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An increasing number of individuals with intellectual developmental disorder (IDD) and heterozygous variants in BCL11A are identified, yet our knowledge of manifestations and mutational spectrum is lacking. To address this, we performed detailed analysis of 42 individuals with BCL11A-related IDD (BCL11A-IDD, a.k.a. Dias-Logan syndrome) ascertained through an international collaborative network, and reviewed 35 additional previously reported patients. Analysis of 77 affected individuals identified 60 unique disease-causing variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique BCL11A microdeletions. We define the most prevalent features of BCL11A-IDD: IDD, postnatal-onset microcephaly, hypotonia, behavioral abnormalities, autism spectrum disorder, and persistence of fetal hemoglobin (HbF), and identify autonomic dysregulation as new feature. BCL11A-IDD is distinguished from 2p16 microdeletion syndrome, which has a higher incidence of congenital anomalies. Our results underscore BCL11A as an important transcription factor in human hindbrain development, identifying a previously underrecognized phenotype of a small brainstem with a reduced pons/medulla ratio. Genotype-phenotype correlation revealed an isoform-dependent trend in severity of truncating variants: those affecting all isoforms are associated with higher frequency of hypotonia, and those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S), are associated with higher frequency of postnatal microcephaly. With the largest international cohort to date, this study highlights persistence of fetal hemoglobin as a consistent biomarker and hindbrain abnormalities as a common feature. It contributes significantly to our understanding of BCL11A-IDD through an extensive unbiased multi-center assessment, providing valuable insights for diagnosis, management and counselling, and into BCL11A's role in brain development., (© 2024. The Author(s).)

AIMSWERNER SYNDROME IS A RARE PREMATURE AGEING AUTOSOMAL RECESSIVE DISORDER CAUSED BY PATHOGENIC VARIANTS IN THE WRN GENE. PEOPLE WITH WERNER SYNDROME MAY DEVELOP DIABETES MELLITUS. CHRONIC FOOT ULCERATION IS SEEN, WITH SOME CHARACTERISTICS OVERLAPPING WITH DIABETIC FOOT DISEASE. HOWEVER, THE CLINICAL COURSE OF THE ULCERATION IS ATYPICAL OF DIABETIC FOOT DISEASE. WE PRESENT FOUR SIBLINGS FROM AN IRISH TRAVELLER FAMILY WITH WERNER SYNDROME TO HIGHLIGHT THE COMPLEXITY OF THIS CONDITION. THE IRISH TRAVELLER POPULATION ARE AN INDIGENOUS, ENDOGAMOUS POPULATION IN WHICH CONSANGUINITY IS COMMON. AS A RESULT, RARE AUTOSOMAL RECESSIVE DISORDERS ARE PREVALENT AMONG THIS POPULATION: ., Methods: We describe our experience managing the complex foot disease seen in all four siblings. Foot complications present in the siblings include painful peripheral neuropathy, chronic foor ulceration, underlying osteomyelitis and acral melanoma., Results: The cases are described individually, with a particular focus on the complex foot disease associated with the condition., Conclusions: Although the siblings attend a diabetic foot clinic, we suggest that the combination of clinical features seen in these cases is unique to Werner syndrome and warrants the title 'Werner Syndrome' (rather than 'Diabetic') foot., (© 2024 Diabetes UK.)

Translation elongation factor eEF1A2 constitutes the alpha subunit of the elongation factor-1 complex, responsible for the enzymatic binding of aminoacyl-tRNA to the ribosome. Since 2012, 21 pathogenic missense variants affecting EEF1A2 have been described in 42 individuals with a severe neurodevelopmental phenotype including epileptic encephalopathy and moderate to profound intellectual disability (ID), with neurological regression in some patients. Through international collaborative call, we collected 26 patients with EEF1A2 variants and compared them to the literature. Our cohort shows a significantly milder phenotype. 83% of the patients are walking (vs. 29% in the literature), and 84% of the patients have language skills (vs. 15%). Three of our patients do not have ID. Epilepsy is present in 63% (vs. 93%). Neurological examination shows a less severe phenotype with significantly less hypotonia (58% vs. 96%), and pyramidal signs (24% vs. 68%). Cognitive regression was noted in 4% (vs. 56% in the literature). Among individuals over 10 years, 56% disclosed neurocognitive regression, with a mean age of onset at 2 years. We describe 8 novel missense variants of EEF1A2. Modeling of the different amino-acid sites shows that the variants associated with a severe phenotype, and the majority of those associated with a moderate phenotype, cluster within the switch II region of the protein and thus may affect GTP exchange. In contrast, variants associated with milder phenotypes may impact secondary functions such as actin binding. We report the largest cohort of individuals with EEF1A2 variants thus far, allowing us to expand the phenotype spectrum and reveal genotype-phenotype correlations., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

