Publications by authors named "Edward Blair"

81 Publications

The Musculoskeletal Manifestations of Marfan Syndrome: Diagnosis, Impact, and Management.

Curr Rheumatol Rep 2021 Nov 26;23(11):81. Epub 2021 Nov 26.

Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK.

Purpose Of Review: Marfan syndrome (MFS) is an autosomal dominant heritable disorder of fibrillin-1 (FBN1) with predominantly ocular, cardiovascular, and musculoskeletal manifestations that has a population prevalence of approximately 1 in 5-10,000 (Chiu et al. Mayo Clin Proc. 89(1):34-42, 146, Dietz 3, Loeys et al. J Med Genet. 47(7):476-85, 4).

Recent Findings: The vascular complications of MFS still pose the greatest threat, but effective management options, such as regular cardiac monitoring and elective surgical intervention, have reduced the risk of life-threatening cardiovascular events, such as aortic dissection. Although cardiovascular morbidity and mortality remains high, these improvements in cardiovascular management have extended the life expectancy of those with MFS by perhaps 30-50 years from an estimated mean of 32 years in 1972 (Dietz 3, Gott et al. Eur J Cardio-thoracic Surg. 10(3):149-58, 147, Murdoch et al. N Engl J Med. 286(15):804-8, 148). The musculoskeletal manifestations of MFS, which to date have received less attention, can also have a significant impact on the quality of life and are likely to become more important as the age of the Marfan syndrome population increases (Hasan et al. Int J Clin Pract. 61(8):1308-1320, 127). In addition, musculoskeletal manifestations are often critically important in the diagnosis of MFS. Here, we review the main clinically relevant and diagnostically useful musculoskeletal features of MFS, which together contribute to the "systemic features score" (referred to hereafter as systemic score), part of the revised Ghent nosology for MFS. We discuss current treatment strategies and highlight the need for a multidisciplinary approach to diagnosis and management. Finally, we review new pharmacological approaches that may be disease modifying and could help to improve the outcome for individuals with this syndrome.
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http://dx.doi.org/10.1007/s11926-021-01045-3DOI Listing
November 2021

Loeys-Dietz syndrome in pregnancy.

Obstet Med 2021 Mar 15;14(1):42-45. Epub 2019 Jun 15.

Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Loeys-Dietz syndrome is a recently described condition which causes cardiovascular, craniofacial, neurocognitive and skeletal abnormalities due to mutations in components of the transforming growth factor-β signalling pathway. Associated vascular abnormalities include vessel tortuosity and an increased incidence of vascular dissection. Pregnancy increases the risk of aortic dissection compared to non-pregnant individuals and an underlying condition such as Loeys-Dietz syndrome increases this further. While aortic dissection is well described in pregnancy in Loeys-Dietz syndrome, some women can have uncomplicated deliveries, particularly when the risks of the condition are actively managed. Such pregnancies should be considered high-risk, and women should be counselled and managed accordingly. Here we describe two pregnancies in one woman, both with successful outcomes, followed by a summary of the key management principles.
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http://dx.doi.org/10.1177/1753495X19852819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107958PMC
March 2021

Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening.

Nat Commun 2021 03 12;12(1):1626. Epub 2021 Mar 12.

Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, 55455, USA.

Minichromosome maintenance protein 10 (MCM10) is essential for eukaryotic DNA replication. Here, we describe compound heterozygous MCM10 variants in patients with distinctive, but overlapping, clinical phenotypes: natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus. To understand the mechanism of MCM10-associated disease, we modeled these variants in human cell lines. MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion. Our data suggest that loss of MCM10 function constrains telomerase activity by accumulating abnormal replication fork structures enriched with single-stranded DNA. Terminally-arrested replication forks in MCM10-deficient cells require endonucleolytic processing by MUS81, as MCM10:MUS81 double mutants display decreased viability and accelerated telomere shortening. We propose that these bi-allelic variants in MCM10 predispose specific cardiac and immune cell lineages to prematurely arrest during differentiation, causing the clinical phenotypes observed in both NKD and RCM patients.
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http://dx.doi.org/10.1038/s41467-021-21878-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955084PMC
March 2021

Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum.

Am J Med Genet A 2021 01 7;185(1):15-25. Epub 2020 Oct 7.

Department of Paediatric Neurology, University Hospital of Wales, Cardiff, UK.

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8.
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http://dx.doi.org/10.1002/ajmg.a.61907DOI Listing
January 2021

Heterozygous de novo variants in CSNK1G1 are associated with syndromic developmental delay and autism spectrum disorder.

Clin Genet 2020 12 12;98(6):571-576. Epub 2020 Oct 12.

