Publications by authors named "Sean Ennis"

58 Publications

NRXN1α is associated with increased excitability in ASD iPSC-derived neurons.

BMC Neurosci 2021 Sep 15;22(1):56. Epub 2021 Sep 15.

Trinity Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.

Background: NRXN1 deletions are identified as one of major rare risk factors for autism spectrum disorder (ASD) and other neurodevelopmental disorders. ASD has 30% co-morbidity with epilepsy, and the latter is associated with excessive neuronal firing. NRXN1 encodes hundreds of presynaptic neuro-adhesion proteins categorized as NRXN1α/β/γ. Previous studies on cultured cells show that the short NRXN1β primarily exerts excitation effect, whereas the long NRXN1α which is more commonly deleted in patients involves in both excitation and inhibition. However, patient-derived models are essential for understanding functional consequences of NRXN1α deletions in human neurons. We recently derived induced pluripotent stem cells (iPSCs) from five controls and three ASD patients carrying NRXN1α and showed increased calcium transients in patient neurons.

Methods: In this study we investigated the electrophysiological properties of iPSC-derived cortical neurons in control and ASD patients carrying NRXN1α using patch clamping. Whole genome RNA sequencing was carried out to further understand the potential underlying molecular mechanism.

Results: NRXN1α cortical neurons were shown to display larger sodium currents, higher AP amplitude and accelerated depolarization time. RNASeq analyses revealed transcriptomic changes with significant upregulation glutamatergic synapse and ion channels/transporter activity including voltage-gated potassium channels (GRIN1, GRIN3B, SLC17A6, CACNG3, CACNA1A, SHANK1), which are likely to couple with the increased excitability in NRXN1α cortical neurons.

Conclusions: Together with recent evidence of increased calcium transients, our results showed that human NRXN1α isoform deletions altered neuronal excitability and non-synaptic function, and NRXN1α patient iPSCs may be used as an ASD model for therapeutic development with calcium transients and excitability as readouts.
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http://dx.doi.org/10.1186/s12868-021-00661-0DOI Listing
September 2021

Rapid and Laboratory SARS-CoV-2 Antibody Testing in High-Risk Hospital Associated Cohorts of Unknown COVID-19 Exposure, a Validation and Epidemiological Study After the First Wave of the Pandemic.

Front Med (Lausanne) 2021 26;8:642318. Epub 2021 Aug 26.

Infectious Diseases Department, Mater Misericordiae University Hospital, Dublin, Ireland.

We aimed to use SARS-CoV-2 antibody tests to assess the asymptomatic seroprevalence of individuals in high-risk hospital cohorts who's previous COVID-19 exposure is unknown; staff, and patients requiring haemodialysis or chemotherapy after the first wave. In a single Center, study participants had five SARS-CoV-2 antibody tests done simultaneously; one rapid diagnostic test (RDT) (Superbio Colloidal Gold IgM/IgG), and four laboratory tests (Roche Elecsys® Anti-SARS-CoV-2 IgG [RE], Abbott Architect i2000SR IgG [AAr], Abbott Alinity IgG [AAl], and Abbott Architect IgM CMIA). To determine seroprevalence, only positive test results on laboratory assay were considered true positives. There were 157 participants, of whom 103 (65.6%) were female with a median age of 50 years (range 19-90). The IgG component of the RDT showed a high number of false positives ( = 18), was inferior to the laboratory assays ( < 0.001 RDT vs. AAl/AAr, < 0.001 RDT vs. RE), and had reduced specificity (85.5% vs. AAl/AAr, 87.2% vs. RE). Sero-concordance was 97.5% between IgG laboratory assays (RE vs. AAl/AAr). Specificity of the IgM component of the RDT compared to Abbott IgM CMIA was 95.4%. Ten participants had positivity in at least one laboratory assay, seven (9.9%) of which were seen in HCWs. Two (4.1%) hematology/oncology (H/O) patients and a single (2.7%) haemodialysis (HD) were asymptomatically seropositive. Asymptomatic seroprevalence of HCWs compared to patients was not significant ( = 0.105). HCWs (9.9%) had higher, although non-significant asymptomatic seroprevalence of SARS-CoV-2 antibodies compared to high-risk patients (H/O 4.1%, HD 2.7%). An IgM/IgG rapid diagnostic test was inferior to laboratory assays. Sero-concordance of 97.5% was found between IgG laboratory assays, RE vs. AAl/AAr.
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http://dx.doi.org/10.3389/fmed.2021.642318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427142PMC
August 2021

Rare Disease Research Partnership (RAinDRoP): a collaborative approach to identify research priorities for rare diseases in Ireland.

HRB Open Res 2020 11;3:13. Epub 2020 Nov 11.

UCD School of Nursing, Midwifery and Health Systems, University College Dublin, Belfield, County Dublin, D04 V1W8, Ireland.

