Robin Forbes

Using record linkage and manual follow-up to evaluate the Victorian maternal serum screening quadruple test for Down's syndrome, trisomy 18 and neural tube defects.

Objectives: The Genetic Health Services Victoria maternal serum screening (MSS) quadruple test has been available to pregnant women in Victoria since 1996. The objectives of this study were to follow up the pregnancies screened by MSS between July 1998 and June 2000 and to determine the performance characteristics of the test for Downs syndrome, trisomy 18 and neural tube defects (NTDs). Methods: MSS results were matched to pregnancy outcome information from the Perinatal Data Collection Unit and Birth Defects Register, using automated probabilistic record linkage. For unmatched pregnancies, manual follow-up was carried out by contacting referring doctors and hospitals, resulting in a very high follow-up rate of 99.2% (18,989/19,143). Results: The sensitivity of MSS for Downs syndrome was 85% (23/27–95%CI 72–99%) with a falsepositive rate (FPR) of 6.8% (risk threshold ≥ 1 in 250). While using a fixed 5% FPR, the sensitivity for Downs syndrome was slightly lower (78%). The sensitivity for trisomy 18 was 44% (4/9 – 95% CI 12–77%) with a FPR of 0.5% (risk threshold of ≥ 1 in 200). 11 of the 15 (73 – 95%CI 51–97%) cases of open NTDs were detected from screening, with a 1% FPR (risk threshold alpha-fetoprotein [AFP] ≥2.5 MoM). All cases of anencephaly had increased AFP levels. Conclusion: Probabilistic record linkage and manual follow-up is an efficient method for ascertainment of pregnancy outcomes, with a higher follow-up rate than that reported in similar studies. MSS should remain an available option for all pregnant women in Victoria, with test characteristics comparable with other recent reports of the quadruple test.

Phenotypic variability of distal 22q11.2 copy number abnormalities

The availability of microarray technology has led to the recent recognition of copy number abnormalities of distal chromosome 22q11.2 that are distinct from the better‐characterized deletions and duplications of the proximal region. This report describes five unrelated individuals with copy number abnormalities affecting distal chromosome 22q11.2. We report on novel phenotypic features including diaphragmatic hernia and uterine didelphys associated with the distal microdeletion syndrome; and frontomedial polymicrogyria and callosal agenesis associated with the distal microduplication syndrome. We describe the third distal chromosome 22q11.2 microdeletion patient with Goldenhar syndrome. Patients with distal chromosome 22q11.2 copy number abnormalities exhibit inter‐ and intra‐familial phenotypic variability, and challenge our ability to draw meaningful genotype–phenotype correlations.

Follow up and evaluation of the Victorian first‐trimester combined screening programme for Down syndrome and trisomy 18

Objective  The objective of this study was to follow up and evaluate the statewide first‐trimester combined screening programme for Down syndrome and trisomy 18 at Genetic Health Services Victoria, Australia.

Community-wide screening for cystic fibrosis carriers could replace newborn screening for the diagnosis of cystic fibrosis

Abstract:  Most babies with cystic fibrosis (CF) are born to parents who did not know they were carriers until their baby was diagnosed with CF, usually by newborn screening. It is only after the birth of their first child with CF that couples are offered genetic counselling and reproductive choices. Most use this information for prenatal testing of subsequent pregnancies. With the high uptake of first trimester screening for Down syndrome (80% in Victoria) most couples have had screening during the CF affected pregnancy. Yet screening for CF carrier status is available, costs are similar to that for Down syndrome screening and CF carrier screening only ever needs to be done once. Waiting for couples to have a baby with CF before they are identified as carriers denies them choice. A national policy on CF carrier screening in Australia, and determination to equitably fund such a programme, is required.

5q31.3 Microdeletion syndrome: Clinical and molecular characterization of two further cases

The 5q31.3 microdeletion syndrome has recently emerged as a distinct clinical entity, and we report two new patients with de novo deletions of this region, bringing the total to seven. Similarly to previously reported cases, the phenotype of our patients is characterized by marked hypotonia, apnea, developmental delay, and feeding difficulties. Both patients had abnormal movements which did not correlate with epileptiform activity on electroencephalogram (EEG). Developmental brain changes on neuroimaging consisted of abnormalities predominantly affecting the white matter and frontal lobes. The 5q31.3 deleted regions overlap those of previously reported cases, and allow further refinement of the shortest region of overlap to 101 kb, including only three genes. Of these, the purine‐rich element binding protein A (PURA) gene has an established role in brain development, and we propose that haploinsufficiency for this gene is primarily responsible for the neurodevelopmental features observed.

Consumer contribution to the delivery of genetic health services

Clinical genetics services have been the focus of evaluation and guidelines since the 1970s. In this study we used consumer satisfaction as the evaluative measure with the aim being to seek feedback from consumers of a genetics service to inform quality measures for client‐centered genetic services. In the first phase of the study issues were identified by consumers and health professionals around delivering genetics services and the priorities ranked into five themes: expectations, information, respect, privacy and logistics. These themes then formed the basis of a questionnaire that was distributed to consumers of a genetics service in Victoria, Australia. Three hundred ninety‐seven out of 821 questionnaires were completed (49.8% response rate). More than 85% of consumers were satisfied in the theme of expectations, with the only issue being waiting times for genetic test results (68.6% satisfied). Over 83% of consumers were satisfied with the information received from the genetics service. The matter of interruptions during appointments was the only area in the theme of respect that rated less than 80% satisfactory (79.1%). In relation to privacy, consumers rated over 95% satisfaction. Logistics was the theme where satisfaction was lowest with ratings of less than 75% for issues such as availability of public transport to the clinic, parking and wheelchair access. Consumer satisfaction was related to the information received before and after consultations and also to the attitudes and behaviors of health professionals. These findings have implications for genetics services both in Australia and internationally and recommendations from the findings are outlined.

