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This work aims to analyze near-surface air temperature at Carlini Argentine Antarctic Station, in Potter Cove (PC), in order to study the extreme events in which the record-breaking low and high temperatures for the 1985-2022 period were registered over this area of 25 de Mayo (King George) Island at the South Shetland Archipelago, located to the northwest of the Antarctic Peninsula (AP). The coldest event took place between 23 and 26 July 1994, with a low record-breaking temperature of -27.3°C for Carlini station since records began, while the warmest was observed 7 and 8 February 2022 reaching a high record-breaking temperature of +13.6°C. Reanalysis data from NCEP/NCAR and ERA5 from ECWMF are used to analyze the circulation patterns associated to these extreme events in PC, evidencing an easterly (northerly) large-scale flow which may favour conditions for the occurrence of the coldest (warmest) extreme events. Furthermore, sea ice extent may have played a relative role for the development of such extreme cold event, as well as a foehn effect for the warm event. Even though, reanalysis data resolution may not be suitable for understanding the whole forcings of such local events, they give an approximate diagnosis of the situation which led to the conditions for the observed extreme events., The 28th IUGG General Assembly (IUGG2023) (Berlin 2023)

Embryo splitting can be used in cattle in vitro production (IVP) to improve embryo availability and to increase selection intensity. Despite this widespread utility, a comparative investigation of the viability of IVP embryos split at Day 2 (2-cell stage), Day 3 (8-cell stage), and blastocyst stage has not been undertaken. Similarly, the suitability of splitting Day 3 embryos with atypical numbers of blastomeres, and the feasibility of serial-splitting cleavage stage embryos, have not been investigated in cattle. Here, we demonstrate that the strategy most likely to produce the greatest output of viable embryos is the splitting of Day 3 embryos into four parts, regardless of whether embryos with exactly eight cells or an atypical number of blastomeres are used. This approach was found to produce 1.8 blastocysts per zygote on average compared to just 0.4 blastocysts per zygote for non-split controls. Single-splitting was also found to be superior to serial-splitting which, whilst feasible, impaired embryo viability as judged by cell number at day 7 post-insemination. Interestingly, zygotes (?2 cells) split once on either Day 2 or Day 3 post-insemination, whilst resulting in smaller blastocysts than control embryos, displayed higher cell counts than expected at the blastocyst stage, suggesting a compensatory mechanism might be at play. Indeed, time-lapse imagery revealed that zygotes split at 2-cells reached the compact morula and expanded blastocyst stages earlier than either those split at Day 3 or non-split controls. Developmental events between splits originating from the same progenitor appeared well synchronized only up to the third cleavage division.

In this work, we provide a deterministic alternative to the stochastic variational training of generative autoencoders. We refer to these new generative autoencoders as AutoEncoders within Flows (AEF), since the encoder and decoder are defined as affine layers of an overall invertible architecture. This results in a deterministic encoding of the data, as opposed to the stochastic encoding of VAEs. The paper introduces two related families of AEFs. The first family relies on a partition of the ambient space and is trained by exact maximum-likelihood. The second family exploits a deterministic expansion of the ambient space and is trained by maximizing the log-probability in this extended space. This latter case leaves complete freedom in the choice of encoder, decoder and prior architectures, making it a drop-in replacement for the training of existing VAEs and VAE-style models. We show that these AEFs can have strikingly higher performance than architecturally identical VAEs in terms of log-likelihood and sample quality, especially for low dimensional latent spaces. Importantly, we show that AEF samples are substantially sharper than VAE samples., International Conference on Learning Representations 2023

Residual lobar volume reduction in treated lobes measured by QCT was found to be the driving mechanism of action of endobronchial coils leading to positive clinical outcomes. However, the improvement in exercise capacity and quality of life seems to be affected by the presence of cardiac disease. See related Editorial, Background and objective The RENEW trial demonstrated that bronchoscopic lung volume reduction using endobronchial coils improves quality of life, pulmonary function and exercise performance. In this post hoc analysis of RENEW, we examine the mechanism of action of endobronchial coils that drives improvement in clinical outcomes. Methods A total of 78 patients from the RENEW coil‐treated group who were treated in one or both lobes that were deemed as the most destroyed were included in this retrospective analysis. Expiratory and inspiratory HRCT scans were used to assess lobar volume change from baseline to 12 months post coil treatment in treated and untreated lobes. Results Reduction in lobar RV in treated lobes was significantly associated with favourable clinical improvement. Independent predictor of the change in RV and FEV1 was the change in lobar RV reduction in the treated lobes and for change in 6MWD the absence of cardiac disease and the change in SGRQ, while the independent predictor of change in SGRQ was the change in 6MWD. Conclusion Our results suggest that residual lobar volume reduction in treated lobes measured by QCT is the driving mechanism of action of endobronchial coils leading to positive clinical outcomes. However, the improvement in exercise capacity and quality of life seems to be affected by the presence of cardiac disease.