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., (© 2024. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)

The International Rare Diseases Research Consortium (IRDiRC) Diagnostic Scientific Committee (DSC) is charged with discussion and contribution to progress on diagnostic aspects of the IRDiRC core mission. Specifically, IRDiRC goals include timely diagnosis, use of globally coordinated diagnostic pipelines, and assessing the impact of rare diseases on affected individuals. As part of this mission, the DSC endeavored to create a list of research priorities to achieve these goals. We present a discussion of those priorities along with aspects of current, global rare disease needs and opportunities that support our prioritization. In support of this discussion, we also provide clinical vignettes illustrating real-world examples of diagnostic challenges., (Copyright © 2024. Published by Elsevier Masson SAS.)

There is an emerging body of evidence showing that young patients, post haematopoietic stem cell transplantation (HSCT), can develop skeletal changes that mimic an osteochondrodysplasia process. The key discriminator is that these children have had otherwise normal growth and skeletal development before the therapeutic intervention (HSCT), typically for a haematological malignancy. Herein we present that case of a boy who underwent HSCT for Haemophagocytic Lymphohistiocytosis (HLH) aged 2 years. Following Intervention with HSCT this boy's growth has severely decelerated (stature less than 1st centile matched for age) and he has developed a spondyloepiphyseal dysplasia., (© 2024 Wiley Periodicals LLC.)

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) mediate fast excitatory neurotransmission in the brain. AMPARs form by homo- or heteromeric assembly of subunits encoded by the GRIA1-GRIA4 genes, of which only GRIA3 is X-chromosomal. Increasing numbers of GRIA3 missense variants are reported in patients with neurodevelopmental disorders (NDD), but only a few have been examined functionally. Here, we evaluated the impact on AMPAR function of one frameshift and 43 rare missense GRIA3 variants identified in patients with NDD by electrophysiological assays. Thirty-one variants alter receptor function and show loss-of-function or gain-of-function properties, whereas 13 appeared neutral. We collected detailed clinical data from 25 patients (from 23 families) harbouring 17 of these variants. All patients had global developmental impairment, mostly moderate (9/25) or severe (12/25). Twelve patients had seizures, including focal motor (6/12), unknown onset motor (4/12), focal impaired awareness (1/12), (atypical) absence (2/12), myoclonic (5/12) and generalized tonic-clonic (1/12) or atonic (1/12) seizures. The epilepsy syndrome was classified as developmental and epileptic encephalopathy in eight patients, developmental encephalopathy without seizures in 13 patients, and intellectual disability with epilepsy in four patients. Limb muscular hypotonia was reported in 13/25, and hypertonia in 10/25. Movement disorders were reported in 14/25, with hyperekplexia or non-epileptic erratic myoclonus being the most prevalent feature (8/25). Correlating receptor functional phenotype with clinical features revealed clinical features for GRIA3-associated NDDs and distinct NDD phenotypes for loss-of-function and gain-of-function variants. Gain-of-function variants were associated with more severe outcomes: patients were younger at the time of seizure onset (median age: 1 month), hypertonic and more often had movement disorders, including hyperekplexia. Patients with loss-of-function variants were older at the time of seizure onset (median age: 16 months), hypotonic and had sleeping disturbances. Loss-of-function and gain-of-function variants were disease-causing in both sexes but affected males often carried de novo or hemizygous loss-of-function variants inherited from healthy mothers, whereas affected females had mostly de novo heterozygous gain-of-function variants., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP 3 ) receptor type 1 (IP 3 R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood., Objectives: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy., Methods: Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction., Results: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP 3 -binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype-phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression., Conclusions: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Purpose: ATP2B2 encodes the variant-constrained plasma-membrane calcium-transporting ATPase-2, expressed in sensory ear cells and specialized neurons. ATP2B2/Atp2b2 variants were previously linked to isolated hearing loss in patients and neurodevelopmental deficits with ataxia in mice. We aimed to establish the association between ATP2B2 and human neurological disorders., Methods: Multinational case recruitment, scrutiny of trio-based genomics data, in silico analyses, and functional variant characterization were performed., Results: We assembled 7 individuals harboring rare, predicted deleterious heterozygous ATP2B2 variants. The alleles comprised 5 missense substitutions that affected evolutionarily conserved sites and 2 frameshift variants in the penultimate exon. For 6 variants, a de novo status was confirmed. Unlike described patients with hearing loss, the individuals displayed a spectrum of neurological abnormalities, ranging from ataxia with dystonic features to complex neurodevelopmental manifestations with intellectual disability, autism, and seizures. Two cases with recurrent amino-acid variation showed distinctive overlap with cerebellar atrophy-associated ataxia and epilepsy. In cell-based studies, all variants caused significant alterations in cytosolic calcium handling with both loss- and gain-of-function effects., Conclusion: Presentations in our series recapitulate key phenotypic aspects of Atp2b2-mouse models and underline the importance of precise calcium regulation for neurodevelopment and cerebellar function. Our study documents a role for ATP2B2 variants in causing heterogeneous neurodevelopmental and movement-disorder syndromes., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Irish Health Service objectives state that patients with rare diseases should have timely access to genomic diagnostics with appropriate pre and post-test counselling. However, waiting times for clinical genetics outpatient appointments, during the study period, were up to two years as staffing levels remain low. A targeted public online survey was conducted in January 2022 to capture the experiences of Rare Disease families trying to access genetic testing and clinical genetic clinics in the Irish Republic. Irish patients experience significant waiting times to access clinical genetic services and self-report anxiety and stress, related to delayed access to diagnosis, clarity around recurrence risk and follow-up management. This negatively impacts personal decisions around family planning, education and employment and has a significant impact on family members seeking clarity on their own risk. Mainstream genetic testing activity is significant. Families report concern over the competency of health care professionals arranging and delivering genetic results and delays in accessing clinical genetics expertise to take them through the clinical implications. Timely access to clinical genetics expertise is important to ensure families with rare diseases have an appropriate understanding of the medical and reproductive implications of a genetic diagnosis and access to relevant care pathways. A national framework to develop competency in genomic literacy for health-care professionals including a national genetic test directory may be beneficial. Clinical genetics teams require ongoing support and investment to ensure the delivery of a safe and effective service for Irish families with rare diseases., (© 2023. The Author(s).)

Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability syndrome caused by variants in the PHF6 gene. We ascertained 19 individuals from 15 families with likely pathogenic or pathogenic PHF6 variants (11 males and 8 females). One family had previously been reported. Six variants were novel. We analysed the clinical and genetic findings in our series and compared them with reported BFLS patients. Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity. Carrier female relatives of affected males were unaffected or had only mild symptoms. The phenotype of affected females with de novo variants overlapped with the males but included linear skin hyperpigmentation and a higher frequency of dental, retinal and cortical brain anomalies. Complications observed in our series included keloid scarring, digital fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and talipes. Our analysis highlighted sex-specific differences in PHF6 variant types and locations. Affected males often have missense variants or small in-frame deletions while affected females tend to have truncating variants or large deletions/duplications. Missense variants were found in a minority of affected females and clustered in the highly constrained PHD2 domain of PHF6. We propose recommendations for the evaluation and management of BFLS patients. These results further delineate and extend the genetic and phenotypic spectrum of BFLS., (© 2023. The Author(s).)

Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Termination is achieved through autophagic degradation or recycling of STING by retrograde Golgi-to-ER transport. Here, we identify the GTPase ADP-ribosylation factor 1 (ARF1) as a crucial negative regulator of cGAS-STING signalling. Heterozygous ARF1 missense mutations cause a previously unrecognized type I interferonopathy associated with enhanced IFN-stimulated gene expression. Disease-associated, GTPase-defective ARF1 increases cGAS-STING dependent type I IFN signalling in cell lines and primary patient cells. Mechanistically, mutated ARF1 perturbs mitochondrial morphology, causing cGAS activation by aberrant mitochondrial DNA release, and leads to accumulation of active STING at the Golgi/ERGIC due to defective retrograde transport. Our data show an unexpected dual role of ARF1 in maintaining cGAS-STING homeostasis, through promotion of mitochondrial integrity and STING recycling., (© 2023. Springer Nature Limited.)