Children's Hospital of Philadelphia, Division of Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

The gamma-1 isoform of casein kinase 1, the protein encoded by CSNK1G1, is involved in the growth and morphogenesis of cells. This protein is expressed ubiquitously among many tissue types, including the brain, where it regulates the phosphorylation of N-methyl-D-aspartate receptors and plays a role in synaptic transmission. One prior individual with a de novo variant in CSNK1G presenting with severe developmental delay and early-onset epilepsy has been reported. Here we report an updated clinical history of this previously published case, as well as four additional individuals with de novo variants in CSNK1G1 identified via microarray-based comparative genomic hybridization, exome, or genome sequencing. All individuals (n = 5) had developmental delay. At least three individuals had diagnoses of autism spectrum disorder. All participants were noted to have dysmorphic facial features, although the reported findings varied widely and therefore may not clearly be recognizable. None of the participants had additional major malformations. Taken together, our data suggest that CSNK1G1 may be a cause of syndromic developmental delay and possibly autism spectrum disorder.
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http://dx.doi.org/10.1111/cge.13851DOI Listing
December 2020

Reevaluation of the South Asian Intronic Deletion in Hypertrophic Cardiomyopathy.

Circ Genom Precis Med 2020 06 12;13(3):e002783. Epub 2020 Mar 12.

Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom (A.R.H., A.G., E.O., S.N., M.F., H.W., K.L.T.).

Background: The common intronic deletion, , detected in 4% to 8% of South Asian populations, is reported to be associated with cardiomyopathy, with ≈7-fold increased risk of disease in variant carriers. Here, we examine the contribution of to hypertrophic cardiomyopathy (HCM) in a large patient cohort.

Methods: Sequence data from 2 HCM cohorts (n=5393) was analyzed to determine frequency and co-occurrence of pathogenic variants in HCM genes. Case-control and haplotype analyses were performed to compare variant frequencies and assess disease association. Analyses were also undertaken to investigate the pathogenicity of a candidate variant c.1224-52G>A.

Results: Our data suggest that the risk of HCM, previously attributed to , can be explained by enrichment of a derived haplotype, , whereby a small subset of individuals bear both and a rare pathogenic variant, c.1224-52G>A. The intronic c.1224-52G>A variant, which is not routinely evaluated by gene panel or exome sequencing, was detected in ≈1% of our HCM cohort.

Conclusions: The c.1224-52G>A variant explains the disease risk previously associated with in the South Asian population and is one of the most frequent pathogenic variants in HCM in all populations; genotyping services should ensure coverage of this deep intronic mutation. Individuals carrying alone are not at increased risk of HCM, and this variant should not be tested in isolation; this is important for the large majority of the 100 million individuals of South Asian ancestry who carry and would previously have been declared at increased risk of HCM.
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http://dx.doi.org/10.1161/CIRCGEN.119.002783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299222PMC
June 2020

Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients.

Am J Med Genet C Semin Med Genet 2019 12 12;181(4):638-643. Epub 2019 Nov 12.

South West Thames Regional Genetics Service, St George's University NHS Foundation Trust, London, UK.

BRWD3 has been described as a cause of X-linked intellectual disability, but relatively little is known about the specific phenotype. We report the largest BRWD3 patient series to date, comprising 17 males with 12 distinct null variants and 2 partial gene deletions. All patients presented with intellectual disability, which was classified as moderate (65%) or mild (35%). Behavioral issues were present in 75% of patients, including aggressive behavior, attention deficit/hyperactivity and/or autistic spectrum disorders. Mean head circumference was +2.8 SD (2.8 standard deviations above the mean), and mean BMI was +2.0 SD (in the context of a mean height of +1.3 SD), indicating a predominant macrocephaly/obesity phenotype. Shared facial features included a tall chin, prognathism, broad forehead, and prominent supraorbital ridge. Additional features, reported in a minority (<30%) of patients included cryptorchidism, neonatal hypotonia, and small joint hypermobility. This study delineates the clinical features associated with BRWD3 null variants and partial gene deletions, and suggests that BRWD3 should be included in the differential diagnosis of patients with an overgrowth-intellectual disability (OGID) phenotype, particularly in male patients with a mild or moderate intellectual disability associated with macrocephaly and/or obesity.
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http://dx.doi.org/10.1002/ajmg.c.31750DOI Listing
December 2019

The phenotype of Sotos syndrome in adulthood: A review of 44 individuals.

Am J Med Genet C Semin Med Genet 2019 12 3;181(4):502-508. Epub 2019 Sep 3.

Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.