Rare diseases are individually rare, but collectively these conditions are common. Research on rare diseases are currently focused on disease-specific needs rather than a life-course perspective. The Rare Disease Research Partnership (RAinDRoP) was established in 2018 to bring together a wide variety of diverse voices in the rare disease community in Ireland and form a research partnership. A participatory multiple phase approach was used to identify research priorities for rare diseases. The research process involved three main phases: Phase I, Public Consultation Survey(PCS); Phase II, Research Prioritisation Workshop (RPW); Phase III, Public Prioritisation Ranking Survey (PRS). The time frame for the entire study was from November 2018 to June 2019. In total, 240 individuals completed the phase I, of which only 96 survey participants provided information on their background,  32% (n=31) self-identified as a person living with a rare disease(s). One thousand and fifteen statements were collected, which reflected issues and shared challenges in rare diseases. MSExcel was used to gain frequencies and percentages. Phase II was focused on three main themes (1) Route to Diagnosis (2) Living with Rare Disease (3) Integrated and Palliative Care. 42 participants engaged at each workshop. Seventy-five individuals completed the phase III prioritisation ranking survey and ranked the top 15 research priorities.  The top five priorities were (1)Support at the time of diagnosis, (2) Diagnostic test for rare diseases (3)Education and training (4) Patient voice (5) Data sharing and integration of services for rare diseases. The research priorities identified here for rare diseases were developed jointly in collaboration with patients, families, healthcare professionals and policymakers. So, we encourage researchers, funding bodies and other stakeholders to use this priority list as a guiding document for future research work to improve the health and lives of people living with rare diseases.
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http://dx.doi.org/10.12688/hrbopenres.13017.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702160PMC
November 2020

The role of rare compound heterozygous events in autism spectrum disorder.

Transl Psychiatry 2020 06 22;10(1):204. Epub 2020 Jun 22.

Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

The identification of genetic variants underlying autism spectrum disorders (ASDs) may contribute to a better understanding of their underlying biology. To examine the possible role of a specific type of compound heterozygosity in ASD, namely, the occurrence of a deletion together with a functional nucleotide variant on the remaining allele, we sequenced 550 genes in 149 individuals with ASD and their deletion-transmitting parents. This approach allowed us to identify additional sequence variants occurring in the remaining allele of the deletion. Our main goal was to compare the rate of sequence variants in remaining alleles of deleted regions between probands and the deletion-transmitting parents. We also examined the predicted functional effect of the identified variants using Combined Annotation-Dependent Depletion (CADD) scores. The single nucleotide variant-deletion co-occurrence was observed in 13.4% of probands, compared with 8.1% of parents. The cumulative burden of sequence variants (n = 68) in pooled proband sequences was higher than the burden in pooled sequences from the deletion-transmitting parents (n = 41, X = 6.69, p = 0.0097). After filtering for those variants predicted to be most deleterious, we observed 21 of such variants in probands versus 8 in their deletion-transmitting parents (X = 5.82, p = 0.016). Finally, cumulative CADD scores conferred by these variants were significantly higher in probands than in deletion-transmitting parents (burden test, β = 0.13; p = 1.0 × 10). Our findings suggest that the compound heterozygosity described in the current study may be one of several mechanisms explaining variable penetrance of CNVs with known pathogenicity for ASD.
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http://dx.doi.org/10.1038/s41398-020-00866-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308334PMC
June 2020

Increased Ca signaling in neurons derived from ASD induced pluripotent stem cells.

Mol Autism 2019 30;10:52. Epub 2019 Dec 30.

1Regenerative Medicine Institute, School of Medicine, Biomedical Science Building BMS-1021, National University of Ireland Galway, Dangan, Upper Newcastle, Galway, Ireland.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a high co-morbidity of epilepsy and associated with hundreds of rare risk factors. deletion is among the commonest rare genetic factors shared by ASD, schizophrenia, intellectual disability, epilepsy, and developmental delay. However, how deletions lead to different clinical symptoms is unknown. Patient-derived cells are essential to investigate the functional consequences of lesions to human neurons in different diseases.

Methods: Skin biopsies were donated by five healthy donors and three ASD patients carrying deletions. Seven control and six iPSC lines were derived and differentiated into day 100 cortical excitatory neurons using dual SMAD inhibition. Calcium (Ca) imaging was performed using Fluo4-AM, and the properties of Ca transients were compared between two groups of neurons. Transcriptome analysis was carried out to undercover molecular pathways associated with neurons.

Results: neurons were found to display altered calcium dynamics, with significantly increased frequency, duration, and amplitude of Ca transients. Whole genome RNA sequencing also revealed altered ion transport and transporter activity, with upregulated voltage-gated calcium channels as one of the most significant pathways in neurons identified by STRING and GSEA analyses.

Conclusions: This is the first report to show that human neurons derived from ASD patients' iPSCs present novel phenotypes of upregulated VGCCs and increased Ca transients, which may facilitate the development of drug screening assays for the treatment of ASD.
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http://dx.doi.org/10.1186/s13229-019-0303-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937972PMC
June 2020

Genetic Associations with Aging Muscle: A Systematic Review.

Cells 2019 12 19;9(1). Epub 2019 Dec 19.

Institute for Sport and Health, University College Dublin, Dublin 4, Ireland.