Competing Interests: None declared

Background: Clinical genetics is an under-resourced service in the Republic of Ireland. There can be a number of avenues that lead to barriers in patient triage noted within the department., Aims: To evaluate the reasons for referral rejection in the triage pathway. To identify the time and cost implications., Methods: A retrospective analysis of rejected referrals consecutively triaged by one consultant was undertaken over an 18-month period. Calculation of costs used data from a previous study., Results: The consultant rejected 128/1581 (8.3%) of referrals. The rejection reasons included the following: 75% had not included the family/patient genetic report, 10% were conditions not accepted by our service, 8% redirected to other specialities, 3% given written advice in lieu of appointment and 4% for other reasons. Follow-up information was requested on 78% of rejected referrals. For 57% this was received; in 43% no response was received, and these cases remain closed. Median response time was 33 days. Of those who sent back appropriate information, 39% remain on waiting list, 50% attended OPD or were given appropriate advice, 5% did not attend and 4% had alternative follow-up pathways. The estimated time cost of rejected referrals equated to 88.5 h (59 h/year). Using this as our cost of rejection letter, it equated €11,878.4/year departmental cost., Conclusion: The majority of referrals are rejected for non-enclosure of patient genetic reports. Many referrals would have accepted to the waiting list if the appropriate report had been attached. This means patients at risk of genetic disorders are not accessing clinical services because the referrer is not providing the necessary information to allow triage. Active management of the waiting list via upfront letters is costly, with a 57% response rate. Should similar rejection rates exist in other specialities, we estimate this would equate to a cost of €2,714,214.40/year to the HSE., (© 2023. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)

HNRNPU encodes a multifunctional RNA-binding protein that plays critical roles in regulating pre-mRNA splicing, mRNA stability, and translation. Aberrant expression and dysregulation of HNRNPU have been implicated in various human diseases, including cancers and neurological disorders. We applied a next generation sequencing based assay (EPIC-NGS) to investigate genome-wide methylation profiling for >2 M CpGs for 7 individuals with a neurodevelopmental disorder associated with HNRNPU germline pathogenic loss-of-function variants. Compared to healthy individuals, 227 HNRNPU-associated differentially methylated positions were detected. Both hyper- and hypomethylation alterations were identified but the former predominated. The identification of a methylation episignature for HNRNPU-associated neurodevelopmental disorder (NDD) implicates HNPRNPU-related chromatin alterations in the aetiopathogenesis of this disorder and suggests that episignature profiling should have clinical utility as a predictor for the pathogenicity of HNRNPU variants of uncertain significance. The detection of a methylation episignaure for HNRNPU-associated NDD is consistent with a recent report of a methylation episignature for HNRNPK-associated NDD., (© 2023. The Author(s).)

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population., (© 2023 Wiley Periodicals LLC.)

POU3F3 variants cause developmental delay, behavioral problems, hypotonia and dysmorphic features. We investigated the phenotypic and genetic landscape, and genotype-phenotype correlations in individuals with POU3F3-related disorders. We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals. Trio exome sequencing or single exome sequencing followed by segregation analysis were performed in the novel cohort. Functional effects of missense variants were investigated with 3D protein modeling. We included 28 individuals (5 previously published) from 26 families carrying POU3F3 variants; 23 de novo and one inherited from an affected parent. Median age at study inclusion was 7.4 years. All had developmental delay mainly affecting speech, behavioral difficulties, psychiatric comorbidities and dysmorphisms. Additional features included gastrointestinal comorbidities, hearing loss, ophthalmological anomalies, epilepsy, sleep disturbances and joint hypermobility. Autism, hearing and eye comorbidities, dysmorphisms were more common in individuals with truncating variants, whereas epilepsy was only associated with missense variants. In silico structural modeling predicted that all (likely) pathogenic variants destabilize the DNA-binding region of POU3F3. Our study refined the phenotypic and genetic landscape of POU3F3-related disorders, it reports the functional properties of the identified pathogenic variants, and delineates some genotype-phenotype correlations., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and aims Being metabolically unhealthy (MU) is defined as having either hypertension, hyperlipidemia, type 2 diabetes mellitus/pre-diabetes, or fatty liver disease. We aimed to determine if MU was associated with severe COVID-19 pneumonia (severe disease). Methods We performed a single-center retrospective study between March 2020 and August 2021 for patients with overweight or obesity hospitalized with COVID-19 pneumonia. Logistic regression analysis was utilized to derive a risk score for severe disease. The accuracy of the model was assessed using the area under the receiver operating characteristic curve (AUROCC) and bootstrap resampling. Results A total of 334 of 450 patients hospitalized with COVID-19 pneumonia (74.2%) were MU. Patients who were MU had higher in-hospital mortality (10.5% vs. 2.6%) and longer length of hospitalization (median 6 vs. 4 days). MU was not associated with severe disease, p=0.311. On multivariable analysis, older age, male sex, and Asian race were associated with severe disease. Not being vaccinated was associated with doubled odds of severe disease. The AUROCC of the final model was 0.66 (95% CI: 0.60 to 0.71). The risk score at the lowest quintile had a 33.1% to 65.5% predicted risk and a 58.7% observed risk of severe disease, whereas, at the highest quintile, there was an 85.7% to 97.7% predicted risk and an 89.7% observed risk of severe disease. Conclusion Being MU was not a predictor of severe disease, even though mortality was higher despite having higher rates of vaccination. This risk score may help to predict severe disease in hospitalized patients with obesity or overweight. External validation is recommended., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Cortés et al.)

