Using a bedside test to detect genetic susceptibility to aminoglycoside-induced hearing loss: Has the future arrived?

Aminoglycosides are among the most commonly prescribed antibiotics in hospitalised Australian adults and children. A proportion of individuals with an underlying genetic predisposition to aminoglycoside-induced hearing loss (AIHL) can develop bilateral sensorineural hearing loss that is immediate and profound after just a single standard dose of an aminoglycoside. A recent publication described the use of a rapid point-of-care test (POCT) in a neonatal nursery in the United Kingdom for real-time detection of infants at risk of AIHL, in whom exposure to aminoglycosides could then be avoided. This proof of concept study should provide a catalyst for further development of similar assays that would be suitable for Australia's genetically diverse population. The barriers to mitigating the impact of AIHL on Australian children are not primarily technical, but involve a lack of data on the prevalence of the MT-RNR1 mutations in our current neonatal and paediatric populations and intensive care nurseries.

Socioeconomic status and uptake of reproductive carrier screening in Australia.

Reproductive carrier screening enables the early identification of genetic conditions that may impact the long-term health of a child, including cystic fibrosis, fragile X syndrome, and spinal muscular atrophy. We used unique data from the major providers of pathology services in Australia to profile women who intend on becoming, or who are, pregnant and access basic to advanced testing for genetic conditions. We found a strong socioeconomic gradient in the uptake of reproductive carrier screening, with women living in the most advantaged postcodes across Australia significantly being more likely to have reproductive carrier screening than those living in the most disadvantaged areas. These results highlight the need to minimise social and financial barriers that are currently limiting access.

Letter to the editor: reply to Bousman et al.

Letter regarding: Bousman CA, Arandjelovic K, Mancuso SG, Eyre HA, Dunlop BW. Pharmacogenetic tests and depressive symptom remission: a meta-analysis of randomized controlled trials. Pharmacogenomics 20(1), 37-47 (2019).

Pharmacogenomics in general practice: The time has come.

BACKGROUND: Patients respond to medications differently because of variations in the genes that determine medication exposure and medication response. OBJECTIVE: The aim of this review is to introduce pharmacogenomic testing and explain how to start using pharmacogenomic tests in general practice. DISCUSSION: Knowledge of the variants in pharmacogenomics is useful when prescribing a variety of medications. International guidelines have identified at least 15 genes for which testing can inform the prescribing of 30 different medications with good evidence of clinical benefit. Nonetheless, pharmacogenomic tests should not be used as the sole basis for prescribing decisions, and should be considered in the context of other relevant clinical and laboratory features. General practitioners can incorporate pharmacogenomic tests into their clinical practice for patients with medication-related problems or those who are likely to require medications for which pharmacogenomics can provide guidance.

Diagnostic performance and costs of contingent screening models for trisomy 21 incorporating non-invasive prenatal testing.

BACKGROUND: Contingent screening for trisomy 21 using non-invasive prenatal testing has the potential to reduce invasive diagnostic testing and increase the detection of trisomy 21. AIM: To describe the diagnostic and economic performance of prenatal screening models for trisomy 21 that use non-invasive prenatal testing as a contingent screen across a range of combined first trimester screening risk cut-offs from a public health system perspective. METHODS: Using a hypothetical cohort of 300 000 pregnancies, we modelled the outcomes of 25 contingent non-invasive prenatal testing screening models and compared these to conventional screening, offering women with a high-risk (1 > 300) combined first trimester screening result an invasive test. The 25 models used a range of risk cut-offs. High-risk women were offered invasive testing. Intermediate-risk women were offered non-invasive prenatal testing. We report the cost of each model, detection rate, costs per diagnosis, invasive tests per diagnosis and the number of fetal losses per diagnosis. RESULTS: The cost per prenatal diagnosis of trisomy 21 using the conventional model was $51 876 compared to the contingent models which varied from $49 309-66 686. The number of diagnoses and cost per diagnosis increased as the intermediate-risk threshold was lowered. Results were sensitive to trisomy 21 incidence, uptake of testing and cost of non-invasive prenatal testing. CONCLUSION: Contingent non-invasive prenatal testing models using more sensitive combined first trimester screening risk cut-offs than conventional screening improved the detection rate of trisomy 21, reduced procedure-related fetal loss and could potentially be provided at a lower cost per diagnosis than conventional screening.

Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies.

Recently our group and others have identified DDX41 mutations both as germ line and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), suggesting that DDX41 acts as a tumor suppressor. To determine whether novel DDX41 mutations could be identified in families with additional types of hematologic malignancies, our group screened two cohorts of families with a diverse range of hematologic malignancy subtypes. Among 289 families, we identified nine (3%) with DDX41 mutations. As previously observed, MDS and AML were the most common malignancies, often of the erythroblastic subtype, and 1 family displayed early-onset follicular lymphoma. Five novel mutations were identified, including missense mutations within important functional domains and start-loss and splicing mutations predicted to result in truncated proteins. We also show that most asymptomatic mutation carriers have normal blood counts until malignancy develops. This study expands both the mutation and phenotypic spectra observed in families with germ line DDX41 mutations. With an increasing number of both inherited and acquired mutations in this gene being identified, further study of how DDX41 disruption leads to hematologic malignancies is critical.

Mosaic Epigenetic Inheritance as a Cause of Early-Onset Colorectal Cancer.

IMPORTANCE: Constitutional hypermethylation of 1 allele throughout the soma (constitutional epimutation) is an accepted mechanism of cancer predisposition. Understanding the origin and inheritance of epimutations is important for assessing cancer risk in affected families. OBSERVATIONS: We report a 29-year-old man with early-onset colorectal cancer who showed a constitutional MLH1 epimutation (approximately 50% of alleles methylated and allele-specific loss of MLH1 expression) that was stable over a 16-year period. The epimutation was inherited without a genetic alteration from his asymptomatic mother. She showed methylation on the same allele but in less than 5% of her somatic cells. CONCLUSIONS AND RELEVANCE: These findings indicate that low-level somatic mosaicism for an epimutation in an asymptomatic parent can produce a nonmosaic constitutional epimutation in a child. Asymptomatic low-level methylation in some individuals may be associated with substantial cancer risk to their offspring.

Rising incidence of early-onset colorectal cancer in Australia over two decades: report and review.

The average age at diagnosis for colorectal cancer (CRC) in Australia is 69, and the age-specific incidence rises rapidly after age 50 years. The incidence has stabilized or is declining in older age groups in Australia during recent decades, possibly related to the increased uptake of screening and high-risk surveillance. In the same time frame, a rising incidence of CRC in younger adults has been well-documented in the United States. This rise in incidence in the young has not been reported from other countries that share long-term exposure to westernised urban lifestyles. Using data from the Australian Institute of Health and Welfare, we examined trends in national incidence rates for CRC under age 50 years and observed that rates in people under age 40 years have been rising for the last two decades. We further performed a review of the literature regarding CRC in young adults to outline the extent of current understanding, explore potential risk factors such as obesity, alcohol, and sedentary lifestyles, and to identify the questions remaining to be addressed. Although absolute numbers might not justify a population screening approach, the dispersal of young adults with CRC across the primary health-care system decreases probability of their recognition. Patient and physician awareness, aided by stool and emerging blood-screening tests and risk profiling tools, have the potential to aid in identification of those young adults who would most benefit from a colonoscopy through early detection of CRCs or by removal of advanced polyps.

Lynch syndrome-associated breast cancers do not overexpress chromosome 11-encoded mucins.

