Ancestry, race and ethnicity: the role and relevance of language in clinical genetics practice.

BACKGROUND: The terms ancestry, race and ethnicity are used variably within the medical literature and within society and clinical care. Biological lineage can provide an important context for the interpretation of genomic data, but the language used, and practices around when to ascertain this, vary. METHODS: Using a fictional case scenario we explore the relevance of questions around ancestry, race and ethnicity in clinical genetic practice. RESULTS: In the UK, data on 'ethnicity' are routinely collected by those using genomic medicine, as well as within the wider UK National Health Service, although the reasons for this are not always clear to practitioners and patients. Sometimes it is requested as a proxy for biological lineage to aid variant interpretation, refine estimations of carrier frequency and guide decisions around the need for pharmacogenetic testing. CONCLUSION: There are many challenges around the use and utility of these terms. Currently, genomic databases are populated primarily with data from people of European descent, and this can lead to health disparities and poorer service for minoritised or underserved populations. Sensitivity and consideration are needed when communicating with patients around these areas. We explore the role and relevance of language around biological lineage in clinical genetics practice.

Ethical preparedness in genomic medicine: how NHS clinical scientists navigate ethical issues.

Much has been published about the ethical issues encountered by clinicians in genetics/genomics, but those experienced by clinical laboratory scientists are less well described. Clinical laboratory scientists now frequently face navigating ethical problems in their work, but how they should be best supported to do this is underexplored. This lack of attention is also reflected in the ethics tools available to clinical laboratory scientists such as guidance and deliberative ethics forums, developed primarily to manage issues arising within the clinic.We explore what ethical issues are being experienced by clinical scientists, how they think such issues could be best analysed and managed, and whether their practice might be enhanced by more situated approaches to ethics deliberation and practice such as ethical preparedness. From thematic analysis of cases presented by clinical scientists at a specially convened meeting of the UK Genethics Forum, we derived three main ethical themes: (1) the redistribution of labour and responsibilities resulting from the practice of genomic medicine; (2) the interpretation and certainty of results and (3) the proposal that better standardisation and consistency of ethical approaches (for example, more guidelines and policy) could resolve some of the challenges arising.We argue that although standardisation is important for promoting shared understandings of good (including ethical) practice, supplementary approaches to enhance and sustain ethical preparedness will be important to help clinical scientists and others in the recently expanded genetic/genomic medicine environment foster quality ethical thinking.

Isolated- and Beckwith-Wiedemann syndrome related- lateralised overgrowth (hemihypertrophy): Clinical and molecular correlations in 94 individuals.

The congenital imprinting disorder, Beckwith-Wiedemann syndrome (BWS) is associated with variable clinical features including hemihypertrophy/lateralised overgrowth (LO) and embryonal tumour predisposition. BWS-associated (epi)genetic alterations occur in a subset of patients with isolated LO (ILO), leading to the concept of BWS spectrum disorder (BWSp). We investigated the relationship between clinical features and molecular diagnostic results in a cohort with LO using the BWSp international consensus group (BWSICG) clinical scoring system. Clinical/molecular findings in 94 previously-unreported patients with LO referred for BWSp molecular studies were reviewed retrospectively. The BWSICG score was assigned and diagnostic rate calculated. BWSp-associated (epi)genetic alteration was identified in 15/94 (16%). The molecular diagnostic rate by MS-MLPA (blood DNA) for BWS-related molecular findings in patients with LO was positively correlated with the BWSICG score. 3/48 with ILO had a molecular alteration. No individuals with ILO had developed an embryonal tumour at last follow up. Among a cohort of individuals with LO referred for BWSp molecular testing, the BWSICG score correlated with diagnostic yield. The embryonal tumour risk in children with ILO and negative molecular testing appeared very low, however longer- and more complete follow up is required to better define tumour risks in this group.

Ocular presentation of myasthenia gravis: A natural history cohort.

INTRODUCTION: There are limited data on the natural history of untreated myasthenia gravis (MG) with ocular presentation. METHODS: We analyzed 93 patients from symptom onset who presented to the Birmingham Midlands Eye Centre (BMEC) between January 2004 and July 2015. We used multiple stepwise logistic regression to identify predictive factors of generalization and Kaplan-Meier analysis on time to generalization. RESULTS: Forty-six percent of patients developed generalized symptoms during the study period. Median time to generalization was 7 months. Time to generalization was earlier in patients seropositive for acetylcholine receptor (AChR) antibody (median 5 months vs. 21 months, P < 0.0001) and bilateral ptosis at onset (P = 0.015). Multivariate analysis identified AChR seropositivity [hazard ratio (HR) 5.03; 95% confidence interval (CI) 1.48-17.14; P = 0.001] and disease onset < 50 years (HR 3.58; 95% CI 1.18-10.90; P = 0.035) as risk factors for generalization. DISCUSSION: As patients were steroid-naive before generalization, our cohort approximated the natural history of the condition. Muscle Nerve 57: 622-627, 2018.

Diagnosis of lethal or prenatal-onset autosomal recessive disorders by parental exome sequencing.

