128 results found
Engel C, Valence S, Delplancq G, et al., 2023, BRAT1-related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients., Eur J Hum Genet, Vol: 31, Pages: 1023-1031
BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17).
Hanna L, Gibbs RGJ, London Aortic Mechanobiology Working Group, 2023, Type II Endoleaks and Culprit Vessels: Will 4D MRI Change the Paradigm?, Eur J Vasc Endovasc Surg, Vol: 66
Carapancea E, Cornet M-C, Milh M, et al., 2023, Clinical and Neurophysiologic Phenotypes in Neonates With BRAT1 Encephalopathy., Neurology, Vol: 100, Pages: e1234-e1247
BACKGROUND AND OBJECTIVES: BRAT1 encephalopathy is an ultra-rare autosomal recessive neonatal encephalopathy. We delineate the neonatal electroclinical phenotype at presentation and provide insights for early diagnosis. METHODS: Through a multinational collaborative, we studied a cohort of neonates with encephalopathy associated with biallelic pathogenic variants in BRAT1 for whom detailed clinical, neurophysiologic, and neuroimaging information was available from the onset of symptoms. Neuropathologic changes were also analyzed. RESULTS: We included 19 neonates. Most neonates were born at term (16/19) from nonconsanguineous parents. 15/19 (79%) were admitted soon after birth to a neonatal intensive care unit, exhibiting multifocal myoclonus, both spontaneous and exacerbated by stimulation. 7/19 (37%) had arthrogryposis at birth, and all except 1 progressively developed hypertonia in the first week of life. Multifocal myoclonus, which was present in all but 1 infant, was the most prominent manifestation and did not show any EEG correlate in 16/19 (84%). Video-EEG at onset was unremarkable in 14/19 (74%) infants, and 6 (33%) had initially been misdiagnosed with hyperekplexia. Multifocal seizures were observed at a median age of 14 days (range: 1-29). During the first months of life, all infants developed progressive encephalopathy, acquired microcephaly, prolonged bouts of apnea, and bradycardia, leading to cardiac arrest and death at a median age of 3.5 months (range: 20 days to 30 months). Only 7 infants (37%) received a definite diagnosis before death, at a median age of 34 days (range: 25-126), and almost two-thirds (12/19, 63%) were diagnosed 8 days to 12 years postmortem (median: 6.5 years). Neuropathology examination, performed in 3 patients, revealed severely delayed myelination and diffuse astrogliosis, sparing the upper cortical layers. DISCUSSION: BRAT1 encephalopathy is a neonatal-onset, rapidly progressive neurologic disorder. Neonates are often misdiagn
Salmasi MY, Alwis S, Cyclewala S, et al., 2023, The genetic basis of thoracic aortic disease: The future of aneurysm classification?, Hellenic Journal of Cardiology, Vol: 69, Pages: 41-50, ISSN: 1109-9666
The expansion in the repertoire of genes linked to thoracic aortic aneurysms (TAA) has revolutionised our understanding of the disease process. The clinical benefits of such progress are numerous, particularly helping our understanding of non-syndromic hereditary causes of TAA (HTAAD) and further refinement in the subclassification of disease. Furthermore, the understanding of aortic biomechanics and mechanical homeostasis has been significantly informed by the discovery of deleterious mutations and their effect on aortic phenotype. The drawbacks in genetic testing in TAA lie with the inability to translate genotype to accurate prognostication in the risk of thoracic aortic dissection (TAD), which is a life-threatening condition. Under current guidelines, there are no metrics by which those at risk for dissection with normal aortic diameters may undergo preventive surgery. Future research lies with more advanced genetic diagnosis of HTAAD and investigation of the diverse pathways involved in its pathophysiology, which will i) serve to improve our understanding of the underlying mechanisms, ii) improve guidelines for treatment and iii) prevent complications for HTAAD and sporadic aortopathies.