The age-related decline in skeletal muscle mass, strength and function known as 'sarcopenia' is associated with multiple adverse health outcomes, including cardiovascular disease, stroke, functional disability and mortality. While skeletal muscle properties are known to be highly heritable, evidence regarding the specific genes underpinning this heritability is currently inconclusive. This review aimed to identify genetic variants known to be associated with muscle phenotypes relevant to sarcopenia. PubMed, Embase and Web of Science were systematically searched (from January 2004 to March 2019) using pre-defined search terms such as "aging", "sarcopenia", "skeletal muscle", "muscle strength" and "genetic association". Candidate gene association studies and genome wide association studies that examined the genetic association with muscle phenotypes in non-institutionalised adults aged ≥50 years were included. Fifty-four studies were included in the final analysis. Twenty-six genes and 88 DNA polymorphisms were analysed across the 54 studies. The , and genes were the most frequently studied, although the , , , and genes were also shown to be significantly associated with muscle phenotypes in two or more studies. Ten DNA polymorphisms (rs154410, rs2228570, rs1800169, rs3093059, rs1800629, rs1815739, rs1799752, rs7412, rs429358 and 192 bp allele) were significantly associated with muscle phenotypes in two or more studies. Through the identification of key gene variants, this review furthers the elucidation of genetic associations with muscle phenotypes associated with sarcopenia.
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http://dx.doi.org/10.3390/cells9010012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016601PMC
December 2019

Causing Complex Hereditary Spastic Paraplegia With Dysphonia: Expanding the Disease Spectrum.

J Child Neurol 2019 09 19;34(10):621. Epub 2019 May 19.

Department of Neurology and Neurophysiology, Children's University Hospital, Dublin, Ireland.

Herein we present two siblings with hereditary spastic paraplegia caused by novel compound heterozygous variant and deletion in and expansion of the disease spectrum to include dysphonia.
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http://dx.doi.org/10.1177/0883073819846805DOI Listing
September 2019

Author Correction: The Irish DNA Atlas: Revealing Fine-Scale Population Structure and History within Ireland.

Sci Rep 2018 May 3;8(1):7208. Epub 2018 May 3.

Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, St Stephen's Green, Dublin 2, Ireland.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-24846-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934401PMC
May 2018

Personalized Cardio-Metabolic Responses to an Anti-Inflammatory Nutrition Intervention in Obese Adolescents: A Randomized Controlled Crossover Trial.

Mol Nutr Food Res 2018 05;62(10):e1701008

Nutrigenomics Research Group, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, D04 N2E5, Ireland.

Scope: Chronic inflammation and hypoadiponectinemia are characteristics of obesity-induced insulin resistance (IR). The effect of an anti-inflammatory nutrition supplement (AINS) on IR and adiponectin biology in overweight adolescents was investigated. The secondary objective was to examine the extent to which individuals' biomarker profiles, derived from baseline phenotypes, predicted response or not to the AINS. Additionally, the impact of DNA methylation on intervention efficacy was assessed.

Methods And Results: Seventy overweight adolescents (13-18 years) were recruited to this randomized controlled crossover trial. Participants received an AINS (long chain n-3 PUFA, vitamin C, α-tocopherol, green tea extract, and lycopene) and placebo for 8 weeks each. Homeostatic model assessment (HOMA)-IR, adiponectin, inflammatory profiles, and DNA methylation were assessed. HOMA-IR was unchanged in the total cohort. High-molecular-weight (HMW) adiponectin was maintained following the AINS while it decreased over time following the placebo intervention. HOMA-IR decreased in 40% of subjects (responders) following the AINS. Responders' pretreatment phenotype was characterized by higher HOMA-IR, total and LDL cholesterol, but similar BMI in comparison to nonresponders. HMW adiponectin response to the AINS was associated with bidirectional modulation of adipogenic gene methylation.

Conclusion: The AINS modulated adiponectin biology, an early predictor of type 2 diabetes risk, was associated with bidirectional modulation of adipogenic gene methylation in weight-stable overweight adolescents. HOMA-IR decreased in a sub-cohort of adolescents with an adverse metabolic phenotype. Thus, suggesting that more stratified or personalized nutrition approaches may enhance efficacy of dietary interventions.
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http://dx.doi.org/10.1002/mnfr.201701008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079645PMC
May 2018

Catalogue of inherited disorders found among the Irish Traveller population.

J Med Genet 2018 04 22;55(4):233-239. Epub 2018 Jan 22.

Academic Centre on Rare Diseases, University College Dublin, Dublin, Republic of Ireland.

Irish Travellers are an endogamous, nomadic, ethnic minority population mostly resident on the island of Ireland with smaller populations in Europe and the USA. High levels of consanguinity result in many rare autosomal recessive disorders. Due to founder effects and endogamy, most recessive disorders are caused by specific homozygous mutations unique to this population. Key clinicians and scientists with experience in managing rare disorders seen in this population have developed a de facto advisory service on differential diagnoses to consider when faced with specific clinical scenarios. To catalogue all known inherited disorders found in the Irish Traveller population. We performed detailed literature and database searches to identify relevant publications and the disease mutations of known genetic disorders found in Irish Travellers. We identified 104 genetic disorders: 90 inherited in an autosomal recessive manner; 13 autosomal dominant and one a recurring chromosomal duplication. We have collated our experience of inherited disorders found in the Irish Traveller population to make it publically available through this publication to facilitate a targeted genetic approach to diagnostics in this ethnic group.
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http://dx.doi.org/10.1136/jmedgenet-2017-104974DOI Listing
April 2018

The Irish DNA Atlas: Revealing Fine-Scale Population Structure and History within Ireland.