Triplication of chromosomal region 1p36.3 is a rare genomic rearrangement. In this report, we delineate the phenotypic spectrum associated with 1p36.3 triplications. We describe four patients with microtriplications of variable size, but with a strong phenotypic overlap, and compare them to previously described patients with an isolated triplication or duplication of this region. The 1p36.3 triplication syndrome is associated with a distinct phenotype, characterized by global developmental delay, moderate intellectual disability, seizures, behavioral problems, and specific facial dysmorphic features, including ptosis, hypertelorism, and arched eyebrows. The de novo occurrence of these microtriplications demonstrates the reduced reproductive fitness associated with this genotype, in contrast to 1p36.3 duplications which are mostly inherited and can be associated with similar facial features but with a less severe developmental phenotype. The shared triplicated region encompasses four disease-related genes of which GABRD and SKI are most likely to contribute to the phenotype., (© 2023 Wiley Periodicals LLC.)

Coupling light from a point source to a propagating mode is an important problem in nano-photonics and is essential for many applications in quantum optics. Circular "bullseye" cavities, consisting of concentric rings of alternating refractive index, are a promising technology that can achieve near-unity coupling into a first lens. Here we design a bullseye structure suitable for enhancing the emission from dye molecules, 2D materials and nano-diamonds positioned on the surface of these cavities. A periodic design of cavity, meeting the Bragg scattering condition, achieves a Purcell factor of 22.5 and collection efficiency of 80%. We also tackle the more challenging task of designing a cavity for coupling to a low numerical aperture fibre in the near field. Finally, using an iterative procedure, we study how the collection efficiency varies with apodised (non-periodic) rings., (© 2023. The Author(s).)

De novo truncating and splicing pathogenic variants in the Additional Sex Combs-Like 3 (ASXL3) gene are known to cause neurodevelopmental delay, intellectual disability, behavioral difficulties, hypotonia, feeding problems and characteristic facial features. We previously reported 45 patients with ASXL3-related disorder including three individuals with a familial variant. Here we report the detailed clinical and molecular characteristics of these three families with inherited ASXL3-related disorder. First, a father and son with c.2791&#95;2792del p.Gln931fs pathogenic variant. The second, a mother, daughter and son with c.4534C > T, p.Gln1512Ter pathogenic variant. The third, a mother and her daughter with c.4441dup, p.Leu1481fs maternally inherited pathogenic variant. This report demonstrates intrafamilial phenotypic heterogeneity and confirms heritability of ASXL3-related disorder., (© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Purpose: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported., Methods: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp)., Results: Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period., Conclusion: We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved.)