Background Age-related cognitive decline results in increased difficulty in performing tasks that require memory or rapid information processing. Cognitive resilience is the ability to withstand the negative effects of stress on cognitive functioning. The polygenetic contribution to cognitive resilience requires large data sets for analysis. In addition, longitudinal data is needed to identify individual differences in cognitive performance over time. The UK Biobank cohort of over 500,000 participants over the age of 40 offers the potential to advance research on the genetics and biology of cognitive resilience. Methods We created a longitudinal cognitive resilience phenotype by combining the phenotypic cognitive parameter of current reaction time with a proxy phenotype of education years (EY). We used this resilience phenotype, in genome-wide association studies (GWAS) to identify genes and gene sets that influence the biological pathways involved in resilience. To remove the influence of the EY on the analysis we compared genetic data on participants that displayed resilience to those that showed expected cognitive decline. Results GWAS outputs analysis showed 273 significantly enriched genes for participants that demonstrated resilience. Genotype–tissue expression was significant in brain tissue, particularly in the anterior cingulate cortex, frontal cortex, and hippocampus. Biological Pathway analysis includes synapse, post synaptic density and neuron guidance. Conclusion This analysis shows an association between cognitive resilience and enrichment of neuronal activity. Confirmatory examination of these findings in datasets with strong longitudinal cognitive data, such and the Health and Retirement Study, is ongoing., Introduction Type 1 diabetes (T1D) is a polygenic disease characterised by autoimmune inflammatory destruction of the pancreas and subsequent hyperglycaemia. Several GWAS have identified loci associated with T1D risk, but recent evidence suggests that epigenetic changes in DNA methylation may have a causal role in T1D. Methods To identify potential methylation-based biomarkers of T1D, blood-derived DNA from 250 individuals with ≥15 years duration of T1D was compared to 391 controls with no evidence of diabetes. All individuals were from the British Isles. DNA was bisulphite treated using the EZ DNA Methylation Kit (Zymo). The Infinium HD Methylation Assay MethylationEPIC BeadChips (Illumina) were used to determine the methylation status of >850,000 CpG sites, gene bodies and promoters. Results MethylationEPIC data was analysed using GenomeStudio v2011 and Partek Genomics Suite v7.0. Comparing T1D with controls identified 1,706 CpG sites with significantly different (p±2 fold change). Genes including HLA‐DRB1, HLA‐DQA1 and PLEKHA1 have been previously linked to T1D and contained >2 differently methylated CpG sites ≥p, Introduction Rare diseases (RDs) are a public health priority but their scarcity and diversity leads to a lack of knowledge and expertise. Accurate epidemiological information about RDs is necessary to inform public policy, but without an Irish rare disease registry, there is a dearth of primary data. Methods Collaborative work with Orphanet Coordination derived a global point prevalence of RDs from the ‘Orphanet Epidemiological File’ (http://www.orphadata.org) by selecting RDs described by ‘point prevalence’ from predefined geographic regions, and summing point prevalences. In the National Rare Disease Office, expert opinion and disease-specific publications were used to adapt a ‘high prevalence’ list for Ireland. Results Globally, ‘point prevalence’ describes 5,304 RDs ≥85.9%). The minimum cumulative point prevalence of RDs is 3.5‐5.9% of the population. While globally 84.5% RDs analysed ≥n=3585) had a point prevalence of 1/100,000. To construct a comparable Irish ‘high‐ prevalence’ list, 191 RDs with known prevalence >1/100,000 across all countries were drawn from the global list. A further 147 diseases with possible prevalence >1/100,000 in Ireland due to ethnic, environmental or founder‐effect are currently under consideration for inclusion. Conclusion 3.5%‐5.9% is the first evidence‐based estimate of the global population prevalence of RDs. Creation of an Irish list of high‐prevalence RDs permits development of care pathways and systems that address the needs of the majority of Irish people with RDs. Implementation of RD codification in eHealth Ireland will provide more accurate data., Introduction The acute hepatic porphyrias, including acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HP) along with familial Porphyria Cutanea Tarda (fPCT) are autosomal