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SLC1A4 deficiency is a recently described neurodevelopmental disorder associated with microcephaly, global developmental delay, abnormal myelination, thin corpus callosum and seizures. It has been mainly reported in the Ashkenazi-Jewish population with affected individuals homozygous for the p.Glu256Lys variant. Exome sequencing performed in an Irish proband identified a novel homozygous nonsense SLC1A4 variant [p.Trp453*], confirming a second case of SLC1A4-associated infantile spasms. As this is the first European identified, population ancestry analysis of the Exome Aggregation Consortium database was performed to determine the wider ethnic background of SLC1A4 deficiency carriers. p.Glu256Lys was found in Hispanic and South Asian populations. Other potential disease-causing variants were also identified. Investigation for SLC1A4 deficiency should be performed regardless of ethnicity and extend to include unexplained early-onset epileptic encephalopathy.

TARP (talipes equinovarus, atrial septal defect (ASD), Robin sequence, persistent left superior vena cava) syndrome is a rare X-linked disorder affecting the RBM10 gene. It was previously viewed as universally fatal in the early neonatal period, however, recent cases have shown patients surviving beyond this stage. We present a male toddler diagnosed with TARP syndrome due to a a previously unreported splicing mutation c.2295+1G>A in the RBM10 gene. At birth, he had an ASD and Robin sequence, two of the eponymous features, as well as other associated phenotypic features. During infancy, he had an extremely high alpha-fetoprotein, conjugated hyperbilirubinaemia and thrombocytopaenia, features not previously described in TARP syndrome. We discuss these findings as well as our patient’s survival past the neonatal period with special consideration to recent genotype–phenotypes correlations.

Next generation sequencing provides an important opportunity for improved diagnosis in epilepsy. To date, the majority of diagnostic genetic testing is conducted in the paediatric arena, while the utility of such testing is less well understood in adults with epilepsy. We conducted whole exome sequencing (WES) and copy number variant analyses in an Irish cohort of 101 people with epilepsy and co-morbid intellectual disability to compare the diagnostic yield of genomic testing between adult and paediatric patients. Variant interpretation followed American College of Medical Genetics and Genomics (ACMG) guidelines. We demonstrate that WES, in combination with array-comparative genomic hybridisation, provides a diagnostic rate of 27% in unrelated adult epilepsy patients and 42% in unrelated paediatric patients. We observe a 2.7% rate of ACMG-defined incidental findings. Our findings indicate that WES has similar utility in both adult and paediatric cohorts and is appropriate for diagnostic testing in both epilepsy patient groups.

Journal club is a long-standing pedagogy within clinical practice and education. While journal clubs throughout the world traditionally follow an established format, new approaches have emerged in recent times, including learner-centred and digital approaches. Key factors to journal club success include an awareness of the learning goals of the target audience, judicious article selection and emphasis on promoting the engagement of participant learners. This article reviews the role that journal club plays in modern clinical education and considers how to optimise its benefit for contemporary learners.

Human induced pluripotent stem cells (hiPSCs) have been widely used in cardiac disease modelling, drug discovery, and regenerative medicine as they can be differentiated into patient-specific cardiomyocytes. Long QT syndrome type 3 (LQT3) is one of the more malignant congenital long QT syndrome (LQTS) variants with an SCN5A gain-of-function effect on the gated sodium channel. Moreover, the predominant pathogenic variants in LQTS genes are single nucleotide substitutions (missense) and small insertion/deletions (INDEL). CRISPR/Cas9 genome editing has been utilised to create isogenic hiPSCs to control for an identical genetic background and to isolate the pathogenicity of a single nucleotide change. In this study, we described an optimized and rapid protocol to introduce a heterozygous LQT3-specific variant into healthy control hiPSCs using ribonucleoprotein (RNP) and single-stranded oligonucleotide (ssODN). Based on this protocol, we successfully screened hiPSCs carrying a heterozygous LQT3 pathogenic variant ( SCN5A ± ) with high efficiency (6 out of 69) and confirmed no off-target effect, normal karyotype, high alkaline phosphatase activity, unaffected pluripotency, and in vitro embryonic body formation capacity within 2 weeks. In addition, we also provide protocols to robustly differentiate hiPSCs into cardiomyocytes and evaluate the electrophysiological characteristics using Multi-electrode Array. This protocol is also applicable to introduce and/or correct other disease-specific variants into hiPSCs for future pharmacological screening and gene therapeutic development. Graphical Abstract