Sotos syndrome is an overgrowth-intellectual disability (OGID) syndrome caused by NSD1 pathogenic variants and characterized by a distinctive facial appearance, an intellectual disability, tall stature and/or macrocephaly. Other associated clinical features include scoliosis, seizures, renal anomalies, and cardiac anomalies. However, many of the published Sotos syndrome clinical descriptions are based on studies of children; the phenotype in adults with Sotos syndrome is not yet well described. Given that it is now 17 years since disruption of NSD1 was shown to cause Sotos syndrome, many of the children first reported are now adults. It is therefore timely to investigate the phenotype of 44 adults with Sotos syndrome and NSD1 pathogenic variants. We have shown that adults with Sotos syndrome display a wide spectrum of intellectual ability with functioning ranging from fully independent to fully dependent. Reproductive rates are low. In our cohort, median height in adult women is +1.9 SD and men +0.5 SD. There is a distinctive facial appearance in adults with a tall, square, prominent chin. Reassuringly, adults with Sotos syndrome are generally healthy with few new medical issues; however, lymphedema, poor dentition, hearing loss, contractures and tremor have developed in a small number of individuals.
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http://dx.doi.org/10.1002/ajmg.c.31738DOI Listing
December 2019

Defective tubulin detyrosination causes structural brain abnormalities with cognitive deficiency in humans and mice.

Hum Mol Genet 2019 10;28(20):3391-3405

Grenoble Institut Neurosciences, Université Grenoble Alpes, Inserm, U1216, CEA, CNRS, 38000 Grenoble, France.

Reversible detyrosination of tubulin, the building block of microtubules, is crucial for neuronal physiology. Enzymes responsible for detyrosination were recently identified as complexes of vasohibins (VASHs) one or two with small VASH-binding protein (SVBP). Here we report three consanguineous families, each containing multiple individuals with biallelic inactivation of SVBP caused by truncating variants (p.Q28* and p.K13Nfs*18). Affected individuals show brain abnormalities with microcephaly, intellectual disability and delayed gross motor and speech development. Immunoblot testing in cells with pathogenic SVBP variants demonstrated that the encoded proteins were unstable and non-functional, resulting in a complete loss of VASH detyrosination activity. Svbp knockout mice exhibit drastic accumulation of tyrosinated tubulin and a reduction of detyrosinated tubulin in brain tissue. Similar alterations in tubulin tyrosination levels were observed in cultured neurons and associated with defects in axonal differentiation and architecture. Morphological analysis of the Svbp knockout mouse brains by anatomical magnetic resonance imaging showed a broad impact of SVBP loss, with a 7% brain volume decrease, numerous structural defects and a 30% reduction of some white matter tracts. Svbp knockout mice display behavioural defects, including mild hyperactivity, lower anxiety and impaired social behaviour. They do not, however, show prominent memory defects. Thus, SVBP-deficient mice recapitulate several features observed in human patients. Altogether, our data demonstrate that deleterious variants in SVBP cause this neurodevelopmental pathology, by leading to a major change in brain tubulin tyrosination and alteration of microtubule dynamics and neuron physiology.
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http://dx.doi.org/10.1093/hmg/ddz186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891070PMC
October 2019

Encephalopathies with KCNC1 variants: genotype-phenotype-functional correlations.

Ann Clin Transl Neurol 2019 07 1;6(7):1263-1272. Epub 2019 Jul 1.

Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Melbourne, Australia.

Objective: To analyze clinical phenotypes associated with KCNC1 variants other than the Progressive Myoclonus Epilepsy-causing variant p.Arg320His, determine the electrophysiological functional impact of identified variants and explore genotype-phenotype-physiological correlations.

Methods: Ten cases with putative pathogenic variants in KCNC1 were studied. Variants had been identified via whole-exome sequencing or gene panel testing. Clinical phenotypic data were analyzed. To determine functional impact of variants detected in the K 3.1 channel encoded by KCNC1, Xenopus laevis oocyte expression system and automated two-electrode voltage clamping were used.

Results: Six unrelated patients had a Developmental and Epileptic Encephalopathy and a recurrent de novo variant p.Ala421Val (c.1262C > T). Functional analysis of p.Ala421Val revealed loss of function through a significant reduction in whole-cell current, but no dominant-negative effect. Three patients had a contrasting phenotype of Developmental Encephalopathy without seizures and different KCNC1 variants, all of which caused loss of function with reduced whole-cell currents. Evaluation of the variant p.Ala513Val (c.1538C > T) in the tenth case, suggested it was a variant of uncertain significance.

