Background Inherited cardiomyopathies (HCM, DCM, ACM) and cardiac ion channelopathies (long QT/Brugada syndromes, CPVT) are associated with significant morbidity and mortality; however, diagnosis of a familial pathogenic variant in a proband allows for subsequent cascade screening of their at-risk relatives. Aims We investigated the diagnostic yield from cardiac gene panel testing and reviewed variants of uncertain significance from patients attending three specialist cardiogenetics services in Ireland in the years 2002 to 2020. Results Reviewing molecular genetic diagnostic reports of 834 patients from 820 families, the initial diagnostic yield of pathogenic/likely pathogenic variants was 237/834 patients (28.4%), increasing to 276/834 patients (33.1%) following re-evaluation of cases with variant(s) of uncertain significance. Altogether, 42/85 patients with VUS reviewed (49.4%) had a re-classification that could change their clinical management. Females were more likely to carry pathogenic/likely pathogenic variants than males (139/374, 37.2% vs 137/460, 29.8%, respectively, p = 0.03), and the diagnostic yields were highest in the 0 to < 2 years age group (6/12, 50.0%) and amongst those tested for cardiomyopathy gene panels (13/35, 37.1%). Variants in the MYBPC3/MYH7 (87/109, 79.8%) and KCNQ1/KCNH2 (91/100, 91.0%) genes were the predominant genetic causes for hypertrophic cardiomyopathy and long QT syndrome, respectively. Conclusion Our study highlights the importance of collation and review of pre-ACMG genetic variants to increase diagnostic utility of genetic testing for inherited heart disease. Almost half of patients with pre-ACMG VUS reviewed had their variant re-classified to likely pathogenic/likely benign which resulted in a positive clinical impact for patients and their families.

Background Estimates of rare disease (RD) population impact in terms of number of affected patients and accurate disease definition is hampered by their under-representation in current coding systems. This study tested the use of a specific RD codification system (ORPHAcodes) in five European countries/regions (Czech Republic, Malta, Romania, Spain, Veneto region-Italy) across different data sources over the period January 2019-September 2021. Results Overall, 3133 ORPHAcodes were used to describe RD diagnoses, mainly corresponding to the disease/subtype of disease aggregation level of the Orphanet classification (82.2%). More than half of the ORPHAcodes (53.6%) described diseases having a very low prevalence (< 1 case per million), and most commonly captured rare developmental defects during embryogenesis (31.3%) and rare neurological diseases (17.6%). ORPHAcodes described disease entities more precisely than corresponding ICD-10 codes in 83.4% of cases. Conclusions ORPHAcodes were found to be a versatile resource for the coding of RD, able to assure easiness of use and inter-country comparability across population and hospital databases. Future research on the impact of ORPHAcoding as to the impact of numbers of RD patients with improved coding in health information systems is needed to inform on the real magnitude of this public health issue.

Genetic counseling is a fast‐growing profession in Canada. Yet, despite its growth, genetic counseling lacks legal recognition in the majority of Canadian provinces. Legal recognition serves to regulate professions, including genetic counseling, that if not properly regulated, expose the public to the risk of harm. Under Canadian law, there are three models of legal recognition: 1) the constitution of a professional order, 2) inclusion in a professional order, and 3) delegation. This paper explores the practical implications of these different models of legal recognition for genetic counselors. It focuses on the balancing act between protecting the public and the resources required to seek legal recognition under the three different models. With a small number of genetic counselors ( n = 484, with 89% found in 4 provinces) compared to other professions, the route toward professional regulation for genetic counselors can be challenging. Though legal recognition occurs at the provincial rather than federal level in Canada, we nonetheless advocate for pan‐Canadian discussions that may benefit future pursuits of legal recognition.

The aim of the study was to provide accurate information regarding live-born infant survival after diagnosis of fatal fetal anomaly (FFA) to aid decision-making in respect of pregnancy management, and to ascertain the natural history of live-born infants with FFAs via a retrospective analysis of death records (2006-2018), from the National Paediatric Mortality Registry (source Central Statistics Office 2019). Diagnoses and survival times were ascertained from narrative records with further ascertainment and reconciliation of trisomies 13 and 18 cases by review of cytogenetic test records, the National Death Events Register and National Perinatal Epidemiology Centre data. During the study period, termination of pregnancy was not permitted under the Irish Constitution. Patients are live-born babies with fatal fetal anomalies whose deaths were registered in the Republic of Ireland. The main outcome measure was construction of anomaly-specific survival curves, or survival time range and median for those anomalies with rare occurrence. Survival curves for anencephaly, bilateral renal agenesis, thanatophoric dysplasia, trisomy 13, and trisomy 18 show that 90% (n = 95), 93% (n = 60), 100% (n = 14), 37% (n = 92) and 33% (n = 162), respectively, were deceased by 24 h and 98%, 100%, 100%, 73%, and 53%, respectively, by 1 week post-delivery. Survival time range and median were calculated for triploidy (3.5 h-20 days; 10.5 days), whose occurrence was rare. Anhydramnios, craniorachischisis, hydranencephaly and severe hydrocephalus were extremely rare and all deaths were neonatal deaths. Our results provide 13 years of national natural history data of live birth FFA survival. This provides objective information to aid obstetric counselling of couples upon diagnosis of an FFA.