dominantly inherited disorders affecting key enzymes in the haem biosynthetic pathway. Clinically these disorders may manifest as photosensitive skin lesions (VP, HP and PCT) and/or acute neuropathic episodes (AIP, VP and HP). All demonstrate variable penetrance and expressivity. Thus, while biochemical investigations, including blood, urine and faecal porphyrin analysis, are critical for the diagnosis of active porphyric disease, these investigations may not be sensitive enough to identify presymptomatic variant carriers. Hence molecular genetic analysis has become an important component in kindred follow-up for identifying porphyria susceptibility. Methods The Biochemistry Department, St James’s Hospital, Dublin, has established a molecular diagnostic service based on direct nucleotide sequencing to facilitate diagnosis of genetic susceptibility to AIP, VP, HCP and PCT respectively. Results To date over 30 different genetic variants linked with a porphyria phenotype have been identified in different kindreds including non‐Irish. The spectrum of variants includes missense, nonsense, splice‐site and small insertions and deletions e.g. HMBS ≥R26C, R26H, IVS4+1G>A), PPOX ≥IVS4‐1G>A, Q435X, W427X, A150D, Q375X) and CPO ≥R332Q, R332W, c.1291‐1292 ins TG). In addition, novel variants have been identified in collaboration with Cardiff Porphyria Centre. Conclusion This unique insight into the molecular basis of porphyrias in the ROI indicates that acute porphyrias and fPCT are genetically heterogeneous. Furthermore, the variant scanning assay in St James’s Hospital has identified pathogenic variants in >93% of confirmed porphyria kindreds, Background The developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies which co-present with intellectual disability, and occur in cases without a family history of epilepsy. Their severe phenotype means that DEEs are thought to be primarily monogenic, caused by highly damaging rare mutations. Currently, analysis of exome sequence data can identify a causative mutation in around 40% of DEEs. Little is known about the genetic architecture of the remaining DEEs which screen-negative after genomic analysis. Here, we used a method known as polygenic risk scoring (PRS) to test whether the burden of common genetic variation is relevant to the development of the DEEs. Methods Exome and GWAS data on DEE cases (n=745), and population controls (n=75,000) were obtained from the DDD cohort and Ukbiobank, respectively. Damaging mutations in known epilepsy genes were bioinformatically inferred. PRS were calculated using the most recent ILAE GWAS of epilepsy and compared between i) DEE cases and the general population, and ii) DEE cases with and without damaging mutations. Results DEE cases with and without inferred damaging mutations were found to have elevated PRS for epilepsy. We did not detect a significant difference in PRS between DEE cases with and without damaging mutations. Discussion This research provides the first evidence that common genetic variation contributes to the development of the DEEs. Our results suggest common genetic variation contributes to DEE status irrespective of the presence of a highly damaging rare genetic variant. Further work in additional cohorts is required to extend these results., Rationale The phenotypic features in a person with epilepsy are often complex with regards to seizure presentations, which is acknowledged by the most recent revision of the seizure classification by the International League Against Epilepsy (ILAE). We provide updated seizure-related human phenotype ontology (HPO) terms to facilitate a deep phenotypic interpretation of heretofore unexplained genetic epilepsies. Methods The Epilepsiome project is a Task Force of the Genetics Commission of the ILAE and represent the link to the gene curation efforts within the ClinGen Epilepsy Clinical Domain Working Group (CDWG). Within the efforts to align terminology used in the diagnostic space, the Epilepsiome Project revised HPO terms for epileptic seizures. The updated classification was built through an online portal and consensus was achieved through biweekly conference calls. Results Focal, generalised and neonatal HPO seizure terminologies were constructed according to the most recent ILAE classification and aligned with the existing HPO structure. This ontology allows capture of clinical information at various levels of detail and aims to preserve the onset, awareness and motor/non-motor nature of each seizure type, using multiple parentages. We integrated other frequently observed seizures currently not included in the ILAE, which required a separate branch