Sci Rep 2017 12 8;7(1):17199. Epub 2017 Dec 8.

Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, St Stephen's Green, Dublin 2, Ireland.

The extent of population structure within Ireland is largely unknown, as is the impact of historical migrations. Here we illustrate fine-scale genetic structure across Ireland that follows geographic boundaries and present evidence of admixture events into Ireland. Utilising the 'Irish DNA Atlas', a cohort (n = 194) of Irish individuals with four generations of ancestry linked to specific regions in Ireland, in combination with 2,039 individuals from the Peoples of the British Isles dataset, we show that the Irish population can be divided in 10 distinct geographically stratified genetic clusters; seven of 'Gaelic' Irish ancestry, and three of shared Irish-British ancestry. In addition we observe a major genetic barrier to the north of Ireland in Ulster. Using a reference of 6,760 European individuals and two ancient Irish genomes, we demonstrate high levels of North-West French-like and West Norwegian-like ancestry within Ireland. We show that that our 'Gaelic' Irish clusters present homogenous levels of ancient Irish ancestries. We additionally detect admixture events that provide evidence of Norse-Viking gene flow into Ireland, and reflect the Ulster Plantations. Our work informs both on Irish history, as well as the study of Mendelian and complex disease genetics involving populations of Irish ancestry.
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http://dx.doi.org/10.1038/s41598-017-17124-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722868PMC
December 2017

Cost of exome sequencing in epileptic encephalopathy: is it 'worth it'?

Arch Dis Child 2018 Mar 22;103(3):304. Epub 2017 Sep 22.

Department of Neurology and Neurophysiology, Temple Street Children's University Hospital, Dublin, Ireland.

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http://dx.doi.org/10.1136/archdischild-2017-313240DOI Listing
March 2018

Novel SMC1A variant and epilepsy of infancy with migrating focal seizures: Expansion of the phenotype.

Epilepsia 2017 07;58(7):1301-1302

Department of Paediatric Neurology and Clinical Neurophysiology, Children's University Hospital, Dublin, Ireland.

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http://dx.doi.org/10.1111/epi.13794DOI Listing
July 2017

A novel gain-of-function mutation in the ITPR1 suppressor domain causes spinocerebellar ataxia with altered Ca signal patterns.

J Neurol 2017 Jul 15;264(7):1444-1453. Epub 2017 Jun 15.

Clinical Genetics, Temple Street Children's University Hospital, Dublin 1, Ireland.

We report three affected members, a mother and her two children, of a non-consanguineous Irish family who presented with a suspected autosomal dominant spinocerebellar ataxia characterized by early motor delay, poor coordination, gait ataxia, and dysarthria. Whole exome sequencing identified a novel missense variant (c.106C>T; p.[Arg36Cys]) in the suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor gene (ITPR1) as the cause of the disorder, resulting in a molecular diagnosis of spinocerebellar ataxia type 29. In the absence of grandparental DNA, microsatellite genotyping of healthy family members was used to confirm the de novo status of the ITPR1 variant in the affected mother, which supported pathogenicity. The Arg36Cys variant exhibited a significantly higher IP-binding affinity than wild-type (WT) ITPR1 and drastically changed the property of the intracellular Ca signal from a transient to a sigmoidal pattern, supporting a gain-of-function disease mechanism. To date, ITPR1 mutation has been associated with a loss-of-function effect, likely due to reduced Ca release. This is the first gain-of-function mechanism to be associated with ITPR1-related SCA29, providing novel insights into how enhanced Ca release can also contribute to the pathogenesis of this neurological disorder.
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http://dx.doi.org/10.1007/s00415-017-8545-5DOI Listing
July 2017

Genomic insights into the population structure and history of the Irish Travellers.

Sci Rep 2017 02 9;7:42187. Epub 2017 Feb 9.

Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, St Stephen's Green, Dublin 2, Ireland.

The Irish Travellers are a population with a history of nomadism; consanguineous unions are common and they are socially isolated from the surrounding, 'settled' Irish people. Low-resolution genetic analysis suggests a common Irish origin between the settled and the Traveller populations. What is not known, however, is the extent of population structure within the Irish Travellers, the time of divergence from the general Irish population, or the extent of autozygosity. Using a sample of 50 Irish Travellers, 143 European Roma, 2232 settled Irish, 2039 British and 6255 European or world-wide individuals, we demonstrate evidence for population substructure within the Irish Traveller population, and estimate a time of divergence before the Great Famine of 1845-1852. We quantify the high levels of autozygosity, which are comparable to levels previously described in Orcadian 1/2 cousin offspring, and finally show the Irish Traveller population has no particular genetic links to the European Roma. The levels of autozygosity and distinct Irish origins have implications for disease mapping within Ireland, while the population structure and divergence inform on social history.
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http://dx.doi.org/10.1038/srep42187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299991PMC
February 2017

Intra-familial variability associated with recessive RYR1 mutation diagnosed prenatally by exome sequencing.