Background ‘Slaintecare’ aims to address complex patient care needs in an integrated fashion with an emphasis on patient-centred, patient-empowered community care.Currently there is a lack of knowledge of the impact of rare disease management in primary care and of the information tools required by general practitioners to deliver integrated care for rare disease patients. Aims To complete a pilot survey to estimate the general practice clinical workload attributable to selected rare diseases and assess the use of relevant information sources. Methods A retrospective cross-sectional survey was carried out of general practice consultations (2013–2017) for patients with 22 commonly recognised rare diseases. Results Around 31 general practitioners from 10 Irish practices completed information on 171 patients with rare diseases over 3707 consultations. General practice-specific coding systems were inadequate for rare disease patient identification. Over 139 (81.3%) patients were adult, and 32 (18.7%) were children. Management of care was hospital and not primary care based in 63%. Those eligible for state-reimbursed care had a significantly higher median number of consultations (23 consultations, IQR = 13–37, or 5.8 consultations/year) than those who paid privately (10 consultations, IQR = 4–19, or 2.5 consultations/year) ( p < 0.005).General practitioners had access to public information resources on rare diseases but few had knowledge of (35.5%), or had ever used (12.9%) Orphanet, the international rare disease information portal. Conclusions Both specific rare disease-specific coding and use of the relevant rare disease information sources are lacking in general practice in Ireland.

Aims To ascertain the number of paediatric deaths (0–14 years) with an underlying rare disease in the Republic of Ireland between the years 2006–2016, and to analyse bed usage by a paediatric cohort of rare disease inpatients prior to in-hospital death. Background Rare diseases are often chronically debilitating and sometimes life-threatening diseases, with the majority (69.9%) of rare diseases being of paediatric onset. The Orphanet database contains information on 6172 unique rare diseases. Under-representation of rare diseases in hospital healthcare coding systems leads to a paucity of rare disease epidemiological data required for healthcare planning. Studies have cited variable incidence rates for rare disease, however the burden of rare diseases to healthcare services still remains unclear. This study represents a thorough effort to identify the percentage of child mortality and paediatric bed usage attributable to rare diseases in the Republic of Ireland, thus addressing a major gap in the rare disease field. Methods Retrospective analysis of paediatric death registration details for the Republic of Ireland in the 11-year period 2006–2016 from the National Paediatric Mortality Register. Data was subcategorised as Neonatal (0–28 days), Post Neonatal (29 days < 1 year) and older (1–14 years). Bed usage data (ICD-10 code, narrative and usage) of paediatric inpatients who died during hospitalisation from January 2015 to December 2016 was extracted from the National Quality Assurance Improvement System of in-patient data. Orphacodes were assigned to rare disease cases from ICD-10 codes or diagnostic narrative of both datasets. Results There were 4044 deaths registered from 2006–2016, aged < 15 years, of these 2368 (58.6%) had an underlying rare disease. Stratifying by age group; 55.6% (1140/2050) of neonatal deaths had a rare disease, 57.8% (450/778) post-neonatal, and 64% (778/1216) of children aged 1–14 years. Mortality coding using ICD-10 codes identified 42% of rare disease cases with the remainder identified using death certificate narrative records. Rare disease patients occupied 87% of bed days used by children < 15 years who died during hospitalisation from January 2015 to December 2016. Conclusion Additional routine rare disease coding is necessary to identify rare diseases within Irish healthcare systems to enable better healthcare planning. Rare disease patients are overrepresented in paediatric mortality statistics and in-patient length of stay during hospital admission prior to death.