within the ontology due to biological peculiarity of their age of onset, their clinical significance or genetic architecture. Conclusions Improvements in HPO terms for epileptic seizures will enable a more versatile seizure ontology leading to deep phenotyping of people with epilepsy to improve associations with genomic data in both a research and diagnostic setting., Purpose Target5000 aims to genetically characterise approximately 5000 people in Ireland with an inherited retinal degeneration (IRD). Thus far, over 1,000 IRD patients have been sequenced for variants in 260 IRD genes. One arm of the project focuses on improving detection of candidate variants by whole genome sequencing (WGS), by analysing non-coding mutations and performing functional analysis. Approach IRD patients are clinically diagnosed by Target5000 ophthalmologists. When informed consent is given, the Target5000 study employs target capture next generation sequencing (NGS), with a positive candidate detection rate of 68%. To improve detection rates, whole-gene or WGS was employed on a case-dependent basis to identify pathogenic intronic variants not previously captured. Results One common form of IRD is ABCA4-associated Stargardt disease (STGD1), often caused by deep-intronic variants. Thus far, 36 ‘unresolved’ STGD1 and cone-rod dystrophy cases have undergone targeted ABCA4 whole-gene sequencing, positively identifying a candidate in ~50% of cases. A variant in intron 30 resulting in a pseudoexon inclusion was particularly frequent and found in 5/16 (likely) solved cases. Furthermore, 40 patient samples have undergone WGS. Conclusions An objective of Target5000 is to provide actionable outcomes empowering patients with genetic diagnoses and potentially future access to clinical trials or approved treatments, where appropriate. The results presented highlight the significant value of a target capture NGS strategy as a preliminary diagnostic measure, with remaining elusive cases undergoing more extensive genetic analysis. This methodology improves variant detection rates and progresses the goal of fully elucidating the genetic architecture of IRDs in Ireland., Background Copy Number Variants (CNVs) are large genomic deletions/duplications of >1kb, spanning regions that can encompass one or many genes. Though a common form of structural variation, pathogenic CNVs, of population freq., The Ladakhi people dwell in the Jammu and Kashmir regions of India, between the Karakoram and Himalayan mountain ranges, at ≥3400 meters altitude. The Ladakhi share similar linguistic, cultural and religious practices with Tibetans. However, relative to Tibetans, the Ladakhi are very poorly studied at the level of population structure and genetic selection. In this context, we set out to conduct a genomic survey of population structure in representative samples of the Ladakhi people. Methods We genotyped 310 Ladakhi DNA samples using the Illumina Global Screening Array gene chip. We merged the Ladakhi with data from 800 individuals representing different reference language groups including; Sino-Tibetan (Tibetans, Sherpa, Han), Indo-European (Indo-Aryan, Hazara), Austroasiatic (Munda) and Burusho (a linguistic isolate in Jammu-Kashmir). We performed ADMIXTURE, principal component analysis (PCA), fineSTRUCTURE and ChromoPainter analysis on the combined autosomal data. Results In PCA plots, the Ladakhi population cluster together with Sherpa and Tibetans, forming a distinct Himalayan group, different from other mainland populations of South and East Asia. ADMIXTURE analysis at k=4 suggests ancestry proportions in the Ladakhi to be approximately 50% Highlander (Tibetan/Sherpa) and 50% Indo-European. These results suggest contemporary Ladakhi people are the admixed of Tibetans and Indo-Europeans. Conclusions Our results suggests a considerable component of the Ladakhi genome descends from ancestral highlander populations residing on the Tibetan plateau for the last 35,000 years, with subsequent admixture with neighbouring Indo-European populations., Background The EU recognises rare disease (RD) as life threatening with delays in establishing a diagnosis and treatment. 