Mismatch repair-deficient breast cancers may be identified in Lynch syndrome mutation carriers, and have clinicopathological features in common with mismatch repair-deficient colorectal and endometrial cancers such as tumour-infiltrating lymphocytes and poor differentiation. Mismatch repair-deficient colorectal cancers frequently show mucinous differentiation associated with upregulation of chromosome 11 mucins. The aim of this study was to compare the protein expression of these mucins in mismatch repair-deficient and -proficient breast cancers. Cases of breast cancer (n=100) were identified from families where (1) both breast and colon cancer co-occurred and (2) families met either modified Amsterdam criteria or had at least one early-onset (<50 years) colorectal cancer. Tumour sections were stained for the epithelial mucins, MUC2, MUC5AC, MUC5B and MUC6, and the homeobox protein CDX2, a regulator of MUC2 expression. In all, 16 mismatch repair-deficient Lynch syndrome breast cancers and 84 non-Lynch breast cancers were assessed for altered mucin expression. No significant difference in the expression of MUC2, MUC5AC or MUC6 was observed between the mismatch repair-deficient and mismatch repair-proficient breast cancers; however, there was a trend for mismatch repair-deficient tumours to express high levels of MUC5B less frequently (P=0.07, OR=0.2 (0.0-1.0)). Co-expression of two or more gel-forming mucins was common. Ectopic expression of CDX2 was associated with expression of MUC2 (P=0.035, OR=8.7 (1.3-58.4)). Mismatch repair-deficient breast cancers do not show differential expression of the mucins genes on chromosome 11 when compared with mismatch repair-proficient breast cancers, in contrast with mismatch repair-deficient colorectal and endometrial cancers, which frequently have increased mucin protein expression when compared with their mismatch repair-proficient counterparts. In addition, ectopic CDX2 expression is positively associated with de novo MUC2 expression.

Disease-specific databases: why we need them and some recommendations from the Human Variome Project Meeting, May 28, 2011.

The need for Locus-Specific Databases, with disease-specific experts and curators, is an essential ingredient in a process to enable the benefits of the advances in sequencing and mutational analysis to be realized across the genome. Next generation sequencing provides both astounding opportunities and challenges, especially for genetic counsellors. An approach coordinated at a genome wide, international level, supported by well-organized disease-specific respected organizations is a model most likely to be successful, but committed resourceful professionals working in local poorly resourced environments can make valuable contributions that can grow. Bioinformatic tools to sift and integrate multiple domains of information are being developed, and play a major part in meeting the challenges. Regulation of providers, including a requirement for them to submit mutational information to central databases, also should assist to reach the goals needed to realize the opportunities. There is also a need to agree on governance of Locus-Specific Databases (LSDBs) at an international level, and for adequate international funding to support this need, to ensure humanity reaps the benefits of the current molecular genetic revolution. The Human Variome Project offers this, working also with the other major initiatives with similar objectives. This report concludes with Recommendations for the Human Variome Project stemming from the presentations and discussions at the meeting.

Cancer risks for relatives of patients with serrated polyposis.

OBJECTIVES: Serrated polyposis (hyperplastic polyposis) is characterized by multiple polyps with serrated architecture in the colorectum. Although patients with serrated polyposis are known to be at increased risk of colorectal cancer (CRC) and possibly extracolonic cancers, cancer risk for their relatives has not been widely explored. The aim of this study was to estimate the risks of CRC and extracolonic cancers for relatives of patients with serrated polyposis. METHODS: A cohort of the 1,639 first- and second-degree relatives of 100 index patients with serrated polyposis recruited regardless of a family history of polyps or cancer from genetic clinics in Australia, New Zealand, Canada, and the USA, were retrospectively analyzed to estimate the country-, age-, and sex-specific standardized incidence ratios (SIRs) for relatives compared with the general population. RESULTS: A total of 102 CRCs were observed in first- and second-relatives (SIR 2.25, 95% confidence interval (CI) 1.75-2.93; P<0.001), with 54 in first-degree relatives (SIR 5.16, 95% CI 3.70-7.30; P<0.001) and 48 in second-degree relatives (SIR 1.38, 95% CI 1.01-1.91; P=0.04). Six pancreatic cancers were observed in first-degree relatives (SIR 3.64, 95% CI 1.70-9.21; P=0.003). There was no statistical evidence of increased risk for cancer of the stomach, brain, breast, or prostate. CONCLUSIONS: Our finding that relatives of serrated polyposis patients are at significantly increased risk of colorectal and pancreatic cancer adds to the accumulating evidence that serrated polyposis has an inherited component.

Immunohistochemical testing of conventional adenomas for loss of expression of mismatch repair proteins in Lynch syndrome mutation carriers: a case series from the Australasian site of the colon cancer family registry.