Interpretation: These are the first reported cases of Developmental and Epileptic Encephalopathy due to KCNC1 mutation. The spectrum of phenotypes associated with KCNC1 is now broadened to include not only a Progressive Myoclonus Epilepsy, but an infantile onset Developmental and Epileptic Encephalopathy, as well as Developmental Encephalopathy without seizures. Loss of function is a key feature, but definitive electrophysiological separation of these phenotypes has not yet emerged.
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http://dx.doi.org/10.1002/acn3.50822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649578PMC
July 2019

Implementation of a genomic medicine multi-disciplinary team approach for rare disease in the clinical setting: a prospective exome sequencing case series.

Genome Med 2019 07 25;11(1):46. Epub 2019 Jul 25.

National Institute for Health Research Biomedical Research Centre, Oxford, UK.

Background: A multi-disciplinary approach to promote engagement, inform decision-making and support clinicians and patients is increasingly advocated to realise the potential of genome-scale sequencing in the clinic for patient benefit. Here we describe the results of establishing a genomic medicine multi-disciplinary team (GM-MDT) for case selection, processing, interpretation and return of results.

Methods: We report a consecutive case series of 132 patients (involving 10 medical specialties with 43.2% cases having a neurological disorder) undergoing exome sequencing over a 10-month period following the establishment of the GM-MDT in a UK NHS tertiary referral hospital. The costs of running the MDT are also reported.

Results: In total 76 cases underwent exome sequencing following triage by the GM-MDT with a clinically reportable molecular diagnosis in 24 (31.6%). GM-MDT composition, operation and rationale for whether to proceed to sequencing are described, together with the health economics (cost per case for the GM-MDT was £399.61), the utility and informativeness of exome sequencing for molecular diagnosis in a range of traits, the impact of choice of sequencing strategy on molecular diagnostic rates and challenge of defining pathogenic variants. In 5 cases (6.6%), an alternative clinical diagnosis was indicated by sequencing results. Examples were also found where findings from initial genetic testing were reconsidered in the light of exome sequencing including TP63 and PRKAG2 (detection of a partial exon deletion and a mosaic missense pathogenic variant respectively); together with tissue-specific mosaicism involving a cytogenetic abnormality following a normal prenatal array comparative genomic hybridization.

Conclusions: This consecutive case series describes the results and experience of a multidisciplinary team format that was found to promote engagement across specialties and facilitate return of results to the responsible clinicians.
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http://dx.doi.org/10.1186/s13073-019-0651-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659244PMC
July 2019

A clinical scoring system for congenital contractural arachnodactyly.

Genet Med 2020 01 18;22(1):124-131. Epub 2019 Jul 18.

Center for Human Genetics, Institute of Pathology and Genetics (IPG), Gosselies, Belgium.

Purpose: Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and kyphoscoliosis as main features. Due to its rarity, rather aspecific clinical presentation, and overlap with other conditions including Marfan syndrome, the diagnosis is challenging, but important for prognosis and clinical management. CCA is caused by pathogenic variants in FBN2, encoding fibrillin-2, but locus heterogeneity has been suggested. We designed a clinical scoring system and diagnostic criteria to support the diagnostic process and guide molecular genetic testing.

Methods: In this retrospective study, we assessed 167 probands referred for FBN2 analysis and classified them into a FBN2-positive (n = 44) and FBN2-negative group (n = 123) following molecular analysis. We developed a 20-point weighted clinical scoring system based on the prevalence of ten main clinical characteristics of CCA in both groups.

Results: The total score was significantly different between the groups (P < 0.001) and was indicative for classifying patients into unlikely CCA (total score <7) and likely CCA (total score ≥7) groups.

Conclusions: Our clinical score is helpful for clinical guidance for patients suspected to have CCA, and provides a quantitative tool for phenotyping in research settings.
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http://dx.doi.org/10.1038/s41436-019-0609-8DOI Listing
January 2020

Do health professionals value genomic testing? A discrete choice experiment in inherited cardiovascular disease.

Eur J Hum Genet 2019 11 11;27(11):1639-1648. Epub 2019 Jun 11.

Health Economics Research Centre, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK.