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. Objective 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. Methods 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). In addition a detailed analysis of national death registration information for RDs from 2006-2016 was undertaken along with a 2year study (2015-2016) of inpatient RD deaths. Results There were 54,789 livebirths in 2000. Genetics records identified 801 cases of RDs Ongoing HIPE searches identified 1381 cases. Mortality data revealed that of all deaths on the Register (2006-2016), (n=4044) aged 0-14, 58.56% (n=2368) had a RD diagnosis with age distribution; Neonates, 56% (1140/2050), Post-neonates, 58% (450/778), Children aged 1-14 years, 64% (778/1216). Of the total (n=234) inpatient deaths with a RD from 2015-2016, 52.6% (n=123) were cared for at the two major centres. Conclusion This study to-date has identified > 2,200 RD patients presenting by age 17 giving a minimum incidence of 4% for paediatric RDs. We expect the final figure to be higher when we complete analysis of all the HIPE and sub-specialty data from these major centres., Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease. ADPKD is primarily caused by variants in PKD1 and PKD2. Sequencing of PKD1 is difficult due to multiple pseudogenes. There is unexplained variance in the age-of-onset of PKD, even within families. Aim 1) Establish a targeted NGS panel to improve molecular diagnosis of PKD and 2) characterize large ‘super-families’ for the study of new ADPKD genes and genetic modifiers. Methods NGS was performed using a custom Roche SeqCap targeted panel (273 genes) and Illumina NextSeq. Bioinformatics was performed using an in-house GATK pipeline. Pathogenicity was assigned using American College of Medical Genetics and Genomics guidelines and Mayo Clinic PKD in-house methods. Gap-filling Sanger sequencing was utilized in unsolved cases Results 172 PKD patients were sequenced with average coverage 189X. A molecular diagnosis meeting pathogenicity criteria was obtained in 82% (141/172) of patients following gap-filling Sanger of PKD1 and PKD2 (n=41). 46 of the PKD-causing variants we detected were novel. We identified 13 rare, diagnostic PKD variants shared across multiple affected individuals recorded clinically as having no known familial relationship. Second-degree relatedness was confirmed via clinical follow-up. These families form the basis for the assembly of PKD ‘super-families’. Conclusions NGS is suitable for sequencing of PKD genes including PKD1, although some gap filling by Sanger is required for complete coverage. We have identified 13 potential ADPKD ‘super-families’ using genomic data for further study. These results are improving diagnostics of ADPKD in the Irish renal clinic., Purpose Target5000 is a genetic study to detect and characterise variants associated with inherited retinal degenerations (IRD). Choroideremia is an X-Linked recessive chorioretinal degenerative condition with progressive atrophy of several key cells of the retina and the surrounding blood retinal barrier. Here we describe a novel deletion in the CHM gene found in two Irish pedigrees. This 500kb deletion represents the largest yet detected IRD-associated deletion in Ireland. Approach As part of the Irish IRD registry, Target5000, patients with inherited retinal degenerative conditions are recruited. Target capture sequencing was employed to investigate variation in 254 IRD-associated genes. Upon detection of the deletion in CHM, PCR analysis was used to elucidate the full extent of the deletion. Results Two members of a large X-linked Retinitis Pigmentosa pedigree clinically presented with choroideremia and tested negative for the segregating RPGR variant found in other affected members of this pedigree. Both males were sequenced and found to possess large deletions spanning the CHM gene, totalling 500kb. This deletion has also been detected in a second Irish pedigree since its discovery. Two additional males and two carrier females from this second pedigree were all found to be severely affected with progressive choroideremia. Conclusions Typically, female carriers of CHM mutations show mild stationary signs with no symptoms, while males are severely affected. In this instance, females were more severely affected than expected with advanced signs of degeneration and progressive visual decline. This is possibly due to random X-inactivation and the severity of CHM gene deletion., Introduction The largest cohort of patients at The National Centre for Adult Inherited Metabolic Disorders (NCIMD) have Phenylketonuria (PKU). The NCIMD manages patients transitioned from Paediatric services upon reaching adulthood. Improved treatments have extended life expectancy and increased quality of life for patients with PKU; however diet and supplements remained the only means of treatment for life until the recent introduction of Sapropterin dihydrochloride. Aim To analyse the genotype of the PKU cohort in attendance at The NCIMD with a focus on responsiveness to Sapropterin dihydrochloride. Method The data are collated from when the Adult unit