Prenat Diagn 2016 Nov 2;36(11):1020-1026. Epub 2016 Oct 2.

Clinical Genetics, Temple Street Children's University Hospital, Dublin, Ireland.

Objective: To determine the underlying molecular aetiology in a non-consanguineous Irish family who have had three fetal losses because of a primary myopathy characterised by fetal akinesia, arthrogryposis multiplex, bilateral pulmonary hypoplasia and reduced muscle bulk.

Methods: Fetal DNA extracted from amniotic cells was whole genome amplified and subjected to whole exome sequencing.

Results: Whole exome sequencing identified compound heterozygous variants in RYR1 as the cause of the lethal myopathy in this family. All three fetuses were compound heterozygous for a paternally inherited missense variant (c.2113G > A; p.Gly705Arg) and a novel maternally inherited truncating frameshift deletion (c.8843delC; p.Ser2948Cysfs*58). This family did not have the classic cores and fibre type disproportion typically associated with RYR1 mutation. The RYR1 exome finding was made during the couple's third pregnancy and enabled prenatal genetic testing to be undertaken.

Conclusion: We show that recessive RYR1 mutations can be associated with significant intra-familial variability in clinical presentation which can complicate prediction of clinical outcome. RYR1 mutations can also cause diverse muscle pathologies which thwarts diagnosis. This study demonstrates the impact that exome-based diagnoses can have for families with lethal disorders. © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/pd.4925DOI Listing
November 2016

Atypical benign partial epilepsy of childhood with acquired neurocognitive, lexical semantic, and autistic spectrum disorder.

Epilepsy Behav Case Rep 2016 23;6:42-8. Epub 2016 Apr 23.

Department of Paediatric Neurology and Clinical Neurophysiology, Temple Street Children's University Hospital, Dublin 1, Ireland; Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Ireland.

Atypical benign partial epilepsy (ABPE) of childhood or pseudo-Lennox syndrome is a form of idiopathic focal epilepsy characterized by multiple seizure types, focal and/or generalized epileptiform discharges, continuous spike-wave during sleep (CSWS), and sometimes reversible neurocognitive deficits. There are few reported cases of ABPE describing detailed correlative longitudinal follow-up of the various associated neurocognitive, language, social communicative, or motor deficits, in parallel with the epilepsy. Furthermore, the molecular inheritance pattern for ABPE and the wider spectrum of epilepsy aphasia disorders have yet to be fully elucidated. We describe the phenotype-genotype study of a boy with ABPE with follow-up from ages 5 to 13 years showing acquired oromotor and, later, a specific lexical semantic and pervasive developmental disorder. Exome sequencing identified variants in SCN9A, CPA6, and SCNM1. A direct role of the epilepsy in the pathogenesis of the oromotor and neurocognitive deficits is apparent.
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http://dx.doi.org/10.1016/j.ebcr.2016.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969243PMC
August 2016

Beaulieu-Boycott-Innes syndrome: an intellectual disability syndrome with characteristic facies.

Clin Dysmorphol 2016 Oct;25(4):146-51

aDepartment of Clinical Genetics bNational Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital cUCD Academic Centre on Rare Diseases, School of Medicine and Medical Sciences, University College Dublin dDepartment of Clinical Genetics, Our Lady's Children's Hospital, Dublin eNorthern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK.

We report a female child from an Irish Traveller family presenting with severe intellectual disability, dysmorphic features, renal anomalies, dental caries and cyclical vomiting. Current health issues include global developmental delay, mild concentric left ventricular hypertrophy, dental malocclusion and caries and a single duplex left kidney. The proband and her mother also have multiple epiphyseal dysplasia. Whole-exome sequencing was performed to identify the underlying genetic cause. DNA from the proband was enriched with the Agilent Sure Select v5 Exon array and sequenced on an Illumina HiSeq. Rare homozygous variants were prioritized. Whole-exome sequencing identified three linked homozygous missense variants in THOC6 (c.298T>A, p.Trp100Arg; c.700G>C, p.Val234Leu; c.824G>A, p.Gly275Asp) as the likely cause of this child's intellectual disability syndrome, resulting in a molecular diagnosis of Beaulieu-Boycott-Innes syndrome (BBIS). This is the first report of BBIS in Europe. BBIS has been reported previously in two Hutterite families and one Saudi family. A review of all patients to date shows a relatively homogenous phenotype. Core clinical features include low birth weight with subsequent growth failure, short stature, intellectual disability with language delay, characteristic facies, renal anomalies and dental malocclusion with caries. Some patients also have cardiac defects. All patients show characteristic dysmorphic facial features including a tall forehead with high anterior hairline and deep-set eyes with upslanting palpebral fissures. The coexistence of intellectual disability together with these characteristic facies should provide a diagnostic clue for BBIS during patient evaluation.
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http://dx.doi.org/10.1097/MCD.0000000000000134DOI Listing
October 2016

Novel European SLC1A4 variant: infantile spasms and population ancestry analysis.

J Hum Genet 2016 Aug 19;61(8):761-4. Epub 2016 May 19.

Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.