Next generation sequencing (NGS) approaches are moving from research into clinical practice. However, the optimal NGS approach in well-defined adult-onset familial diseases, such as inherited cardiovascular disease, remains unclear. We aimed to determine which attributes encouraged or discouraged the uptake of genomic tests in this context, and whether this differed by test type. We conducted a web-based discrete choice experiment in health professionals in the UK who order NGS tests for inherited cardiovascular disease. Respondents completed 12 hypothetical choice tasks in which they selected a preferred test from four alternatives: whole genome sequencing, whole exome sequencing, panel testing and genetic testing not indicated. Tests were specified in terms of five attributes: diagnostic yield, detection rate for variants of unknown significance, cost, quantity of counselling received and disclosure of secondary findings. Mixed logit regression analysis was used to analyse the choice data. We found that uptake of NGS increases if tests identify more pathogenic mutations, identify fewer variants of unknown significance, or cost less. Respondents were willing to pay £117 for every 1% increase in diagnostic yield. Considerable heterogeneity was observed around preferences for several test attributes. Overall, panel testing had the highest predicted uptake rate. Our results indicate that NGS tests are valued by health professionals for well-defined adult-onset familial diseases, however, these professionals have strong preferences for panel testing rather than whole genome sequencing and whole exome sequencing. This finding suggests that different uptake rates should be explicitly modelled when designing and evaluating future genomic testing services.
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http://dx.doi.org/10.1038/s41431-019-0452-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6870981PMC
November 2019

Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome.

Clin Genet 2019 06 3;95(6):693-703. Epub 2019 Apr 3.

Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1-associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly-acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound-heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss-of-function mutations in NEB, consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities (P = 0.0005), supporting a causal role for LZTR1. Second, targeted sequencing of eight unsolved NS-like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.-38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1-4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected.
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http://dx.doi.org/10.1111/cge.13533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563422PMC
June 2019

Serpin B1 defect and increased apoptosis of neutrophils in Cohen syndrome neutropenia.

J Mol Med (Berl) 2019 05 7;97(5):633-645. Epub 2019 Mar 7.

Inserm UMR1170, Gustave Roussy Cancer Center, F-94800, Villejuif, France.

Cohen syndrome (CS) is a rare genetic disorder due to mutations in VPS13B gene. Among various clinical and biological features, CS patients suffer from inconsistent neutropenia, which is associated with recurrent but minor infections. We demonstrate here that this neutropenia results from an exaggerate rate of neutrophil apoptosis. Besides this increased cell death, which occurs in the absence of any endoplasmic reticulum stress or defect in neutrophil elastase (ELANE) expression or localization, all neutrophil functions appeared to be normal. We showed a disorganization of the Golgi apparatus in CS neutrophils precursors, that correlates with an altered glycosylation of ICAM-1 in these cells, as evidenced by a migration shift of the protein. Furthermore, a striking decrease in the expression of SERPINB1 gene, which encodes a critical component of neutrophil survival, was detected in CS neutrophils. These abnormalities may account for the excessive apoptosis of neutrophils leading to neutropenia in CS. KEY MESSAGES: Cohen syndrome patients' neutrophils display normal morphology and functions. Cohen syndrome patients' neutrophils have an increased rate of spontaneous apoptosis compared to healthy donors' neutrophils. No ER stress or defective ELA2 expression or glycosylation was observed in Cohen syndrome patients' neutrophils. SerpinB1 expression is significantly decreased in Cohen syndrome neutrophils as well as in VPS13B-deficient cells.
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http://dx.doi.org/10.1007/s00109-019-01754-4DOI Listing
May 2019

Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield.

Genet Med 2019 07 11;21(7):1576-1584. Epub 2018 Dec 11.

Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

Purpose: Increasing numbers of genes are being implicated in Mendelian disorders and incorporated into clinical test panels. However, lack of evidence supporting the gene-disease relationship can hinder interpretation. We explored the utility of testing 51 additional genes for hypertrophic cardiomyopathy (HCM), one of the most commonly tested Mendelian disorders.

Methods: Using genome sequencing data from 240 sarcomere gene negative HCM cases and 6229 controls, we undertook case-control and individual variant analyses to assess 51 genes that have been proposed for HCM testing.

Results: We found no evidence to suggest that rare variants in these genes are prevalent causes of HCM. One variant, in a single case, was categorized as likely to be pathogenic. Over 99% of variants were classified as a variant of uncertain significance (VUS) and 54% of cases had one or more VUS.

Conclusion: For almost all genes, the gene-disease relationship could not be validated and lack of evidence precluded variant interpretation. Thus, the incremental diagnostic yield of extending testing was negligible, and would, we propose, be outweighed by problems that arise with a high rate of uninterpretable findings. These findings highlight the need for rigorous, evidence-based selection of genes for clinical test panels.
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http://dx.doi.org/10.1038/s41436-018-0375-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614037PMC
July 2019

KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.

Genet Med 2019 04 24;21(4):850-860. Epub 2018 Sep 24.

Service de Génétique Médicale, CHU Nantes, Nantes, France.

Purpose: Pathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported.

Methods: We obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review.