The Irish Traveller population are an endogamous, traditionally nomadic, Irish population. Irish Travellers practice consanguinity in the majority of marriages, thus resulting in a higher rate of rare autosomal recessive conditions within the population due to homozygous variants. Herein, we outline the clinical phenotypes associated with metabolic conditions seen in this population presenting in the neonatal period, infancy and childhood. Although Irish Travellers are traditionally based in Ireland and the UK, there are populations also living in mainland Europe and the USA. While there is generally an understanding amongst Irish paediatricians of the recessive conditions seen with this population in Ireland, they may be less commonly encountered abroad. It is important to consider a non-genetic aetiology alongside any consideration for a metabolic disorder., Conclusion: This paper acts as a comprehensive review of the metabolic conditions seen and provides a guide for the investigation of an Irish Traveller child with a suspected metabolic condition., What Is Known: • The Irish Traveller population are an endogenous population. • There are higher rates of inherited metabolic conditions in this population compared to the general population in Ireland., What Is New: • This paper is a comprehensive review of all known inherited metabolic conditions encountered in the Irish Traveller population., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Diploid triploid mosaicism (DTM) is a rare genetic condition where there is an extra haploid set of chromosomes in mosaic form. We describe an infant for whom DTM was detected antenatally through amniocentesis. Prenatal counselling suggested a guarded prognosis. The infant's phenotypic presentation and postnatal course reflect the varied presentation and prognosis associated with DTM. We highlight potential challenges in diagnosing DTM postnatally, with many having normal blood karyotype with 46 chromosomes., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Physiological condition can affect survival and reproductive success in seabirds. However, seabirds rarely show outward signs of poor physiological condition, making it difficult to identify and address issues before they result in population level impacts. We investigate physiological condition of breeding northern gannets (Morus bassanus) between years and nesting stages. Blood smears were used to quantify blood cell profiles indicative of chronic stress, infection, disease, and immunocompetence. No blood parasites were observed, but elevated Heterophil to Lymphocyte (H:L) ratios, eosinophils, and monocytes suggest higher prevalence of infection in some years. Chronic stress levels, indicated by high H:L ratio, were elevated in incubation and early chick-rearing compared to late chick-rearing, which coincided with poorer body condition in breeding birds. This study highlights the value of haematology as a tool for identifying changing patterns of health that may serve as an early indicator of breeding failure, overwintering mortality, and population declines., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Prolonged waiting lists increase costs as medical problems may become more expensive to fix. There are also hidden financial costs. Irish Clinical Genetic services have long out-patient waiting times. We noticed duplicate referrals (patients on the waiting list) being re-referred because the patient still had not been seen. These re-referrals waste consultant and administrative time, pose a clinical risk by distracting clinician time, and are costly to our health service., Methods: We prospectively collected duplicate referral data over a 3-month period (1 October 2020-31 January 2021) in order to estimate costs. We costed (1) referring consultant and administrative time; (2) stationary, postage, and storage cost; and (3) receiving consultant and administrative time processing these referrals., Results: We noted 82/986 (8%) referrals to our service over the trial period were duplicate. The mean length of time between first and duplicate referral was 306 days. In 35/82 (42.68%), a duplicate referral had already been received (e.g. 3rd or more referral for same patient). In total, we received 132 re-referral letters for 82 patients. Duplicate referrals changed triage outcome in 7/82 (8.54%) cases., Conclusion: National Treatment Purchase Fund data suggests that 271,560 patients are waiting > 12 months for both in- and out-patient public appointments on 1 January 2021. Assuming duplicate referrals are occurring across the Irish health system with equal frequency after 12 months of waiting (8% of total appointments), then we estimate a conservative cost of 757,392 € per quarter to the health service and an annual cost to the HSE of 3,029,568 €., (© 2021. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)

Purpose: Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants., Methods: We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants through in silico analyses and cell-based experiments., Results: We identified 20 unique, mostly de novo, ANKRD11 missense variants in 29 individuals, presenting with syndromic neurodevelopmental disorders similar to KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in repression domain 2 at the ANKRD11 C-terminus. Of the 10 functionally studied missense variants, 6 reduced ANKRD11 stability. One variant caused decreased proteasome degradation and loss of ANKRD11 transcriptional activity., Conclusion: Our study indicates that pathogenic heterozygous ANKRD11 missense variants cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges because the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping., Competing Interests: Conflict of Interest H.Z.E. and K.G.M. are employees of GeneDx, Inc. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Parasite species richness is influenced by a range of drivers including host related factors (e.g. host size) and environmental factors (e.g. seawater temperature). However, identification of modulators of parasite species richness remains one of the great unanswered questions in ecology. The common cockle Cerastoderma edule is renowned for its diversity and abundance of parasites, yet drivers of parasite species richness in cockles have not been examined to investigate the association of both macro and microparasite communities. Using cockles as a model species, some of the key drivers of parasite prevalence and parasite species richness were investigated. Objectives of this 19-month survey were to determine the influence of the environment, host-parasite dynamics and parasite associations on parasite species richness and prevalence at two different geographic latitudes, chosen based on environmental differences. The highest parasite species richness was recorded in the northern sites, and this was potentially influenced by a range of interactions between the host, the pathogens and the environment. Parasite prevalence increased with host size and age, and parasite species richness increased with reduced salinity. A number of interactions between parasites, and between parasites and pathologies may be influencing parasite infection dynamics. New and concerning information is also presented regarding interactions between parasites and their environment. A number of parasites and potential pathogens (bacteria, Trichodina ciliates, metacercariae, trematode sporocysts) may be advantaged under climate change conditions (warming seas, increased precipitation), increasing disease incidence, which may prove detrimental not just for cockles, but for other bivalve species in the future., Competing Interests: The authors have declared that no competing interests exist.

