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This study aims to identify the clinical utility of targeted-genetic sequencing in a cohort of patients with TAA and establish a new method for regional histological characterisation of TAA disease.Fifty-four patients undergoing surgery for proximal TAA were recruited.connective tissue disease, bicuspid aortic valves, redo surgery. All patients underwent next generation sequencing (NGS) using a custom gene panel containing 63 genes previously associated with TAA on Illumina MiSeqor NextSeq550 platforms. Explanted TAA tissue was obtained en-bloc from 34/54 patients, and complete circumferential strips of TAA tissue processed into whole slides which were subsequently digitalised. Computational pathology methods were employed to quantify elastin, cellularity and collagen in six equally divided regions across the whole aneurysm circumference.Of 54 patients, clearly pathogenic or potentially pathogenic variants were found in 7.4%: namely LOX, PRKG1, TGFBR1 and SMAD3 genes. 55% had at least one variant of unknown significance (VUS) and seven of the VUSs were in genes with a strong disease association (category A) genes, whilst 15 were from moderate risk (category B) genes. Elastin and collagen abundance displayed high regional variation throughout the aneurysm circumference. In patients with60% total elastin, the loss of elastin was more significant on the outer curve (38.0% vs 47.4%, p = 0.0094). The presence of VUS, higher pulse wave velocity and advancing age were predictors of elastin loss (regression analysis: p 0.05).These findings demonstrate the heterogeneity of TAA disease microstructure and the potential link between histological appearance and clinical factors, including genetic variation.

with other laboratory and clinical investigations. Early and accurate diagnosis of inherited conditions generally leads to better medical care for patients and their families, with improved knowledge of the natural history of the condition and early intervention. It is therefore essential that equitable access to such testing is established for indigenous and isolated populations, in order to further narrow the health disparity gap. Although supported by funding from a few sources, this study signals a success for the Silent Genomes Project, with one of the cases having been identified by whole genome sequencing within that project, after negative whole exome sequencing. Furthermore the study has potential life-changing clinical consequences and provides starting points for possible interventions for respiratory medicine in the Inuit population. These include increased awareness of the possibility of PCD in patients presenting with neonatal respiratory distress, bronchiectasis or otitis media leading to early intervention; and in conjunction with Inuit organizations and public health officials, targeted analysis of the DNAH11 variant in the population with the possible introduction of newborn screening for PCD.

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 misdiagnosed as having hyperekplexia, and many die undiagnosed. The key phenotypic features are multifocal myoclonus, an organized EEG, progressive, persistent, and diffuse hypertonia, and an evolution into refractory multifocal seizures, prolonged bouts of apnea, bradycardia, and early death. Early recognition of BRAT1 encephalopathy allows for prompt workup, appropriate management, and genetic counseling.

Background and ObjectivesBRAT1encephalopathy is an ultra-rare autosomal recessive neonatal encephalopathy. We delineate the neonatal electroclinical phenotype at presentation and provide insights for early diagnosis.MethodsThrough a multinational collaborative, we studied a cohort of neonates with encephalopathy associated with biallelic pathogenic variants inBRAT1for whom detailed clinical, neurophysiologic, and neuroimaging information was available from the onset of symptoms. Neuropathologic changes were also analyzed.ResultsWe 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.DiscussionBRAT1encephalopathy is a neonatal-onset, rapidly progressive neurologic disorder. Neonates are often misdiagnosed as having hyperekplexia, and many die undiagnosed. The key phenotypic features are multifocal myoclonus, an organized EEG, progressive, persistent, and diffuse hypertonia, and an evolution into refractory multifocal seizures, prolonged bouts of apnea, bradycardia, and early death. Early recognition ofBRAT1encephalopathy allows for prompt workup, appropriate management, and genetic counseling.

BackgroundGuidelines 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.MethodsSixty 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.ResultsSix 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).ConclusionWe 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.