was first established in 2013 until the end of May 2019. Exclusion criteria include patients over the age of 53 and patients who have two negatively indicated genotypes for the use of Sapropterin dihydrochloride. Genotypes are recorded in a secured database onsite and descriptive analyses were performed. Results The total number of patients examined is 282; 104 were male (36.8%) and 178 were female (63.1%). The total samples processed and available for analysis were 148 (male= 46, 31%; female= 102, 68.9%). The frequency of Saptopterin dihydrochloride responsiveness in both alleles was observed (responsive= 15, 10%; unresponsive= 48, 48.33%; uncertain= 85, 57%). The most common alleles recorded were R408W (41.1%), F39L (13.8%), 165T (11.2%), and L249F (3.8%). Conclusion Due to the uncertainty surrounding Sapropterin dihydrochloride responsiveness for various common mutations in the Irish PKU cohort, there is a need for greater genetic and metabolic collaboration. Analysis and treatment may be impacted by time elapsed from sending samples to receiving results., Introduction The Department of Clinical Genetics at CHI provides services for individuals affected by or at risk of a genetic condition in the Republic of Ireland. There are currently 3,283 referrals waiting to be seen, of whom 930 are waiting longer that the HSE standard of 18 months. A negative consequence of a long waiting list is that patients die whilst waiting. Resulting harm includes: 1) no diagnosis 2) no genetic testing, no DNA stored, 3) family unaware of a hereditary disorder, denied screening, 4) relatives having unnecessary screening as no predictive test for family, 5) future pregnancy options limited if paediatric proband undiagnosed. As of 13/06/2019, we have recorded 33 deaths on our waiting list. We began to systematically collect data on deaths since March 2018. This study concentrates on these cases; n=15/33. Aims To identify the consequences to the relatives of these 15 referrals. Results Nine were adult cancer genetic referrals, 5/9 diagnostic, 3/9 predictive, and a further case had NF2. Only 1/9 had DNA stored. Two adult patients had a cardiac family history (Marfan syndrome, cardiomyopathy) respectively. Neither had DNA stored. Four paediatric patients had multiple malformations secondary to a chromosomal or genetic syndrome. In 3/4 a diagnosis had already been reached. The fourth case, who died unexpectedly of unrelated causes, had no DNA stored. Summary 11/15 patients who died did not have DNA stored, precluding diagnosis and risk calculation for their relatives. As each extended 3 generation Irish family has ~64 relatives, lack of diagnosis has far reaching consequences., Background Women who carry a pathogenic variant in either a BRCA1 or BRCA2 gene have a high lifetime risk of developing breast and tubo-ovarian cancer. To manage this risk, women may choose to undergo risk-reducing surgery to remove breast tissue, ovaries and fallopian tubes. Surgery should increase survival, but can impact women’s lives adversely at a psychological and psychosexual level. Interventions to facilitate psychological adjustment and improve quality of life post risk-reducing surgery are needed. Aim of Review To examine psychosocial interventions in female BRCA carriers who have undergone risk-reducing surgery and to evaluate the effectiveness of such interventions on psychological adjustment and quality of life. Methods We searched the Cochrane Central Register of Controlled trials (CENTRAL) in the Cochrane Library, MEDLINE via Ovid, Embase via Ovid, CINAHL, PsycINFO, Web of Science and Scopus up to April 2019. Results We identified two studies; one randomised controlled trial and one nonrandomised study. Conclusions The effect of psychosocial interventions on quality of life and emotional well-being in female BRCA carriers who undergo risk-reducing surgery is uncertain given limited high quality evidence. Next Generation Sequencing, along with targeted cancer treatments, increasing knowledge around the biology of cancers and the results of the 100K Genome Project will open up genetic testing to many more women. For as long as surgical interventions remain the dominant risk-reducing option for management of women with a deleterious BRCA gene, health professionals have a responsibility to ensure there is provision to holistically manage the outcomes of such surgery., Introduction FATCO (Fibular Aplasia, Tibial Campomelia and Oligosyndactyly) syndrome is a rare descriptive diagnosis first defined by Courtens et al. in 2005, who recognised a comparable pattern of malformations with his own case and 4 others described in the literature. Aetiology