Fisher CL, Dillon R, Anguita E, et al., 2022, A Novel Bead-Capture Nanopore Sequencing Method for Large Structural Rearrangement Detection in Cancer, JOURNAL OF MOLECULAR DIAGNOSTICS, Vol: 24, Pages: 1264-1278, ISSN: 1525-1578
Amin R, Morris-Rosendahl D, Edwards M, et al., 2022, The addition of genetic testing and cardiovascular magnetic resonance to routine clinical data for stratification of aetiology in dilated cardiomyopathy, Frontiers in Cardiovascular Medicine, Vol: 9, ISSN: 2297-055X
Background: Guidelines recommend genetic testing and cardiovascular magnetic resonance (CMR) for the investigation of dilated cardiomyopathy (DCM). However, the incremental value is unclear. We assessed the impact of these investigations in determining etiology.Methods: Sixty consecutive patients referred with DCM and recruited to our hospital biobank were selected. Six independent experts determined the etiology of each phenotype in a step-wise manner based on (1) routine clinical data, (2) clinical and genetic data and (3) clinical, genetic and CMR data. They indicated their confidence (1-3) in the classification and any changes to management at each step.Results: Six physicians adjudicated 60 cases. The addition of genetics and CMR resulted in 57 (15.8%) and 26 (7.2%) changes in the classification of etiology, including an increased number of genetic diagnoses and a reduction in idiopathic diagnoses. Diagnostic confidence improved at each step (p < 0.0005). The number of diagnoses made with low confidence reduced from 105 (29.2%) with routine clinical data to 71 (19.7%) following the addition of genetics and 37 (10.3%) with the addition of CMR. The addition of genetics and CMR led to 101 (28.1%) and 112 (31.1%) proposed changes to management, respectively. Interobserver variability showed moderate agreement with clinical data (κ = 0.44) which improved following the addition of genetics (κ = 0.65) and CMR (κ = 0.68).Conclusion: We demonstrate that genetics and CMR, frequently changed the classification of etiology in DCM, improved confidence and interobserver variability in determining the diagnosis and had an impact on proposed management.
Salmasi MY, Morris-Rosendahl D, Jarral OA, et al., 2022, Determining the genetic contribution in patients with non-syndromic ascending thoracic aortic aneurysms: Correlation with findings from computational pathology, INTERNATIONAL JOURNAL OF CARDIOLOGY, Vol: 366, Pages: 1-9, ISSN: 0167-5273
Shoemark A, Griffin H, Wheway G, et al., 2022, Genome sequencing reveals underdiagnosis of primary ciliary dyskinesia in bronchiectasis, EUROPEAN RESPIRATORY JOURNAL, Vol: 60, ISSN: 0903-1936
Salmasi MYB, Morris-Rosendahl D, Jarral O, et al., 2022, Determining the genetic contribution in patients with non-syndromic ascending thoracic aortic aneurysms: Correlation with findings from computational pathology, International Journal of Cardiology, ISSN: 0167-5273
Mahmood A, Morris-Rosendahl D, Edwards M, et al., 2022, DISEASE PENETRANCE IN ASYMPTOMATIC CARRIERS OF FAMILIAL CARDIOMYOPATHY VARIANTS, Annual Conference of the British-Cardiovascular-Society - 100 Years of Cardiology, Publisher: BMJ PUBLISHING GROUP, Pages: A9-A9, ISSN: 1355-6037
Guimier A, Achleitner MT, de Bellaing AM, et al., 2022, PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families (vol 23, pg 2415, 2021), GENETICS IN MEDICINE, Vol: 24, Pages: 967-967, ISSN: 1098-3600
Morris-Rosendahl DJ, 2022, A glossary of relevant genetic terms., Dialogues Clin Neurosci, Vol: 12, Pages: 116-120, ISSN: 1294-8322
Morris-Rosendahl DJ, 2022, Are there anxious genes?, Dialogues Clin Neurosci, Vol: 4, Pages: 251-260, ISSN: 1294-8322
Anxiety comprises many clinical descriptions and phenotypes. A genetic predisposition to anxiety is undoubted; however, the nature and extent of that contribution is still unclear. Methods for the genetic analysis of such complex disorders is briefly reviewed, followed by a discussion of the comorbidity of anxiety with other psychiatric disorders and their possible common genetic etiology. Extensive genetic studies of the serotonin (5-hydroxytryptamine, 5-HT) transporter (5-HTT) gene have revealed how variation in gene expression can be correlated with anxiety phenotypes. Complete genome-wide linkage scans for panic disorder (PD) susceptibility genes have suggested a locus on chromosome arm 7p, and association studies have highlighted many candidate genes. A highly significant association between phobias, panic disorder, and a duplication at chromosomal region 15q24-26 is one of the most exciting findings to date. Emerging molecular genetic technologies and the use of increasingly sophisticated animal models of anxiety provide great promise for the future of the field.