OBJECTIVE: Rare genetic disorders resulting in prenatal or neonatal death are genetically heterogeneous, but testing is often limited by the availability of fetal DNA, leaving couples without a potential prenatal test for future pregnancies. We describe our novel strategy of exome sequencing parental DNA samples to diagnose recessive monogenic disorders in an audit of the first 50 couples referred. METHOD: Exome sequencing was carried out in a consecutive series of 50 couples who had 1 or more pregnancies affected with a lethal or prenatal-onset disorder. In all cases, there was insufficient DNA for exome sequencing of the affected fetus. Heterozygous rare variants (MAF < 0.001) in the same gene in both parents were selected for analysis. Likely, disease-causing variants were tested in fetal DNA to confirm co-segregation. RESULTS: Parental exome analysis identified heterozygous pathogenic (or likely pathogenic) variants in 24 different genes in 26/50 couples (52%). Where 2 or more fetuses were affected, a genetic diagnosis was obtained in 18/29 cases (62%). In most cases, the clinical features were typical of the disorder, but in others, they result from a hypomorphic variant or represent the most severe form of a variable phenotypic spectrum. CONCLUSION: We conclude that exome sequencing of parental samples is a powerful strategy with high clinical utility for the genetic diagnosis of lethal or prenatal-onset recessive disorders. © 2017 The Authors Prenatal Diagnosis published by John Wiley & Sons Ltd.

Advances in the recognition and management of hereditary cancer.

INTRODUCTION: Constitutional mutations in genes controlling DNA repair, cell-cycle regulation and cell apoptosis can determine an individual's tendency to develop cancer. Hereditary cancer predisposition syndromes present with multiple cancers at a young age and underlie a significant burden of morbidity and mortality. Recent advances in the recognition and management of hereditary cancer will be illustrated with specific examples of developments in diagnosis and treatment. SOURCES OF DATA: Key recent published literature. AREAS OF AGREEMENT: The identification of individuals with hereditary cancer offers important opportunities for cancer prevention, early intervention and personalized management. AREAS OF CONTROVERSY: Individuals at risk of hereditary cancer remain under-recognized. There is a need to develop evidence-based guidelines for the recognition and management of hereditary cancer predisposition conditions. GROWING POINTS: The study of Mendelian cancer susceptibility syndromes has added to our understanding of hereditary and sporadic cancers and facilitated the development of targeted agents directed against cancer-driving mutations. Increasingly, cancer patients with constitutional gene mutations treated with targeted therapies have improved clinical outcomes. AREAS FOR TIMELY RESEARCH: Building the infrastructure to enable constitutional gene mutation testing to become integrated into routine cancer care, including the parallel development of robust referral pathways alongside genomic sequencing technologies.

Genodermatoses - Opportunities for Early Detection and Cancer Prevention.

Purpose of Review: This review describes the clinical features of the major adult-onset genodermatosis-associated hereditary cancer predisposition syndromes. Diagnosis of these conditions can be challenging due to a wide range of clinical features, varied presentations within families and the involvement of multiple medical specialities. Recent Findings: By emphasising the cutaneous and other non-malignant features, we aim to alert clinicians from all specialities to clues in the clinical history which should prompt consideration of a genodermatosis-associated hereditary cancer predisposition syndrome. In recognition of the move towards remote (telephone or video) appointments since the Covid-19 pandemic, we propose criteria which could be used by Cancer Genetics services to triage patients for in-person consultations in order to examine for signs of genodermatosis. Summary: Although individually rare, familiarity with these conditions amongst genetic and non-genetic clinicians is important as early diagnosis provides an opportunity to implement risk-reduction measures prior to a cancer diagnosis.

From Beyond the Grave: Use of Medical Information from the Deceased to Guide Care of Living Relatives.

PURPOSE OF REVIEW: In order to inform patients of their genetic risks, access to the medical records and/or stored samples of their relatives is often helpful. We consider some of the obstacles to such access when these relatives are deceased and suggest how they might be navigated. RECENT FINDINGS: We explore an issue first highlighted in 2004 by Lucassen et al. (Br Med J 328:952-953, 2004) and re-evaluate it in the wake of novel technologies and mainstreaming of genomic medicine. We find that it is still an issue in practice despite professional guidelines advocating access to familial information (Joint Committee on Genomics in Medicine 2019) and that the Human Tissue Act 2004 is often wrongly constructed as a reason to block access. Access is often obstructed by failing to adopt the necessary relational concept of autonomy that applies in genetic medicine as reported by Horton and Lucassen (Curr Genet Med Rep 7:85-91, 2019) and by considering confidentiality to be absolute, even after death. In response to a recent legal case about the confidentiality of genetic test results, and their disclosure to family members (ABC v St George's Healthcare NHS Trust 2020), Dove et al. (J Med Ethics 45:504-507, 2019) suggested that a duty to consider the interests of genetic relatives could co-exist alongside a duty of confidentiality to a patient. In this way, healthcare professionals can use professional judgement about the relative value of genetic information to family members. This is equally relevant in accessing deceased relatives' information. A recent systematic review found a high level of acceptability of postmortem use of genetic data for medical research amongst participants and their relatives, and it is reasonable to assume that this acceptability would extend to clinical practice as reported by Bak et al. (Eur J Hum Genet 28:403-416, 2020). SUMMARY: Within clinical practice, access to medical records/samples of deceased relatives is often obstructed unnecessarily, potentially resulting in harm to the living relatives seeking advice. Consent to such access is important but need not be the bureaucratic hurdle that is often imposed.

Giant aneurysm of the proximal segment of the left anterior descending artery in a patient with Behçet's disease--a combined approach.

Behçet's disease is an autoimmune, multisystem disease presenting with recurrent oral and genital ulceration as well as ocular involvement. Aneurysmal degeneration of coronary arteries remains a rare phenomenon in Behçet's disease. The case of a patient with Behçet's disease who presented with severe stenosis of the left anterior descending artery associated with a giant aneurysm of the proximal segment is described. Surgical revascularization was proposed, followed by percutaneous embolization of the aneurysm.