Rare diseases, an emerging global public health priority, require an evidence-based estimate of the global point prevalence to inform public policy. We used the publicly available epidemiological data in the Orphanet database to calculate such a prevalence estimate. Overall, Orphanet contains information on 6172 unique rare diseases; 71.9% of which are genetic and 69.9% which are exclusively pediatric onset. Global point prevalence was calculated using rare disease prevalence data for predefined geographic regions from the ‘Orphanet Epidemiological file’ ( http://www.orphadata.org/cgi-bin/epidemio.html ). Of the 5304 diseases defined by point prevalence, 84.5% of those analysed have a point prevalence of <1/1 000 000. However 77.3–80.7% of the population burden of rare diseases is attributable to the 4.2% ( n = 149) diseases in the most common prevalence range (1–5 per 10 000). Consequently national definitions of ‘Rare Diseases’ (ranging from prevalence of 5 to 80 per 100 000) represent a variable number of rare disease patients despite sharing the majority of rare disease in their scope. Our analysis yields a conservative, evidence-based estimate for the population prevalence of rare diseases of 3.5–5.9%, which equates to 263–446 million persons affected globally at any point in time. This figure is derived from data from 67.6% of the prevalent rare diseases; using the European definition of 5 per 10 000; and excluding rare cancers, infectious diseases, and poisonings. Future registry research and the implementation of rare disease codification in healthcare systems will further refine the estimates.

Background Although individually rare, (5 per 10,000) and under-recognised in healthcare systems, collectively Rare Diseases (RDs) are common, with 8,000 diseases described. There are an estimated 300,000 Rare Disease (RD) patients in Ireland; 75% of paediatric onset. The EU recognises RDs as serious, chronic, and often life threatening illnesses. The Irish National Plan for RDs (2014) recommended epidemiological studies of RD prevalence to improve both cost efficiencies and care of patients with RD’s. Objectives To derive the incidence of paediatric RD and the number of paediatric RD mortality cases through analysis of records held at two major tertiary paediatric hospitals, for children born in the year 2000. In addition to ascertain in-hospital mortality cases with a RD and respective hospital usage. Methods National population based study of RD patients born in Ireland in the year 2000. Cases were identified using electronic/manual records from: the National Paediatric Mortality Registry office; Clinical, Cytogenetics and Molecular genetics database; Radiology and the Hospital In-Patient Enquiry system (HIPE). A detailed analysis of 10 years national death registration information for RDs from 2006–2016 was undertaken. In addition a study of 2 years data (2015–2016) HIPE, of RD discharges RIP age 0–14 years with analysis of their respective hospital days used. Results There were 54,789 livebirths in 2000. Clinical, Cytogenetic and Molecular Genetics identified 603, 121 and 77 cases of RDs respectively. Ongoing HIPE searches (two major centres) identified 370 and 702 additional cases of RD. Mortality data (2006–2016) revealed 65.7% of 105 deaths from the 2000 cohort had a RD.Of all deaths (n=4044) aged 0–14, on the Register (2006–2016), 58.56% (n=2368) had a RD diagnosis with age distribution; Neonates, 56%, Post-neonates, 58%, Children aged 1–14 years, 64%. Of the total (n=365) 0–14 years (2015–2016) inpatient deaths, (n=234) 64% had a RD, 52.6% (n=123) of the deaths were at the two major centres. Of the total hospital days used by this cohort (n=5566.5) 84%(n=4668.5) of the total day usage and 77% (3137/4059) of ICU days used were by RD patients. Conclusions This study has identified > 1,800 RD patients presenting by age 17 giving a minimum incidence of 3.3% for paediatric RDs. It confirms that the use of acute hospital services by RD patients far exceeds that expected by their numbers. 65.7% of paediatric mortality cases for the year 2000 cohort and 58.6% of all cases from 2006–2016 had a RD confirming the serious nature of these disorders.

Background Irish Travellers are an endogamous, nomadic, ethnic minority population mostly resident on the island of Ireland with smaller populations in Europe and the USA. High levels of consanguinity result in many rare autosomal recessive disorders. Due to founder effects and endogamy, most recessive disorders are caused by specific homozygous mutations unique to this population. Key clinicians and scientists with experience in managing rare disorders seen in this population have developed a de facto advisory service on differential diagnoses to consider when faced with specific clinical scenarios. Objective(s) To catalogue all known inherited disorders found in the Irish Traveller population. Methods We performed detailed literature and database searches to identify relevant publications and the disease mutations of known genetic disorders found in Irish Travellers. Results We identified 104 genetic disorders: 90 inherited in an autosomal recessive manner; 13 autosomal dominant and one a recurring chromosomal duplication. Conclusion We have collated our experience of inherited disorders found in the Irish Traveller population to make it publically available through this publication to facilitate a targeted genetic approach to diagnostics in this ethnic group.