Nusinersen for SMA: expanded access programme

Background Spinal muscular atrophy (SMA) is a devastating motor neuron disorder causing progressive muscle weakness and respiratory insufficiency. We present the initial Australian experiences implementing the expanded access programme (EAP) to enable preapproval access to nusinersen, the first disease-modifying therapy, for SMA type 1. Methods An Australian multicentre, open-label EAP for nusinersen enrolled patients with infantile-onset SMA type 1 from November 2016 to September 2017. Standard-of-care medical therapy and treatment with intrathecal nusinersen were provided to all patients. Clinical and diagnostic characteristics, molecular genetics, treatment administered, and functional motor outcomes were assessed. Results A total of 20 patients with SMA type 1 met the inclusion criteria, of whom 16 consented and received nusinersen treatment. Median time to diagnosis from symptom onset was 5.0 months and was correlated with age of onset (r=0.54, P<0.05). Management shifts included proactive nutritional and pulmonary support in all newly diagnosed patients with increased complexity of decision making. Supplemental nutrition with or without nocturnal non-invasive ventilation was implemented during follow-up in new diagnoses with age of onset <3 months and 2 SMN2 copies. Conclusions The nusinersen EAP highlights difficulties in achieving early diagnosis and/or prevention, the evolution of optimal clinical care in a time of uncertain prognostication, resource implications and ethical issues in clinical practice for SMA type 1. These challenges are broadly relevant to the realisation of all novel therapeutics in neurological disorders.

X-linked Recessive Distal Myopathy With Hypertrophic Cardiomyopathy Caused by a Novel Mutation in the FHL1 Gene.

FHL1 gene mutations are associated with reducing body myopathy, X-linked myopathy with postural muscle atrophy, scapuloperoneal myopathy, Emery-Dreifuss muscular dystrophy, and isolated hypertrophic cardiomyopathy. We describe a boy with a family history consistent with X-linked distal myopathy/cardiomyopathy. The boy first presented at age 14 years and was found to have distal wasting and weakness. Echocardiogram revealed hypertrophic cardiomyopathy. Muscle biopsy showed a vacuolar pathology with no reducing bodies. Sequencing of FHL1 revealed a novel hemizygous c.764G>C missense mutation in exon 8. This is the first report of a predominantly distal myopathy with hypertrophic cardiomyopathy occurring secondary to an FHL1 mutation.

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.

Letter to the Editor Journal of Genetic Counseling

The article “When You Care to Do Your Very Best: Genetic Counselor Experiences of Compassion Fatigue (June 2007, 16:3) raises significant issues that impact on the profession of genetic counseling. As the authors state compassion fatigue is less considered in the literature, compared to the more familiar syndromes of stress and burnout. The suggestions for training and practice are important for the profession, as they draw attention to the need to prepare students better for practice through clinical rotations, and reflective teaching to encourage self-awareness so that students are aware of the realities of genetic counseling practice on graduation. Recently we have, as a supervision group of genetic counselors working in a variety of settings (including cancer genetics, prenatal genetics and general pediatric genetics), had stimulating discussion raised by this article. The article has also generated considerable discussion with a Masters student (M.M) as it is relevant to her Masters project, on supervision. Whilst we appreciated the discussion of and comparisons between compassion fatigue and stress and burnout, we felt that the phenomenon was very similar to the effects of countertransference. We noted that the authors had asked this very question in the focus group, but within the article it is treated as a different phenomenon. If discussed in terms of countertransference then there are strategies for dealing with compassion fatigue in a positive way. Evans (2006) discussing counter transference notes that “The genetic counselor is... exposed to an emotionally highly charged environment which can be personally upsetting, challenging or even draining and stressful.” The literature indicates strategies for dealing with countertransference including the important concept of developing self-awareness through regular supervision and reflective practice. The emotions aroused in countertransference, whilst they may evoke painful emotions are a dynamic that can be worked with constructively to effect change (Likhite 2000, Middleton et al. 2007). We would suggest that it is not good practice to “disconnect emotionally”, as discussed under Domain 1 Detachment. Rather the genetic counselor through developing self-awareness remains sensitive to the emotions of both self and the client “like a human barometer, recording impressions, feelings and attitudes...to develop the self as an instrument and then knowing how to use it” (Evans 2006) and “Clarification of the genetic counselor’s emotional responses may increase understanding of and sensitivity to the counselee’s fears...” (Weil 2000). Many of the themes discussed such as caregiver’s personality characteristics, coping strategies, empathy and delivering bad news are all part of developing self-awareness and sensitizing the genetic counselor to be more aware and empathic rather than detached. J Genet Counsel (2008) 17:139–140 DOI 10.1007/s10897-007-9122-3