remains unknown, however defects involved in SHH (Sonic hedgehog) gene expression have been proposed. Case Description We report on a term male infant born with severe malformations. On examination, there was absence of the left radius and ulna, bilateral anterior angulation of lower limbs with skin dimpling overlying. Both ankle joints were dysplastic and there was oligosyndactly of both feet. Right upper limb was normal. X-rays of the limbs revealed dysplastic tibiae, absence of both fibulae, a right foot containing 3 ossified metatarsals with 2 formed digits, and a left foot with a single ossified metatarsal and two soft tissue digits with small bony elements. The infant had no other associated anomalies, and is developmentally appropriate at 1 year. Management included Symes amputation, prosthetics and following genetic referral FATCO syndrome was suggested as the best fitting diagnosis. Whole genome sequencing of the infants blood is currently being performed. Discussion This is an important case to report as there are very few descriptions in the literature, In keeping with the majority of reports, this case appears to be sporadic and development is normal. Our case is male, keeping with preponderance. Treatment aims at optimising functionality of limbs and stabilisations of joints., Introduction Fibrous cephalic plaques (FCP) are a characteristic manifestation of tuberous sclerosis complex (TSC) and occur in one third of cases. Their natural history and long term course is unknown, as is the outcome of long term follow-up of TSC cases in old age. Phenotype and methods We describe an 80 year old with TSC due to a c.2784dupC TSC2 mutation, who was diagnosed in infancy with an FCP and was regularly followed up at the TSC clinic over 8 decades with regular epilepsy treatment and renal monitoring. Results Regular clinical photography and clinical records document the plaque at different ages. The FCP naturally resolved at 74 years. Facial angiofibromas also faded with time in the last decade. His epilepsy and renal abnormalities remained under control with careful surveillance and monitoring. Discussion Natural aging in the eighth decade causes progressive laxity of collagen and leads to natural resolution of FCPs. This novel finding with a unique 80 year follow up yields valuable insights into the aging changes within FCPs and facial angiofibromas as the pathways linking facial angiofibromas and FCP’s through the TGF-β1 pathway are now being elucidated. Conclusion We present a clinical odyssey showing the natural progression and history of FCPs in TSC and comment on the mechanistic pathways allowing potential interventions in this disfiguring condition. TSC cases can be successfully managed and complications – particularly in the brain and kidney, can be avoided over an entire lifetime. This is encouraging for long term prospects for patients with TSC., Introduction Fabry disease is an X-linked inherited disorder due to deficient activity of the enzyme alpha-galactosidase A and progressive lysosomal deposition of globotriaosylceramide in cells. Aim To report the genotype/phenotype landscape of the adult Fabry disease cohort attending The National Centre for Adult Inherited Metabolic Disorders (NCIMD). Method All Fabry patients (N=70) attending NCIMD until end of May 2019 were included in this analysis. Genotypes and phenotypes were recorded by chart review. Descriptive analyses were performed. Result 26 (37.1%) were male (median age 43 [32:54]) and 44 (62.9%) were female (median age 46 [25:61]). The AGAL pathogenic variants were missense (52, 74.3%), deletion (9, 12.9%), nonsense (8, 11.4%) and duplication (1, 1.4%). Most missense variants occurred in exon 2 (25%), exon 3 (19.2%), exon 5 (23.1%) and exon 6 (21.2%). 21.2% of missense variants were N215S. 28 patients were on enzyme therapy and 2 were on oral chaperone therapy. The incidence of cardiac (M=18/26; F=18/44; p=0.021), renal (M=14/26; F=18/44; p=0.304), neurological (M=17/26; F=20/44; p=0.107) and hearing (M=14/26; F=19/44; p=0.399) involvement were observed. Within N215S cohort, 2 had hypertrophic cardiomyopathy and 5 with a degree of left ventricular hypertrophy. Conclusion Pathogenic variants were observed across the AGAL gene in the cohort. Incidence of cardiac involvement in both genders is similar. Females had more frequently observed renal, neurological and hearing involvement. N215S AGAL variant is the most common variant which is associated with a predominant cardiac phenotype, thus collaboration between clinical geneticists and cardiovascular physicians are important when establishing diagnosis and