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.
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http://dx.doi.org/10.1038/jhg.2016.44DOI Listing
August 2016

Recessive NEK9 mutation causes a lethal skeletal dysplasia with evidence of cell cycle and ciliary defects.

Hum Mol Genet 2016 05 21;25(9):1824-35. Epub 2016 Feb 21.

Clinical Genetics, Children's University Hospital, Temple Street, Dublin 1, Ireland, UCD Academic Centre on Rare Diseases, School of Medicine and Medical Sciences.

Skeletal dysplasias are a clinically and genetically heterogeneous group of bone and cartilage disorders. Whilst >450 skeletal dysplasias have been reported, 30% are genetically uncharacterized. We report two Irish Traveller families with a previously undescribed lethal skeletal dysplasia characterized by fetal akinesia, shortening of all long bones, multiple contractures, rib anomalies, thoracic dysplasia, pulmonary hypoplasia and protruding abdomen. Single nucleotide polymorphism homozygosity mapping and whole exome sequencing identified a novel homozygous stop-gain mutation in NEK9 (c.1489C>T; p.Arg497*) as the cause of this disorder. NEK9 encodes a never in mitosis gene A-related kinase involved in regulating spindle organization, chromosome alignment, cytokinesis and cell cycle progression. This is the first disorder to be associated with NEK9 in humans. Analysis of NEK9 protein expression and localization in patient fibroblasts showed complete loss of full-length NEK9 (107 kDa). Functional characterization of patient fibroblasts showed a significant reduction in cell proliferation and a delay in cell cycle progression. We also provide evidence to support possible ciliary associations for NEK9. Firstly, patient fibroblasts displayed a significant reduction in cilia number and length. Secondly, we show that the NEK9 orthologue in Caenorhabditis elegans, nekl-1, is almost exclusively expressed in a subset of ciliated cells, a strong indicator of cilia-related functions. In summary, we report the clinical and molecular characterization of a lethal skeletal dysplasia caused by NEK9 mutation and suggest that this disorder may represent a novel ciliopathy.
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http://dx.doi.org/10.1093/hmg/ddw054DOI Listing
May 2016

Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion.

Epilepsia 2016 Jan 9;57(1):e12-7. Epub 2015 Dec 9.

Department of Paediatric Neurology and Clinical Neurophysiology, Children's University Hospital, Dublin, Ireland.

Early onset epileptic encephalopathies (EOEEs) represent a significant diagnostic challenge. Newer genomic approaches have begun to elucidate an increasing number of responsible single genes as well as emerging diagnostic strategies. In this single-center study, we aimed to investigate a cohort of children with unexplained EOEE. We performed whole-exome sequencing (WES), targeting a list of 137 epilepsy-associated genes on 50 children with unexplained EOEE. We characterized all phenotypes in detail and classified children according to known electroclinical syndromes where possible. Infants with previous genetic diagnoses, causative brain malformations, or inborn errors of metabolism were excluded. We identified disease-causing variants in 11 children (22%) in the following genes: STXBP1 (n = 3), KCNB1 (n = 2), KCNT1, SCN1A, SCN2A, GRIN2A, DNM1, and KCNA2. We also identified two further variants (in GRIA3 and CPA6) in two children requiring further investigation. Eleven variants were de novo, and in one paternal testing was not possible. Phenotypes were broadened for some variants identified. This study demonstrates that WES is a clinically useful screening tool for previously investigated unexplained EOEE and allows for reanalysis of data as new genes are being discovered. Detailed phenotyping allows for expansion of specific gene disorders leading to epileptic encephalopathy and emerging sub-phenotypes.
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http://dx.doi.org/10.1111/epi.13250DOI Listing
January 2016

Geospatial Resolution of Human and Bacterial Diversity with City-Scale Metagenomics.

Cell Syst 2015 Jul 3;1(1):72-87. Epub 2015 Mar 3.

University of Vermont, Burlington, VT 05405, USA.

The panoply of microorganisms and other species present in our environment influence human health and disease, especially in cities, but have not been profiled with metagenomics at a city-wide scale. We sequenced DNA from surfaces across the entire New York City (NYC) subway system, the Gowanus Canal, and public parks. Nearly half of the DNA (48%) does not match any known organism; identified organisms spanned 1,688 bacterial, viral, archaeal, and eukaryotic taxa, which were enriched for harmless genera associated with skin (e.g., ). Predicted ancestry of human DNA left on subway surfaces can recapitulate U.S. Census demographic data, and bacterial signatures can reveal a station's history, such as marine-associated bacteria in a hurricane-flooded station. Some evidence of pathogens was found (), but a lack of reported cases in NYC suggests that the pathogens represent a normal, urban microbiome. This baseline metagenomic map of NYC could help long-term disease surveillance, bioterrorism threat mitigation, and health management in the built environment of cities.
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http://dx.doi.org/10.1016/j.cels.2015.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4651444PMC
July 2015

NAA10 mutation causing a novel intellectual disability syndrome with Long QT due to N-terminal acetyltransferase impairment.

Sci Rep 2015 Nov 2;5:16022. Epub 2015 Nov 2.

Clinical Genetics, Temple Street Children's University Hospital, Temple Street, Dublin 1, Ireland.