Purpose: ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene., Methods: An international collaboration, exome sequencing, molecular modeling, yeast two-hybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants., Results: ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the DrosophilaZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function., Conclusion: We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability., Competing Interests: Conflict of Interest S.V.M., T.B.P., and M.J.G.S. are employees of GeneDx, Inc. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Monitoring of cold-water corals (CWCs) for pathogens and diseases is limited due to the environment, protected nature of the corals and their habitat and as well as the challenging and sampling effort required. It is recognised that environmental factors such as temperature and pH can expedite the ability of pathogens to cause diseases in cold-water corals therefore the characterisation of pathogen diversity, prevalence and associated pathologies is essential. The present study combined histology and polymerase chain reaction (PCR) diagnostic techniques to screen for two significant pathogen groups (bacteria of the genus Vibrio and the protozoan Haplosporidia) in the dominant NE Atlantic deep-water framework corals Lophelia pertusa (13 colonies) and Madrepora oculata (2 colonies) at three sampling locations (canyon head, south branch and the flank) in the Porcupine Bank Canyon (PBC), NE Atlantic. One M. oculata colony and four L. pertusa colonies were collected from both the canyon flank and the south branch whilst five L. pertusa colonies were collected from the canyon head. No pathogens were detected in the M. oculata samples. Neither histology nor PCR detected Vibrio spp. in L. pertusa, although Illumina technology used in this study to profile the CWCs microbiome, detected V. shilonii (0.03%) in a single L. pertusa individual, from the canyon head, that had also been screened in this study. A macroborer was observed at a prevalence of 0.07% at the canyon head only. Rickettsiales-like organisms (RLOs) were visualised with an overall prevalence of 40% and with a low intensity of 1 to 4 (RLO) colonies per individual polyp by histology. L. pertusa from the PBC canyon head had an RLO prevalence of 13.3% with the highest detection of 26.7% recorded in the south branch corals. Similarly, unidentified cells observed in L. pertusa from the south branch (20%) were more common than those observed in L. pertusa from the canyon head (6.7%). No RLOs or unidentified cells were observed in corals from the flank. Mean particulate organic matter concentration is highest in the south branch (2,612 μg l -1 ) followed by the canyon head (1,065 μg l -1 ) and lowest at the canyon flank (494 μg l -1 ). Although the route of pathogen entry and the impact of RLO infection on L. pertusa is unclear, particulate availability and the feeding strategies employed by the scleractinian corals may be influencing their exposure to pathogens. The absence of a pathogen in M. oculata may be attributed to the smaller number of colonies screened or the narrower diet in M. oculata compared to the unrestricted diet exhibited in L. pertusa, if ingestion is a route of entry for pathogen groups. The findings of this study also shed some light on how environmental conditions experienced by deep sea organisms and their life strategies may be limiting pathogen diversity and prevalence., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: None declared.

Aim: To estimate the prevalence, and evaluate presentation, treatment response, treatment side effects, and long-term seizure outcomes in all known cases of children with Down syndrome and infantile spasms on the island of Ireland., Method: This was a 10-year retrospective multicentre review of clinical records and investigations, focusing on treatment response, side effects, and long-term outcomes., Results: The prevalence of infantile spasms in Down syndrome was 3.0% during the study period. Fifty-four infants were identified with median age of spasm onset at 201 days (interquartile range [IQR] 156-242). Spasm cessation was achieved in 88% (n=46) at a median of 110 days (IQR 5-66). The most common first-line medications were prednisolone (n=20, 37%), vigabatrin (n=18, 33.3%), and sodium valproate (n=9, 16.7%). At follow-up (median age 23.7mo; IQR 13.4-40.6), 25% had ongoing seizures and 85% had developmental concerns. Treatment within 60 days did not correlate with spasm cessation. Seventeen children (31%) experienced medication side effects, with vigabatrin accounting for 52%., Interpretation: Prednisolone is an effective and well-tolerated medication for treating infantile spasms in Down syndrome. Despite the high percentage of spasm cessation, developmental concerns and ongoing seizures were common., (© 2022 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Background: Rare diseases (RDs) are often complex, serious, chronic and multi-systemic conditions, associated with physical, sensory and intellectual disability. Patients require follow-up management from multiple medical specialists and health and social care professionals involving a high level of integrated care, service coordination and specified care pathways., Methods and Objectives: This pilot study aimed to explore the best approach for developing national RD care pathways in the Irish healthcare system in the context of a lack of agreed methodology. Irish clinical specialists and patient/lived experience experts were asked to map existing practice against evidence-based clinical practice guidelines (CPGs) and best practice recommendations from the European Reference Networks (ERNs) to develop optimal care pathways. The study focused on the more prevalent, multisystemic rare conditions that require multidisciplinary care, services, supports and therapeutic interventions., Results: 29 rare conditions were selected across 18 ERNs, for care pathway development. Multidisciplinary input from multiple specialisms was relevant for all pathways. A high level of engagement was experienced from clinical leads and patient organisations. CPGs were identified for 26 of the conditions. Nurse specialist, Psychology, Medical Social Work and Database Manager roles were deemed essential for all care pathways. Access to the therapeutic Health Service Professionals: Physiotherapy, Occupational Therapy, and Speech and Language Therapy were seen as key requirements for holistic care. Genetic counselling was highlighted as a core discipline in 27 pathways demonstrating the importance of access to Clinical Genetics services for many people with RDs., Conclusions: This study proposes a methodology for Irish RD care pathway development, in collaboration with patient/service user advocates. Common RD patient needs and health care professional interventions across all pathways were identified. Key RD stakeholders have endorsed this national care pathway initiative. Future research focused on the implementation of such care pathways is a priority., (© 2022. The Author(s).)