Debate continues as to the usefulness of assessing adenomas for loss of mismatch repair protein expression to identify individuals with suspected Lynch syndrome. We tested 109 polyps from 69 proven mutation carriers (35 females and 34 males) belonging to 49 Lynch syndrome families. All polyps were tested by immunohistochemistry for four mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. Detailed pathology review was performed by specialist gastrointestinal pathologists. The majority of polyps (86%) were conventional adenomas (n=94), with 65 tubular and 28 tubulovillous adenomas and a single villous adenoma. The remaining 15 lesions (14%) were serrated polyps. Overall, loss of mismatch repair expression was noted for 78/109 (72%) of polyps. Loss of mismatch repair expression was seen in 74 of 94 (79%) conventional adenomas, and 4 of 15 (27%) serrated polyps from mismatch repair gene mutation carriers. In all instances, loss of expression was consistent with the underlying germline mutation. Mismatch repair protein expression was lost in 27 of 29 adenomas with a villous component compared with 47 of 65 adenomas without this feature (93 vs 73%; P=0.028). A strong trend was observed for high-grade dysplasia. Mismatch repair deficiency was observed in 12 of 12 conventional adenomas with high-grade dysplasia compared with 60 of 79 with low-grade dysplasia (100 vs 76%; P=0.065). We were unable to demonstrate a significant association between conventional adenoma size or site and mismatch repair deficiency. All (4/4 or 100%) of the serrated polyps demonstrating mismatch repair deficiency were traditional serrated adenomas from a single family. Diagnostic testing of adenomas in suspected Lynch syndrome families is a useful alternative in cases where cancers are unavailable. The overwhelming majority of conventional adenomas from mutation carriers show loss of mismatch repair protein expression concordant with the underlying germline mutation.

Quality standards and samples in genetic testing.

The most critical performance indicator for medical laboratories is the delivery of accurate test results. In any laboratory, there is always the possibility that random or systematic errors may occur and place human health and welfare at risk. Laboratory quality assurance programmes continue to drive improvements in analytical accuracy. The most rigorously scrutinised data on laboratory errors, which come from transfusion medicine, reveal that the incidence of analytical errors has fallen to levels where most of the residual risk is now found in preanalytical links in the chain from patient to result, particularly activities associated with ordering of tests and sample collection. This insight is important for genetic testing because, like pretransfusion testing of patients with unknown blood groups, a substantial proportion of genotyping results cannot be immediately verified. An increasing number of clinical decisions, associated personal and social choices, and legal outcomes are now influenced by genetic test results in the absence of other confirmatory data. An incorrect test result may lead to unnecessary and irreversible interventions, which may in themselves have associated risks for the patient, inaccurate risk assessment regarding the disease, missed opportunities for disease prevention or even wrongful conviction in a court of law. Unfortunately, there is limited information available about the risk of preanalytical errors associated with, and few published guidelines regarding, sample collection for genetic testing. The growing number and range of important decisions made on the basis of genetic findings warrant a reappraisal of current standards to minimise risks in genetic testing.

Familial hypercholesterolaemia: a model of care for Australasia.

Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that causes marked elevation in plasma cholesterol and premature coronary heart disease. There are at least 45,000 people with FH in Australia and New Zealand, but the vast majority remains undetected and those diagnosed with the condition are inadequately treated. To bridge this major gap in coronary prevention the FH Australasia Network (Australian Atherosclerosis Society) has developed a consensus model of care (MoC) for FH. The MoC is based on clinical experience, expert opinion, published evidence and consultations with a wide spectrum of stakeholders, and has been developed for use primarily by specialist centres intending starting a clinical service for FH. This MoC aims to provide a standardised, high-quality and cost-effective system of care that is likely to have the highest impact on patient outcomes. The MoC for FH is presented as a series of recommendations and algorithms focusing on the standards required for the detection, diagnosis, assessment and management of FH in adults and children. The process involved in cascade screening and risk notification, the backbone for detecting new cases of FH, is detailed. Guidance on treatment is based on risk stratifying patients, management of non-cholesterol risk factors, safe and effective use of statins, and a rational approach to follow-up of patients. Clinical and laboratory recommendations are given for genetic testing. An integrative system for providing best clinical care is described. This MoC for FH is not prescriptive and needs to be complemented by good clinical judgment and adjusted for local needs and resources. After initial implementation, the MoC will require critical evaluation, development and appropriate modification.