We report two brothers from a non-consanguineous Irish family presenting with a novel syndrome characterised by intellectual disability, facial dysmorphism, scoliosis and long QT. Their mother has a milder phenotype including long QT. X-linked inheritance was suspected. Whole exome sequencing identified a novel missense variant (c.128 A > C; p.Tyr43Ser) in NAA10 (X chromosome) as the cause of the family's disorder. Sanger sequencing confirmed that the mutation arose de novo in the carrier mother. NAA10 encodes the catalytic subunit of the major human N-terminal acetylation complex NatA. In vitro assays for the p.Tyr43Ser mutant enzyme showed a significant decrease in catalytic activity and reduced stability compared to wild-type Naa10 protein. NAA10 has previously been associated with Ogden syndrome, Lenz microphthalmia syndrome and non-syndromic developmental delay. Our findings expand the clinical spectrum of NAA10 and suggest that the proposed correlation between mutant Naa10 enzyme activity and phenotype severity is more complex than anticipated; the p.Tyr43Ser mutant enzyme has less catalytic activity than the p.Ser37Pro mutant associated with lethal Ogden syndrome but results in a milder phenotype. Importantly, we highlight the need for cardiac assessment in males and females with NAA10 variants as both patients and carriers can have long QT.
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http://dx.doi.org/10.1038/srep16022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629191PMC
November 2015

Periventricular Calcification, Abnormal Pterins and Dry Thickened Skin: Expanding the Clinical Spectrum of RMND1?

JIMD Rep 2016 4;26:13-9. Epub 2015 Aug 4.

Genetics Department, Temple Street Children's University Hospital, Dublin 1, Ireland.

Background: We report a consanguineous Sudanese family whose two affected sons presented with a lethal disorder characterised by severe neonatal lactic acidosis, hypertonia, microcephaly and intractable seizures. One child had additional unique features of periventricular calcification, abnormal pterins and dry thickened skin.

Methods: Exome enrichment was performed on pooled genomic libraries from the two affected children and sequenced on an Illumina HiSeq2000. After quality control and variant identification, rare homozygous variants were prioritised. Respiratory chain complex activities were measured and normalised to citrate synthase activity in cultured patient fibroblasts. RMND1 protein levels were analysed by standard Western blotting.

Results: Exome sequencing identified a previously reported homozygous missense variant in RMND1 (c.1250G>A; p.Arg417Gln), the gene associated with combined oxidation phosphorylation deficiency 11 (COXPD11), as the most likely cause of this disorder. This finding suggests the presence of a mutation hotspot at cDNA position 1250. Patient fibroblasts showed a severe decrease in mitochondrial respiratory chain complex I, III and IV activities and protein expression, albeit with normal RMND1 levels, supporting a generalised disorder of mitochondrial translation caused by loss of function.

Conclusions: The current study implicates RMND1 in the development of calcification and dermatological abnormalities, likely due to defective ATP-dependent processes in vascular smooth muscle cells and skin. Review of reported patients with RMND1 mutations shows intra-familial variability and evidence of an evolving phenotype, which may account for the clinical variability. We suggest that COXPD11 should be considered in the differential for patients with calcification and evidence of a mitochondrial disorder.
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http://dx.doi.org/10.1007/8904_2015_479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580737PMC
May 2016

Ancestry of the Timorese: age-related macular degeneration associated genotype and allele sharing among human populations from throughout the world.

Front Genet 2015 9;6:238. Epub 2015 Jul 9.

Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah Salt Lake City, UT, USA.

We observed that the third leading cause of blindness in the world, age-related macular degeneration (AMD), occurs at a very low documented frequency in a population-based cohort from Timor-Leste. Thus, we determined a complete catalog of the ancestry of the Timorese by analysis of whole exome chip data and haplogroup analysis of SNP genotypes determined by sequencing the Hypervariable I and II regions of the mitochondrial genome and 17 genotyped YSTR markers obtained from 535 individuals. We genotyped 20 previously reported AMD-associated SNPs in the Timorese to examine their allele frequencies compared to and between previously documented AMD cohorts of varying ethnicities. For those without AMD (average age > 55 years), genotype and allele frequencies were similar for most SNPs with a few exceptions. The major risk allele of HTRA1 rs11200638 (10q26) was at a significantly higher frequency in the Timorese, as well as 3 of the 5 protective CFH (1q32) SNPs (rs800292, rs2284664, and rs12066959). Additionally, the most commonly associated AMD-risk SNP, CFH rs1061170 (Y402H), was also seen at a much lower frequency in the Korean and Timorese populations than in the assessed Caucasian populations (C ~7 vs. ~40%, respectively). The difference in allele frequencies between the Timorese population and the other genotyped populations, along with the haplogroup analysis, also highlight the genetic diversity of the Timorese. Specifically, the most common ancestry groupings were Oceanic (Melanesian and Papuan) and Eastern Asian (specifically Han Chinese). The low prevalence of AMD in the Timorese population (2 of 535 randomly selected participants) may be due to the enrichment of protective alleles in this population at the 1q32 locus.
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http://dx.doi.org/10.3389/fgene.2015.00238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496576PMC
July 2015

A case report of primary ciliary dyskinesia, laterality defects and developmental delay caused by the co-existence of a single gene and chromosome disorder.