The profession of genetic counseling (also called genetic counselling in many countries) began nearly 50 years ago in the United States, and has grown internationally in the past 30 years. While there have been many papers describing the profession of genetic counseling in individual countries or regions, data remains incomplete and has been published in diverse journals with limited access. As a result of the 2016 Transnational Alliance of Genetic Counseling (TAGC) conference in Barcelona, Spain, and the 2017 World Congress of Genetic Counselling in the UK, we endeavor to describe as fully as possible the global state of genetic counseling as a profession. We estimate that in 2018 there are nearly 7000 genetic counselors with the profession established or developing in no less than 28 countries.

Introduction: In Europe a ‘rare disease’ (RD) is defined as a life-threatening or chronically debilitating disease affecting no more than 5/10,000 people. There are an estimated 6-8,000 known RD affecting up to 6% of the total EU population, (at least 30 million Europeans), and perhaps up to 300,000 Irish people during their lives. As chronic conditions, many of which are multisystemic, accurate and timely diagnosis and access to treatment is essential for empowering patients and Health Care Providers to manage care effectively. It is recognised that poorly coordinated care and delays in diagnosis are major issues for patients and families affected by rare diseases which are noted to be more problematic in smaller countries with more limited highly specialised expertise, (Rare Diseases UK, 2015 and Irish HSE 2012 ‘Have your say’ Rare Diseases Public Consultation) and as emphasised in the recent EC Expert Group on Rare Diseases ‘Recommendations to support the incorporation of rare diseases into social services and policies’ (April 2016).Practice change and implementation: In 2014 Ireland published its first National Plan for RD (2014-2018). Establishing a National Rare Diseases Office (NRDO) was a central recommendation of the plan to improve access to reliable information and empower patients and HCPs to make informed decisions about the management of RD.Aims and theory of change: The aim of the NRDO (established in June 2015 by the Irish HSE) is to provide current and reliable information about genetic and RD to patients, families and health professionals. The functions of the office include:Centralisation of Irish RD information through Orphanet Ireland; an international online portal for RD information and resources encompassing > 6,000 RD. (www.orpha.net)Staffing a RD Information Line to provide patients, families and HCPs with information and supports relating to RD.Hosting a website with information and links to relevant RD services and organisations around Ireland and Europe www.rarediseases.ieEngaging with clinicians, expert centres and researchers to map-out Irish RD resources to act as a ‘hub’ for integrating National Centres of Expertise in the emerging European Reference Networks.Initial outcomes: In its first year of functioning, greater than 50% of calls to the information line were from patients and families, most commonly requesting signposting of medical specialists for specific RD.Conclusions and Outlook: Over time, it is proposed that the NRDO will liaise with all national RD Centres of Expertise, with the Irish national integrated care programmes, and Rare Diseases European Reference Networks to progress improved integrated care pathways for RD patients and function as a national ‘hub’ within the Irish and European contexts, in line with the EC Expert Group on Rare Diseases April 2016 Recommendations.

Described as the commonest single gene cause of learning disability internationally, the incidence of Fragile X syndrome (FXS) has never previously been determined in Ireland. The aim of this work was to determine the observed incidence of FXS in the island of Ireland; the Republic of Ireland (ROI) and Northern Ireland (NI) separately and combined. Ascertainment was achieved for a cross-sectional study by a retrospective, clinical and laboratory database review of positive FXS cases, born in either ROI or NI, between years 2000-2009 inclusive. The observed incidence of FXS per 10,000 live births in the island of Ireland in males was 0.94 (95%CI: 0.75-1.13) or ∼1:10,600 and in females was 0.23 (95%CI: 0.14-0.32) or ∼1:43,000. Comparable testing rates for FXS are present in ROI and NI, with on average 1.48% (1.30% in ROI, 1.96% in NI) of live male births and 0.4% (0.35% in ROI, 0.55% in NI) of live female births undergoing analysis which is comparable to other centres internationally. This study demonstrates the observed incidence of FXS in the island of Ireland is (i) approximately half the estimated worldwide incidence in males and is not explained by low levels of testing, and (ii) approximately one quarter the estimated worldwide incidence in females which may be explained by low levels of testing. © 2017 Wiley Periodicals, Inc.

Medullary thyroid cancer consists of a spectrum of disease that ranges from extremely indolent tumors to aggressive types associated with a high mortality rate. The objective of our study is to evaluate the prognostic factors and outcomes of patients diagnosed with MTC in a homogenous population, and to examine patients diagnosed with MTC for mutations in the RET proto-oncogene from the same period.