Nastase A, Mandal A, Lu SK, et al., 2022, Integrated genomics point to immune vulnerabilities in pleural mesothelioma (vol 11, 19138, 2021), SCIENTIFIC REPORTS, Vol: 12, ISSN: 2045-2322
Nastase A, Mandal A, Lu SK, et al., 2021, Integrated genomics point to immune vulnerabilities in pleural mesothelioma, Scientific Reports, Vol: 11, ISSN: 2045-2322
Pleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Our results suggest new therapeutic avenues in mesothelioma and indicate targets and biomarkers for immunotherapy.
Mani R, Gomes M, Gonzalez AR, et al., 2021, Development and first results of the BEAT-PCD international Primary Ciliary Dyskinesia gene variant database: CiliaVar, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Guimier A, Achleitner MT, de Bellaing AM, et al., 2021, PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families, Genetics in Medicine, Vol: 23, Pages: 2415-2425, ISSN: 1098-3600
PurposeBiallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants.MethodsSynthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized.ResultsAmong the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure. One case was diagnosed prenatally with cardiomyopathy. Four teenagers drank alcohol before sudden cardiac arrest. Progressive neurological signs were observed in 2/6 surviving individuals. For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity.ConclusionWe expand the clinical and mutational spectrum associated with PPA2 dysfunction. Heart failure and sudden cardiac arrest occur at various ages with inter- and intrafamilial phenotypic variability, and presentation can include progressive neurological disease. Alcohol intake can trigger cardiac arrest and should be strictly avoided.
Shoemark A, Rubbo B, Legendre M, et al., 2021, Topological data analysis reveals genotype-phenotype relationships in primary ciliary dyskinesia, EUROPEAN RESPIRATORY JOURNAL, Vol: 58, ISSN: 0903-1936
Sepahzad A, Morris-Rosendahl D, Davies J, 2021, Cystic fibrosis lung disease modifiers and their relevance in the new era of precision medicine, Genes, Vol: 12, ISSN: 2073-4425
Our understanding of cystic fibrosis (CF) has grown exponentially since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989. With evolving genetic and genomic tools, we have come to better understand the role of CFTR genotypes in the pathophysiology of the disease. This, in turn, has paved the way for the development of modulator therapies targeted at mutations in the CFTR, which are arguably one of the greatest advances in the treatment of CF. These modulator therapies, however, do not target all the mutations in CFTR that are seen in patients with CF and, furthermore, a variation in response is seen in patients with the same genotype who are taking modulator therapies. There is growing evidence to support the role of non-CFTR modifiers, both genetic and environmental, in determining the variation seen in CF morbidity and mortality and also in the response to existing therapies. This review focusses on key findings from studies using candidate gene and genome-wide approaches to identify CF modifier genes of lung disease in cystic fibrosis and considers the interaction between modifiers and the response to modulator therapies. As the use of modulator therapies expands and we gain data around outcomes, it will be of great interest to investigate this interaction further. Going forward, it will also be crucial to better understand the relative influence of genomic versus environmental factors. With this understanding, we can truly begin to deliver personalised care by better profiling the likely disease phenotype for each patient and their response to treatment.