BMC Med Genet 2015 Jun 30;16:45. Epub 2015 Jun 30.

Genetics Department, Temple Street Children's University Hospital, Dublin 1, Ireland.

Background: Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterised by abnormal ciliary motion and impaired mucociliary clearance, leading to recurrent respiratory infections, sinusitis, otitis media and male infertility. Some patients also have laterality defects. We recently reported the identification of three disease-causing PCD genes in the Irish Traveller population; RSPH4A, DYX1C1 and CCNO. We have since assessed an additional Irish Traveller family with a complex phenotype involving PCD who did not have any of the previously identified PCD mutations.

Case Presentation: In this study we report on a family with three children with PCD and various laterality defects. In addition, one child (V:1) has mild-to-moderate developmental delay and one child has speech delay (V:2). Developmental delay is not usually associated with PCD and is likely to be caused by an additional genetic abnormality. Transmission electron microscopy showed variable inner and outer dynein arm defects. Exome sequencing identified a homozygous missense variant in CCDC103 (c.461A > C; p.His154Pro) as the most likely cause of the PCD and laterality defects in this family. However, as mutation in CCDC103 would not account for the developmental delay, array comparative genomic hybridisation was undertaken and identified a maternally inherited gain of ~1.6 Mb (chr17:34,611,352-36,248,918). Gains at this locus are associated with 17q12 duplication syndrome which includes speech and language delay.

Conclusion: We report on a variable and complex phenotype caused by the co-inheritance of a single gene mutation in CCDC103 and a microduplication at 17q12, both on chromosome 17. The co-existence of a single gene and chromosome disorder is unusual but accounts for the spectrum of clinical features in this family. In addition, our study brings the total number of PCD genes in the Irish Traveller population to four and we suspect additional PCD genes are yet to be identified. Although, on a global scale, PCD is associated with extensive genetic heterogeneity, finding such a high number of causative PCD genes within the relatively small Irish Traveller population was unexpected.
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http://dx.doi.org/10.1186/s12881-015-0192-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630905PMC
June 2015

Chromosomal microarray in unexplained severe early onset epilepsy - A single centre cohort.

Eur J Paediatr Neurol 2015 Jul 10;19(4):390-4. Epub 2015 Apr 10.

Department of Child Neurology & Clinical Neurophysiology, Children's University Hospital, Temple St., Dublin, Ireland; Academic Center on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Ireland.

Background: Severe early onset epilepsy may lead to impaired cognitive and motor development, and consists of a group of specific and overlapping electro-clinical phenotypes which may be the result of an inborn error of metabolism, congenital or acquired structural brain lesion, known chromosomal or mono-genetic disorder. A significant proportion of cases however remain unexplained, representing a major diagnostic and management challenge.

Methods: In this study we describe a cohort of children with severe early onset epilepsy and examine the clinical utility of chromosomal microarray (array-comparative genomic hybridisation, CGH) in this group of epilepsies.

Results: In 51 children with unexplained severe early onset epilepsy, all of whom had chromosomal array tested, copy number variants were detected in 17.6% and pathogenic variants in 5.9% of infants.

Conclusions: Chromosomal microarray is a useful investigation in early onset refractory epilepsy and epileptic encephalopathy. Detailed review of the precise array abnormality and phenotypes associated are important for determining significance.
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http://dx.doi.org/10.1016/j.ejpn.2015.03.010DOI Listing
July 2015

Common polygenic variation in coeliac disease and confirmation of ZNF335 and NIFA as disease susceptibility loci.

Eur J Hum Genet 2016 Feb 29;24(2):291-7. Epub 2015 Apr 29.

Department of Medicine, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.

Coeliac disease (CD) is a chronic immune-mediated disease triggered by the ingestion of gluten. It has an estimated prevalence of approximately 1% in European populations. Specific HLA-DQA1 and HLA-DQB1 alleles are established coeliac susceptibility genes and are required for the presentation of gliadin to the immune system resulting in damage to the intestinal mucosa. In the largest association analysis of CD to date, 39 non-HLA risk loci were identified, 13 of which were new, in a sample of 12,014 individuals with CD and 12 228 controls using the Immunochip genotyping platform. Including the HLA, this brings the total number of known CD loci to 40. We have replicated this study in an independent Irish CD case-control population of 425 CD and 453 controls using the Immunochip platform. Using a binomial sign test, we show that the direction of the effects of previously described risk alleles were highly correlated with those reported in the Irish population, (P=2.2 × 10(-16)). Using the Polygene Risk Score (PRS) approach, we estimated that up to 35% of the genetic variance could be explained by loci present on the Immunochip (P=9 × 10(-75)). When this is limited to non-HLA loci, we explain a maximum of 4.5% of the genetic variance (P=3.6 × 10(-18)). Finally, we performed a meta-analysis of our data with the previous reports, identifying two further loci harbouring the ZNF335 and NIFA genes which now exceed genome-wide significance, taking the total number of CD susceptibility loci to 42.
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http://dx.doi.org/10.1038/ejhg.2015.87DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4717209PMC
February 2016
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