not warning them of their genetic risk. Post diagnosis, the collection of information about the genetic condition and continued communication to more distant family members, often using pre-existing family communication patterns, enables the continuation of communication about the genetic condition.

Parental attitudes to the identification of their infants as carriers of cystic fibrosis by newborn screening.

AIM: To investigate parental attitudes to cystic fibrosis (CF) carrier detection of their infant by newborn screening (NBS). METHODS: Data were collected from a postal questionnaire sent to parents of infants identified as CF carriers by NBS in 1996-1997 (inclusive) and 2001 in Victoria, Australia (n = 66). RESULTS: Almost all parents remembered their child being identified as a CF carrier (97%: 1996/1997; 100%: 2001); yet the majority were unaware at the time that NBS could detect carriers (70%: 1996/1997; 49%: 2001). More parents in the later cohort reported having carrier testing compared with the earlier cohort (85% and 53% respectively) but recall was more uncertain in the earlier cohort when validated against health records. Cascade testing was not utilised frequently by other family members in either cohort. Residual risk of being a carrier if testing was negative was not well understood by parents. Some parents (28%: 1996/1997; 18%: 2001) had residual anxiety about the current health of their carrier child and their future reproductive decision making. Most parents were satisfied with the information provided to them at the time of the sweat test. Few differences were seen between the cohorts. CONCLUSION: Although the NBS process for CF in Victoria is working efficiently for the majority of families whose infant is identified as a carrier there are areas that can be improved. We recommend that greater attention should be given to informing parents that a consequence of NBS is CF carrier detection and strategies to improve utilisation of cascade testing should be developed.