management., Background Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease with a worldwide prevalence of 1:500. Genetic etiology is suspected in up to 50% of HCM patients. To gain insight into the diagnostic yield and mutation spectrum of HCM, a retrospective review was performed for 114 consecutive cases with a clinical suspicion of HCM who underwent multigene panel testing at our laboratory between 2014 and 2019. Method Data was manually extracted from laboratory reports with respect to indication for testing, number of genes on panel, variants identified and classification at the time of testing. Results A total of 114 patients with a diagnosis of HCM had samples submitted for diagnostic testing using a multigene panel of between 16 and 20 genes, depending on the year of testing. 56 patients had no genetic variant identified, 33 patients had a pathogenic or likely pathogenic variant identified and 25 had a variant of uncertain significance identified. One 11 year old patient had a normal result from an 18 gene panel for HCM, but was later diagnosed with Friedrich ataxia. One adult female patient had a normal result from a 19 gene panel but was later diagnosed with Fabry disease. Conclusion Clinically actionable ‘Pathogenic’ or ‘Likely pathogenic’ variants were identified in 29% of patients with a Clinical diagnosis of Hypertrophic Cardiomyopathy with VUS being identified in 22%. The most common 2 genes in which clinically actionable variants were found were MYH7 (47%) and MYBPC3 (31%)., Huntington’s disease (HD) is an inherited progressive neurodegenerative condition. In the Republic of Ireland genetic testing for HD is available via two routes. Symptomatic individuals can access testing via a Neurologist. Asymptomatic individuals with a known family history of HD can seek testing via a genetic counselling multi-step process. Aim The aim of the audit was to review the activity of the HD specialty clinic. Methods Retrospective chart, laboratory and clinical database review for HD referrals received for 2016, 2017 and 2018 was carried out. Parameters examined included: number of referrals, age profile, motivation for testing, results. Results Over this 3 year period 93 referrals were received. 80 referrals were for predictive testing and 13 for genetic counselling post testing through neurology. The youngest person was 18 years of age at time of referral. More females requested a referral for predictive testing than males, 48 (60%) and 32 (40%) respectfully. The most common motivation given for predictive testing was with regard to family planning and concerns for children and to help them plan for the future. Of the 30 tests carried out to date, 52% were mutation positive and 42% were mutation negative. The average age of those who proceeded with testing was 37yrs. Conclusion These findings reflect data published from the UK with regard to age of presentation and female to male bias. The most common motivation for testing was family planning unlike the UK where the most common reason provided was to reduce uncertainty.

Social relationship coping efficacy (SRCE) represents the ability to maintain or enhance social relationships in the context of serious illness. The purpose of the current study was to confirm the factor structure, psychometric properties, and utility of the Italian version of the SRCE scale.181 breast cancer patients completed the SRCE-Italian (SRCE-I), the Cancer Behavior Inventory-Brief/Italian (CBI-B/I), quality of life (QOL) measures (EORTC QLQ-C30; EORTC QLQ-BR23), and the Hospital Anxiety and Depression Scale (HADS).The SRCE-I was internally consistent (Cronbach alpha = .95) and factor analysis confirmed that the SRCE-I was a unidimensional construct. In terms of validity, the SRCE-I was correlated with QOL (EORTC QLQ-30, Social Functioning, r = .33, Emotional Functioning, r = .57, and Global Health/Quality of Life; r = .54) and scales of the EORTC QLQ-BR23 (e.g., Future Perspective, r = .38; Breast Symptoms, -.31). SRCE-I was also correlated negatively with the HADS (r = -.72) and positively with the CBI-B/I (r = .79), a measure of coping efficacy (all ps .001). Mediation analyses confirmed the utility of the SRCE-I scale as a mediating mechanism in enhancing social functioning and QOL.The SRCE-I is a structurally sound, reliable, and valid measure that assesses the ability to maintain or enhance social support and mitigate the loss of social support. The SRCE-I can be used as a screening measure to assess low efficacy for maintaining social support or as a measure to detect the change in efficacy for enhancing social support in interventions to improve the QOL of patients.