Results: We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype- phenotype correlations show that late-truncating pathogenic variants (exons 16-17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction.

Conclusion: Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.
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http://dx.doi.org/10.1038/s41436-018-0259-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634310PMC
April 2019

Expanding the phenotypic spectrum of variants in PDE4D/PRKAR1A: from acrodysostosis to acroscyphodysplasia.

Eur J Hum Genet 2018 11 13;26(11):1611-1622. Epub 2018 Jul 13.

Department of Medical Genetics, INSERM UMR 1163, Paris Descartes-Sorbonne Paris Cité University, IMAGINE Institute, Necker Enfants Malades Hospital, Paris, France.

Acrodysostosis (MIM 101800) is a dominantly inherited condition associating (1) skeletal features (short stature, facial dysostosis, and brachydactyly with cone-shaped epiphyses), (2) resistance to hormones and (3) possible intellectual disability. Acroscyphodysplasia (MIM 250215) is characterized by growth retardation, brachydactyly, and knee epiphyses embedded in cup-shaped metaphyses. We and others have identified PDE4D or PRKAR1A variants in acrodysostosis; PDE4D variants have been reported in three cases of acroscyphodysplasia. Our study aimed at reviewing the clinical and molecular findings in a cohort of 27 acrodysostosis and 5 acroscyphodysplasia cases. Among the acrodysostosis cases, we identified 9 heterozygous de novo PRKAR1A variants and 11 heterozygous PDE4D variants. The 7 patients without variants presented with symptoms of acrodysostosis (brachydactyly and cone-shaped epiphyses), but none had the characteristic facial dysostosis. In the acroscyphodysplasia cases, we identified 2 PDE4D variants. For 2 of the 3 negative cases, medical records revealed early severe infection, which has been described in some reports of acroscyphodysplasia. Subdividing our series of acrodysostosis based on the disease-causing gene, we confirmed genotype-phenotype correlations. Hormone resistance was consistently observed in patients carrying PRKAR1A variants, whereas no hormone resistance was observed in 9 patients with PDE4D variants. All patients with PDE4D variants shared characteristic facial features (midface hypoplasia with nasal hypoplasia) and some degree of intellectual disability. Our findings of PDE4D variants in two cases of acroscyphodysplasia support that PDE4D may be responsible for this severe skeletal dysplasia. We eventually emphasize the importance of some specific assessments in the long-term follow up, including cardiovascular and thromboembolic risk factors.
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http://dx.doi.org/10.1038/s41431-018-0135-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189044PMC
November 2018

De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.

Am J Hum Genet 2018 06 31;102(6):1195-1203. Epub 2018 May 31.

Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA 92656, USA.

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.
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http://dx.doi.org/10.1016/j.ajhg.2018.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992133PMC
June 2018

Prediction of response to targeted and immune checkpoint therapies.

Per Med 2018 01;15(1):45-56

Quest-ion, Bunschotenstraat 18, 1324PD Almere, The Netherlands.

Targeted therapies continue to be key components of cancer treatment. New approaches to detection of acquired resistance at the genomic level, in combination with new therapies, help to overcome the challenges that are seen frequently, rapidly and broadly across tumor pathologies, and provide opportunities for cancer management. In the last several years, a new breed of modalities called immune checkpoint inhibitors have come to the forefront of clinically effective treatments. A plethora of rapid approvals and early access initiatives have seen anti-cytotoxic T-lymphocyte-associated antigen-4, and particularly anti-programmed death receptor-1 therapies, deployed in a number of tumor indications of high unmet need. With the rise of immune checkpoint inhibition, and the broader resurgence in the immuno-oncology field, we are facing challenges in the prediction of response.
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http://dx.doi.org/10.2217/pme-2017-0051DOI Listing
January 2018

Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.

Genet Med 2018 10 22;20(10):1175-1185. Epub 2018 Feb 22.

National Institute for Health Research Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.

Purpose: To characterize the molecular genetics of autosomal recessive Noonan syndrome.

Methods: Families underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction.

Results: Twelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings.

Conclusion: These clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.
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http://dx.doi.org/10.1038/gim.2017.249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105555PMC
October 2018

Views of rare disease participants in a UK whole-genome sequencing study towards secondary findings: a qualitative study.

Eur J Hum Genet 2018 05 13;26(5):652-659. Epub 2018 Feb 13.

Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

With large-scale genome sequencing initiatives underway, vast amounts of genomic data are being generated. Results-including secondary findings (SF)-are being returned, although policies around generation and management remain inconsistent. In order to inform relevant policy, it is essential that the views of stakeholders be considered-including participants who have made decisions about SF since the wider debate began. We conducted semi-structured interviews with sixteen rare disease patients and parents enroled in genome sequencing to explore views towards SF. Informed by extensive contact with the healthcare system, interviewees demonstrated high levels of understanding of genetic testing and held pragmatic views: many are content not knowing SF. Interviewees expressed trust in the system and healthcare providers, as well as an appreciation of limited resources; acknowledging existing disease burden, many preferred to focus on their primary condition. Many demonstrated an expectation for recontact and assumed the possibility of later access to initially declined SF. In the absence of such an infrastructure, it is important that responsibilities for recontact are delineated, expectations are addressed, and the long-term impact of decisions is made clear during consent. In addition, some interviewees demonstrated fluid views towards SF, and suggestions were made that perceptions may be influenced by family history. Further research into the changing desirability of SF and behavioural impact of disclosure are needed, and the development and introduction of mechanisms to respond to changes in patient views should be considered.
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http://dx.doi.org/10.1038/s41431-018-0106-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945590PMC
May 2018

"Not pathogenic until proven otherwise": perspectives of UK clinical genomics professionals toward secondary findings in context of a Genomic Medicine Multidisciplinary Team and the 100,000 Genomes Project.

Genet Med 2018 03 26;20(3):320-328. Epub 2017 Oct 26.

Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

PurposeApproaches to secondary findings in genome sequencing (GS) are unresolved. In the United Kingdom, GS is now routinely available through the 100,000 Genomes Project, which offers participants feedback of limited secondary findings.MethodsIn Oxford, a Genomic Medicine Multidisciplinary Team (GM-MDT) governs local access to GS, and reviews findings. Semistructured interviews were conducted with 19 GM-MDT members to explore perspectives on secondary findings.ResultsWhile enthusiastic about GS for diagnosing rare disease, members question the rationale for genome screening largely because of lack of evidence for clinical utility and limited justification for use of resources. Members' views are drawn from diverse experiences; they feel a strong sense of responsibility to act in participants' best interests. The capacity to return limited secondary findings should be enabled, but members favor a cautious approach that is responsive to accumulating evidence. Informed participant choice is considered critical, yet challenging. Discrimination of variants is considered essential, and requiring of specialist input and consensus. Multiple areas requiring enhanced engagement and education are identified, i.e., for patients, the public, and health-care professionals; at present, mainstreaming of genomics may be premature.ConclusionUK experts believe that evidence to inform policy toward secondary findings is lacking, arguing for caution.
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http://dx.doi.org/10.1038/gim.2017.157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880578PMC
March 2018

High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.

Am J Hum Genet 2017 Nov;101(5):664-685

Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK.

Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.
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http://dx.doi.org/10.1016/j.ajhg.2017.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673604PMC
November 2017

A point mutation in the ion conduction pore of AMPA receptor GRIA3 causes dramatically perturbed sleep patterns as well as intellectual disability.

Hum Mol Genet 2017 10;26(20):3869-3882

Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.

The discovery of genetic variants influencing sleep patterns can shed light on the physiological processes underlying sleep. As part of a large clinical sequencing project, WGS500, we sequenced a family in which the two male children had severe developmental delay and a dramatically disturbed sleep-wake cycle, with very long wake and sleep durations, reaching up to 106-h awake and 48-h asleep. The most likely causal variant identified was a novel missense variant in the X-linked GRIA3 gene, which has been implicated in intellectual disability. GRIA3 encodes GluA3, a subunit of AMPA-type ionotropic glutamate receptors (AMPARs). The mutation (A653T) falls within the highly conserved transmembrane domain of the ion channel gate, immediately adjacent to the analogous residue in the Grid2 (glutamate receptor) gene, which is mutated in the mouse neurobehavioral mutant, Lurcher. In vitro, the GRIA3(A653T) mutation stabilizes the channel in a closed conformation, in contrast to Lurcher. We introduced the orthologous mutation into a mouse strain by CRISPR-Cas9 mutagenesis and found that hemizygous mutants displayed significant differences in the structure of their activity and sleep compared to wild-type littermates. Typically, mice are polyphasic, exhibiting multiple sleep bouts of sleep several minutes long within a 24-h period. The Gria3A653T mouse showed significantly fewer brief bouts of activity and sleep than the wild-types. Furthermore, Gria3A653T mice showed enhanced period lengthening under constant light compared to wild-type mice, suggesting an increased sensitivity to light. Our results suggest a role for GluA3 channel activity in the regulation of sleep behavior in both mice and humans.
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http://dx.doi.org/10.1093/hmg/ddx270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5639461PMC
October 2017

Multiple long bone cysts revealed by MRI in trichorhinophalangeal syndrome type II predisposing to pathological fractures.