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7., Competing Interests: Declaration of interests I.E.S. has served on scientific advisory boards for UCB, Eisai, GlaxoSmithKline, BioMarin, Nutricia, Rogcon, Chiesi, Encoded Therapeutics, Xenon Pharmaceuticals, and Knopp Biosciences; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, and Eisai; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, Biomarin and Eisai; has served as an investigator for Zogenix, Zynerba, Ultragenyx, GW Pharma, UCB, Eisai, Anavex Life Sciences, Ovid Therapeutics, Epygenyx, Encoded Therapeutics and Marinus; and has consulted for Zynerba Pharmaceuticals, Atheneum Partners, Ovid Therapeutics, Care Beyond Diagnosis, Epilepsy Consortium and UCB. She may accrue future revenue on pending patent WO2009/086591; her patent for SCN1A testing is held by Bionomics and is licensed to various diagnostic companies; and she has a patent for a molecular diagnostic/therapeutic target for benign familial infantile epilepsy (BFIE) (PRRT2), WO/2013/059884. She receives and/or has received research support from the National Health and Medical Research Council of Australia, Medical Research Future Fund, Health Research Council of New Zealand, CURE, Australian Epilepsy Research Fund, and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. J.P. is co-chief scientific officer for Global Gene Corp. All other authors declare no competing interests., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Global shipping facilitates the introduction of invasive species and parasites via ballast water and hull fouling. Regional management of invasives may be strengthened by identifying the major routes in a network, to allow for targeted ship inspections. This study used cargo shipping records to establish the connectivity of shipping routes between ports in Ireland and other nations. 9291 records were analysed, investigating vessel residence and journey times. On average, vessels spent up to five days in port and less than five days at sea. However, there was strong variation, with general cargo ships recording up to 13 days in port. A horizon scan for species likely to invade in Ireland was incorporated for five species and their associated parasites: American razor clam, Asian shore crab, Brush clawed shore crab, Chinese mitten crab and American slipper limpet. Routes of concern are highlighted and a general framework for effective management is outlined., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

PAX5 is a transcription factor associated with abnormal posterior midbrain and cerebellum development in mice. PAX5 is highly loss-of-function intolerant and missense constrained, and has been identified as a candidate gene for autism spectrum disorder (ASD). We describe 16 individuals from 12 families who carry deletions involving PAX5 and surrounding genes, de novo frameshift variants that are likely to trigger nonsense-mediated mRNA decay, a rare stop-gain variant, or missense variants that affect conserved amino acid residues. Four of these individuals were published previously but without detailed clinical descriptions. All these individuals have been diagnosed with one or more neurodevelopmental phenotypes including delayed developmental milestones (DD), intellectual disability (ID), and/or ASD. Seizures were documented in four individuals. No recurrent patterns of brain magnetic resonance imaging (MRI) findings, structural birth defects, or dysmorphic features were observed. Our findings suggest that PAX5 haploinsufficiency causes a neurodevelopmental disorder whose cardinal features include DD, variable ID, and/or ASD., (© 2022 Wiley Periodicals LLC.)

Recently, others and we identified de novo FBXO11 (F-Box only protein 11) variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data, our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs., (© The Author(s) 2021. Published by Oxford University Press.)