BackgroundBronchiectasis can result from infectious, genetic, immunological and allergic causes. 60–80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis of PCD has management implications including addressing comorbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments. Diagnostic testing can be complex; however, PCD genetic testing is moving rapidly from research into clinical diagnostics and would confirm the cause of bronchiectasis.MethodsThis observational study used genetic data from severe bronchiectasis patients recruited to the UK 100,000 Genomes Project and patients referred for gene panel testing within a tertiary respiratory hospital. Patients referred for genetic testing due to clinical suspicion of PCD were excluded from both analyses. Data were accessed from the British Thoracic Society audit, to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis in the UK.ResultsPathogenic or likely pathogenic variants were identified in motile ciliopathy genes in 17 (12%) out of 142 individuals by whole-genome sequencing. Similarly, in a single centre with access to pathological diagnostic facilities, 5–10% of patients received a PCD diagnosis by gene panel, often linked to normal/inconclusive nasal nitric oxide and cilia functional test results. In 4898 audited patients with bronchiectasis, ConclusionsPCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is predominantly caused by heterozygous missense variants in the cardiac ryanodine receptor, RYR2. However, many RYR2 missense variants are classified as variants of uncertain significance (VUS). We systematically re-evaluated all RYR2 variants in healthy individuals and those with CPVT or arrhythmia using the 2015 American College of Medical Genomics guidelines. RYR2 variants were identified by the NW Genomic Laboratory Hub, from the published literature and databases of sequence variants. Each variant was assessed based on minor allele frequencies, in silico prediction tools and appraisal of functional studies and classified according to the ACMG-AMP guidelines. Phenotype data was collated where available. Of the 326 identified RYR2 missense variants, 55 (16.9%), previously disease-associated variants were reclassified as benign. Application of the gnomAD database of140,000 controls allowed reclassification of 11 variants more than the ExAC database. CPVT-associated RYR2 variants clustered predominantly between amino acid positions 3949-4332 and 4867-4967 as well as the RyR and IP3R homology-associated and ion transport domains (p 0.005). CPVT-associated RYR2 variants occurred at more conserved amino acid positions compared with controls, and variants associated with sudden death had higher conservation scores (p 0.005). There were five potentially pathogenic RYR2 variants associated with sudden death during sleep which were located almost exclusively in the C-terminus of the protein. In conclusion, control sequence databases facilitate reclassification of RYR2 variants but the majority remain as VUS. Notably, pathogenic variants in RYR2 are associated with death in sleep.

PubMedID: 24731844 Background To evaluate clinical, genetic, and radiologic features of our patients with muscle-eye-brain disease. Methods The data of patients who were diagnosed with muscle-eye-brain disease from a cohort of patients with congenital muscular dystrophy in the Division of Pediatric Neurology of Dokuz Eylül University School of Medicine and Gaziantep Children's Hospital between 2005 and 2013 were analyzed retrospectively. Results From a cohort of 34 patients with congenital muscular dystrophy, 12 patients from 10 families were diagnosed with muscle-eye-brain disease. The mean age of the patients was 9 ± 5.5 years (2-19 years). Mean serum creatine kinase value was 2485.80 ± 1308.54 IU/L (700-4267 IU/L). All patients presented with muscular hypotonia at birth followed by varying degrees of spasticity and exaggerated deep tendon reflexes in later stages of life. Three patients were able to walk. The most common ophthalmologic and radiologic abnormalities were cataracts, retinal detachment, periventricular white matter abnormalities, ventriculomegaly, pontocerebellar hypoplasia, and multiple cerebellar cysts. All of the patients had mutations in the POMGNT1 gene. The most common mutation detected in 66% of patients was c.1814 G > A (p.R605H). Two novel mutations were identified. Conclusions We suggest that muscle-eye-brain disease is a relatively common muscular dystrophy in Turkey. It should be suspected in patients with muscular hypotonia, increased creatine kinase, and structural eye and brain abnormalities. The c.1814 G > A mutation in exon 21 of the POMGNT1 gene is apparently a common mutation in the Turkish population. Individuals with this mutation show classical features of muscle-eye-brain disease, but others may exhibit a milder phenotype and retain the ability to walk independently. Congenital muscular dystrophy patients from Turkey carrying the clinical and radiologic features of muscle-eye-brain disease should be evaluated for mutations in POMGNT1 gene. © 2014 Elsevier Inc. All rights reserved.

BACKGROUND: To evaluate clinical, genetic, and radiologic features of our patients with muscle-eye-brain disease. METHODS: The data of patients who were diagnosed with muscle-eye-brain disease from a cohort of patients with congenital muscular dystrophy in the Division of Pediatric Neurology of Dokuz Eylul University School of Medicine and Gaziantep Children’s Hospital between 2005 and 2013 were analyzed retrospectively. RESULTS: From a cohort of 34 patients with congenital muscular dystrophy, 12 patients from 10 families were diagnosed with muscle-eyebrain disease. The mean age of the patients was 9 � 5.5 years (2-19 years). Mean serum creatine kinase value was 2485.80 � 1308.54 IU/L (700-4267 IU/L). All patients presented with muscular hypotonia at birth followed by varying degrees of spasticity and exaggerated deep tendon reflexes in later stages of life. Three patients were able to walk. The most common ophthalmologic and radiologic abnormalities were cataracts, retinal detachment, periventricular white matter abnormalities, ventriculomegaly, pontocerebellar hypoplasia, and multiple cerebellar cysts. All of the patients had mutations in the POMGNT1 gene. The most common mutation detected in 66% of patients was c.1814 G > A (p.R605H). Two novel mutations were identified. CONCLUSIONS: We suggest that muscle-eye-brain disease is a relatively common muscular dystrophy in Turkey. It should be suspected in patients with muscular hypotonia, increased creatine kinase, and structural eye and brain abnormalities. The c.1814 G > A mutation in exon 21 of the POMGNT1 gene is apparently a common mutation in the Turkish population. Individuals with this mutation show classical features of muscle-eye-brain disease, but others may exhibit a milder phenotype and retain the ability to walk independently. Congenital muscular dystrophy patients from Turkey carrying the clinical and radiologic features of muscle-eye-brain disease should be evaluated for mutations in POMGNT1 gene.