"It becomes your whole life"-Exploring experiences of reciprocal translocation carriers and their partners.

Reciprocal translocation carriers are often diagnosed when they are experiencing difficulties conceiving or after a pregnancy affected by an unbalanced set of chromosomes inherited from the balanced carrier parent. Having a reciprocal translocation is not uncommon; carriers can benefit from reproductive options to achieve a healthy, chromosomally balanced, pregnancy. The aim of this study was to explore the lived experience of carriers and their partners. We conducted 13 semi-structured telephone interviews. Participants were recruited through Victorian Clinical Genetics Services and interviews took place between May and September 2020. Interview transcripts were analyzed using thematic analysis. Reciprocal translocation carriers and their partners described long term emotional and reproductive impacts, with carrier status identified at the time of prenatal diagnosis having marked emotional consequences. Couples facing reproductive challenges found the diagnosis created uncertainty for their future. When considering a pregnancy, couples worried about experiencing a miscarriage; during pregnancy, there was a reluctance to have an invasive diagnostic procedure due to fearing the risk of losing an unaffected pregnancy. Adaptation to their new reality involved having access to accurate information, peer support and maintaining hope. Couples valued having the option to know the carrier status of their children. The complex impacts of carrying a reciprocal translocation highlight the importance of access to specialist genetic counseling services to ensure couples are supported in understanding the implications of their translocation.

Ethical considerations in gene selection for reproductive carrier screening.

Genetic carrier screening for reproductive purposes has existed for half a century. It was originally offered to particular ethnic groups with a higher prevalence of certain severe recessive or X-linked genetic conditions, or (as carrier testing) to those with a family history of a particular genetic condition. Commercial providers are increasingly offering carrier screening on a user-pays basis. Some countries are also trialing or offering public reproductive genetic carrier screening with whole populations, rather than only to those known to have a higher chance of having a child with an inherited genetic condition. Such programs broaden the ethical and practical challenges that arise in clinical carrier testing. In this paper we consider three aspects of selecting genes for population reproductive genetic carrier screening panels that give rise to important ethical considerations: severity, variable penetrance and expressivity, and scalability; we also draw on three exemplar genes to illustrate the ethical issues raised: CFTR, GALT and SERPINA1. We argue that such issues are important to attend to at the point of gene selection for RGCS. These factors warrant a cautious approach to screening panel design, one that takes into account the likely value of the information generated by screening and the feasibility of implementation in large and diverse populations. Given the highly complex and uncertain nature of some genetic variants, careful consideration needs to be given to the balance between delivering potentially burdensome or harmful information, and providing valuable information to inform reproductive decisions.

Genome-wide noninvasive prenatal screening for carriers of balanced reciprocal translocations.

PURPOSE: Balanced reciprocal translocation carriers are at increased risk of producing gametes with unbalanced forms of the translocation leading to miscarriage, fetal anomalies, and birth defects. We sought to determine if genome-wide cell-free DNA based noninvasive prenatal screening (gw-NIPS) could provide an alternative to prenatal diagnosis for carriers of these chromosomal rearrangements. METHODS: This pilot series comprises a retrospective analysis of gw-NIPS and clinical outcome data from 42 singleton pregnancies where one parent carried a balanced reciprocal translocation. Gw-NIPS was performed between August 2015 and March 2018. Inclusion criteria required at least one translocation segment to be ≥15 Mb in size. RESULTS: Forty samples (95%) returned an informative result; 7 pregnancies (17.5%) were high risk for an unbalanced translocation and confirmed after diagnostic testing. The remaining 33 informative samples were low risk and confirmed after diagnostic testing or normal newborn physical exam. Test sensitivity of 100% (95% confidence interval [CI]: 64.6-100%) and specificity of 100% (95% CI: 89.6-100%) were observed for this pilot series. CONCLUSION: We demonstrate that gw-NIPS is a potential option for a majority of reciprocal translocation carriers. Further confirmation of this methodology could lead to adoption of this noninvasive alternative.

Correction: Reproductive genetic carrier screening for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy in Australia: outcomes of 12,000 tests.

Zoe McDonald, BSc, was omitted from the list of article coauthors. Her name should have been included as the seventh author, following Clare Elizabeth Hunt. Her affiliation is Victorian Clinical Genetics Services, Parkville, Victoria, Australia. The authors regret the error.

Reproductive genetic carrier screening for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy in Australia: outcomes of 12,000 tests.

PurposeTo describe our experience of offering simultaneous genetic carrier screening for cystic fibrosis (CF), fragile X syndrome (FXS), and spinal muscular atrophy (SMA).MethodsCarrier screening is offered through general practice, obstetrics, fertility, and genetics settings before or in early pregnancy. Carriers are offered genetic counseling with prenatal/preimplantation genetic diagnosis available to those at increased risk.ResultsScreening of 12,000 individuals revealed 610 carriers (5.08%; 1 in 20): 342 CF, 35 FXS, 241 SMA (8 carriers of 2 conditions), approximately 88% of whom had no family history. At least 94% of CF and SMA carriers' partners were tested. Fifty couples (0.42%; 1 in 240) were at increased risk of having a child with one of the conditions (14 CF, 35 FXS, and 1 SMA) with 32 pregnant at the time of testing. Of these, 26 opted for prenatal diagnosis revealing 7 pregnancies affected (4 CF, 2 FXS, 1 SMA).ConclusionThe combined affected pregnancy rate is comparable to the population risk for Down syndrome, emphasizing the need to routinely offer carrier screening. The availability of appropriate genetic counseling support and a collaborative approach between laboratory teams, genetics services, health professionals offering screening, and support organizations is essential.

A mixed methods study of age at diagnosis and diagnostic odyssey for Duchenne muscular dystrophy.

The delayed diagnosis of Duchenne muscular dystrophy (DMD) may be an ongoing problem internationally. We aimed to ascertain age at diagnosis and explore parents' experiences of the diagnosis of DMD in Australia. Using mixed methods, data were collected from laboratory and clinical record audits of testing for DMD in Victoria and Tasmania, interviews and a national survey of parents regarding their experiences from first noticing symptoms to receiving a diagnosis. The audits revealed that the median age at diagnosis for DMD was 5 years (n=49 during 2005-2010); this age had not changed substantially over this period. Fourteen parents interviewed reported age at diagnosis ranging from 2 to 8 years with a 6 month to 4 year delay between initial concerns about their child's development and receiving the DMD diagnosis. Sixty-two survey respondents reported the median age at diagnosis was 3 years and 9 months, while the median age when symptoms were noticed was 2 years and 9 months. Parents experienced many emotions in their search for a diagnosis and consulted with a wide range of health professionals. Half the survey respondents felt that their child could have been diagnosed earlier. Despite advances in testing technologies and increasing awareness of DMD, the age at diagnosis has remained constant in Australia. This mixed methods study shows that this diagnostic delay continues to have a negative impact on parents' experiences, places families at risk of having a second affected child and may have a deleterious effect on affected children's treatment.