Correspondence to Dr Eva B Forman, Department of Neurology and Neurophysiology, Temple Street Children’s University Hospital, Dublin, 1, Ireland; forman.eva@gmail.com Early onset epileptic encephalopathy (EOEE) presents in infancy and results in significant morbidity, disability and reduced life expectancy.1 The aetiology is heterogeneous and includes chromosomal abnormalities, single-gene disorders, structural brain malformations and inborn errors of metabolism. [...]a total of 758 tests were performed on this cohort. Furthermore, with less visits to hospital, the disruption to family life, missed school days, exposure to hospital acquired infection, parental absenteeism from work and cost to the families are significantly reduced.

Sydenham's chorea (SC) is characterised by chorea, emotional lability and hypotonia. In this study, we investigated the incidence and clinical presentation of childhood SC in Ireland (years 2006–2014). Nineteen cases were diagnosed. Five patients had rheumatic fever. An increasing trend with an incidence of 0.23/100 000 is reported. As most referral diagnoses included psychogenic illness, head injury and stroke, modern physicians may not be aware of this age old illness. A review of the manifestations and diagnosis of SC is presented.

[...]the neonatal transport service in the Republic of Ireland is lacking 24-h cover. [...]we carried out a survey to determine current practice regarding TH as well as opinion regarding development of a nationwide strategy. Units Level III Level II Overall response (%) 20 (100%) 8 (40%) 12 (60%) Responders practicing role Neonatologist 8 (40%) 7 (35%) 1 (5%) Paediatrician 11 (55%) - 11 Both 1 (5%) 1 - Delivery rates per annum 1000-3000 13 (65%) 1 12 3000-5000 2 (10%) 2 - 5000-10 000 5 (25%) 5 - Level of knowledge of TH (100% response) Aware of TH as therapy 20 (100%) 8 12 Felt it was effective 20 (100%) 8 12 Effect on mortality Effective enough to consider treatment 12 (60%) 5 7 Not effective 6 (30%) 3 3 More data needed 1 (5%) - 1 Don't know 1 (5%) - 1 Effect on neurological outcome Effective enough to consider treatment 17 (85%) 8 9 Very effective 1 (5%) 1 - More data needed 2 (10%) - 2 Experience and practice of Neonatal Unit Provide TH on-site 6 (30%) 6 - Local access to relevant investigations aEEG 5/6 5 - EEG 6/6 6 - Cerebral ultrasound 6/6 6 - MRI 6/6 6 - MRS 3/6 3 - Do not provide TH on-site 14 (70%) 2 12 Feel parents should know about potential benefit 14/14 2 12 Have definitive plan to transfer infants 4/14 1 3 Plan involves passive cooling 3/4 1 2 Do not have a definitive plan to transfer infants 10/14 1 9 Opinions relating to a national plan (100% response) TH can be realistically achieved for all eligible infants 15 (75%) 8 7 TH cannot be realistically achieved for all eligible infants 5 (25%) - 5 Feel there should be referral hospitals for infants affected 20 (100%) - - Support a central register for babies undergoing TH 20 (100%) - - aEEG, amplitude-integrated EEG; HIE, hypoxic ischaemic encephalopathy; MRI/S, magnetic resonance imaging/spectroscopy; TH, therapeutic hypothermia.

Purpose Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B -related syndrome based on characterizing an expanded patient cohort. Methods We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Results Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Conclusion Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B -related syndrome.