Pediatr Radiol 2017 Jul 10;47(8):1016-1021. Epub 2017 May 10.

Department of Radiology, The Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, UK.

Trichorhinophalangeal syndrome type II is a rare genetic disorder with the few published case reports mainly reporting the radiographic skeletal manifestations. There are no published imaging reports of long bone cysts involving multiple bones in this condition. We report a unique case of bone cysts involving multiple long bones detected with MRI in a patient with trichorhinophalangeal syndrome type II complicated by a subsequent pathological fracture. It is possible that the bone cysts are a previously undescribed feature of this syndrome; however, the evidence is insufficient to establish a definite association. Chromosomal abnormality identified in this patient is consistent with trichorhinophalangeal syndrome type II with no unusual features. Although the nature of these bone cysts is unclear, they are one of the causes of the known increased fracture risk observed in this syndrome.
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http://dx.doi.org/10.1007/s00247-017-3839-4DOI Listing
July 2017

Insights from early experience of a Rare Disease Genomic Medicine Multidisciplinary Team: a qualitative study.

Eur J Hum Genet 2017 06 22;25(6):680-686. Epub 2017 Mar 22.

Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

Whole-exome/whole-genome sequencing (WES/WGS) has the potential to enhance genetic diagnosis of rare disease, and is increasingly becoming part of routine clinical care in mainstream medicine. Effective translation will require ongoing efforts in a number of areas including: selection of appropriate patients, provision of effective consent, pre- and post-test genetic counselling, improving variant interpretation algorithms and practices, and management of secondary findings including those found incidentally and those actively sought. Allied to this is the need for an effective education programme for all members of clinical teams involved in care of patients with rare disease, as well as to maintain public confidence in the use of these technologies. We established a Genomic Medicine Multidisciplinary Team (GM-MDT) in 2014 to build on the experiences of earlier successful research-based WES/WGS studies, to address these needs and to review results including pertinent and secondary findings. Here we report on a qualitative study of decision-making in the GM-MDT combined with analysis of semi-structured interviews with GM-MDT members. Study findings show that members appreciate the clinical and scientific diversity of the GM-MDT and value it for education and oversight. To date, discussions have focussed on case selection including the extent and interpretation of clinical and family history information required to establish likely monogenic aetiology and inheritance model. Achieving a balance between effective use of WES/WGS - prioritising cases in a diverse and highly complex patient population where WES/WGS will be tractable - and meeting the recruitment targets of a large project is considered challenging.
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http://dx.doi.org/10.1038/ejhg.2017.37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427178PMC
June 2017

Combination of Whole Genome Sequencing, Linkage, and Functional Studies Implicates a Missense Mutation in Titin as a Cause of Autosomal Dominant Cardiomyopathy With Features of Left Ventricular Noncompaction.

Circ Cardiovasc Genet 2016 Oct 13;9(5):426-435. Epub 2016 Sep 13.

Background: High throughput next-generation sequencing techniques have made whole genome sequencing accessible in clinical practice; however, the abundance of variation in the human genomes makes the identification of a disease-causing mutation on a background of benign rare variants challenging.

Methods And Results: Here we combine whole genome sequencing with linkage analysis in a 3-generation family affected by cardiomyopathy with features of autosomal dominant left ventricular noncompaction cardiomyopathy. A missense mutation in the giant protein titin is the only plausible disease-causing variant that segregates with disease among the 7 surviving affected individuals, with interrogation of the entire genome excluding other potential causes. This A178D missense mutation, affecting a conserved residue in the second immunoglobulin-like domain of titin, was introduced in a bacterially expressed recombinant protein fragment and biophysically characterized in comparison to its wild-type counterpart. Multiple experiments, including size exclusion chromatography, small-angle x ray scattering, and circular dichroism spectroscopy suggest partial unfolding and domain destabilization in the presence of the mutation. Moreover, binding experiments in mammalian cells show that the mutation markedly impairs binding to the titin ligand telethonin.

Conclusions: Here we present genetic and functional evidence implicating the novel A178D missense mutation in titin as the cause of a highly penetrant familial cardiomyopathy with features of left ventricular noncompaction. This expands the spectrum of titin's roles in cardiomyopathies. It furthermore highlights that rare titin missense variants, currently often ignored or left uninterpreted, should be considered to be relevant for cardiomyopathies and can be identified by the approach presented here.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068189PMC
http://dx.doi.org/10.1161/CIRCGENETICS.116.001431DOI Listing
October 2016
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