Fleming AG, Brett L, Wilkinson S, et al., 2020, Non-segregation of truncating TTN variants in families with dilated cardiomyopathy (DCM), Publisher: SPRINGERNATURE, Pages: 268-268, ISSN: 1018-4813
Domingo-Sabugo C, Starren E, Mandal A, et al., 2020, Distinct Landscapes of Genomic Alterations between Lung Carcinoids and Non-Small Cell Lung Cancers, Publisher: SPRINGERNATURE, Pages: 528-528, ISSN: 1018-4813
Vijayasingam A, Frost E, Wilkins J, et al., 2020, Tablet and web-based audiometry to screen for hearing loss in adults with cystic fibrosis, Thorax, Vol: 75, Pages: 632-639, ISSN: 0040-6376
INTRODUCTION: Individuals with chronic lung disease (eg, cystic fibrosis (CF)) often receive antimicrobial therapy including aminoglycosides resulting in ototoxicity. Extended high-frequency audiometry has increased sensitivity for ototoxicity detection, but diagnostic audiometry in a sound-booth is costly, time-consuming and requires a trained audiologist. This cross-sectional study analysed tablet-based audiometry (Shoebox MD) performed by non-audiologists in an outpatient setting, alongside home web-based audiometry (3D Tune-In) to screen for hearing loss in adults with CF. METHODS: Hearing was analysed in 126 CF adults using validated questionnaires, a web self-hearing test (0.5 to 4 kHz), tablet (0.25 to 12 kHz) and sound-booth audiometry (0.25 to 12 kHz). A threshold of ≥25 dB hearing loss at ≥1 audiometric frequency was considered abnormal. Demographics and mitochondrial DNA sequencing were used to analyse risk factors, and accuracy and usability of hearing tests determined. RESULTS: Prevalence of hearing loss within any frequency band tested was 48%. Multivariate analysis showed age (OR 1.127; (95% CI: 1.07 to 1.18; p value<0.0001) per year older) and total intravenous antibiotic days over 10 years (OR 1.006; (95% CI: 1.002 to 1.010; p value=0.004) per further intravenous day) were significantly associated with increased risk of hearing loss. Tablet audiometry had good usability, was 93% sensitive, 88% specific with 94% negative predictive value to screen for hearing loss compared with web self-test audiometry and questionnaires which had poor sensitivity (17% and 13%, respectively). Intraclass correlation (ICC) of tablet versus sound-booth audiometry showed high correlation (ICC >0.9) at all frequencies ≥4 kHz. CONCLUSIONS: Adults with CF have a high prevalence of drug-related hearing loss and tablet-based audiometry can be a practical, accurate screening tool within integrated ototoxicity monitoring programmes for early detection.
Morris-Rosendahl DJ, Edwards M, McDonnell MJ, et al., 2020, Whole-gene sequencing of CFTR reveals a high prevalence of the intronic variant c.3874-4522A>G in cystic fibrosis., American Journal of Respiratory and Critical Care Medicine, Vol: 201, Pages: 1438-1441, ISSN: 1073-449X
Fassad MR, Patel MP, Shoemark A, et al., 2020, Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort, JOURNAL OF MEDICAL GENETICS, Vol: 57, Pages: 322-330, ISSN: 0022-2593
Olubando D, Hopton C, Eden J, et al., 2020, Classification and correlation of RYR2 missense variants in individuals with catecholaminergic polymorphic ventricular tachycardia reveals phenotypic relationships, JOURNAL OF HUMAN GENETICS, Vol: 65, Pages: 531-539, ISSN: 1434-5161
Morris-Rosendahl DJ, Crocq M-A, 2020, Neurodevelopmental disorders-the history and future of a diagnostic concept, DIALOGUES IN CLINICAL NEUROSCIENCE, Vol: 22, Pages: 65-72, ISSN: 1294-8322
Rubbo B, Shoemark A, Legendre M, et al., 2020, Topological Data Analysis Coupled with Machine Learning Reveals New Genotype-Phenotype Relationships in Primary Ciliary Dyskinesia, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Yazdani MF, Morris-Rosendahl D, Chen L, et al., 2020, Images of the month 1: Cough before the storm: A case of pulmonary alveolar microlithiasis, Clinical Medicine, Vol: 20, Pages: 110-111, ISSN: 1470-2118
Shovlin CL, Morris-Rosendahl DJ, Copeland F, et al., 2019, DELIVERING THE 100,000 GENOMES PROJECT TO ESTABLISH THE FUNCTIONAL ROLE OF DNA SEQUENCE VARIANTS IN RESPIRATORY RARE DISEASES, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A44-A45, ISSN: 0040-6376
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