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FLAGS, frequently mutated genes in public exomes
2014
BMC Medical Genomics
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Dramatic improvements in DNA-sequencing technologies and computational analyses have led to wide use of whole exome sequencing (WES) to identify the genetic basis of Mendelian disorders. More than 180 novel rare-disease-causing genes with Mendelian inheritance patterns have been discovered through sequencing the exomes of just a few unrelated individuals or family members. As rare/novel genetic variants continue to be uncovered, there is a major challenge in distinguishing true pathogenic
doi:10.1186/s12920-014-0064-y
pmid:25466818
pmcid:PMC4267152
fatcat:kjakuslqnrfshfhhlwlwv5oefe
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... ts from rare benign mutations. Methods: We used publicly available exome cohorts, together with the dbSNP database, to derive a list of genes (n = 100) that most frequently exhibit rare (<1%) non-synonymous/splice-site variants in general populations. We termed these genes FLAGS for FrequentLy mutAted GeneS and analyzed their properties.
Correction to: FLAGS, frequently mutated genes in public exomes
2017
BMC Medical Genomics
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Exome sequencing pilot study in children with carbamazepine-induced serious skin reactions
2014
Clinical and Translational Allergy
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Linkage analysis identifies an isolated strabismus locus at 14q12 overlapping with FOXG1 syndrome region
[article]
2020
medRxiv
pre-print
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Strabismus is a common condition, affecting 1-4% of individuals. Isolated strabismus has been studied in families with Mendelian inheritance patterns. Despite the identification of multiple loci via linkage analyses, no specific genes have been identified from these studies. The current study is based on a seven-generation family with isolated strabismus inherited in an autosomal dominant manner. A total of 13 individuals from a common ancestor have been included for linkage analysis, and a
doi:10.1101/2020.04.24.20077586
fatcat:nmrsnok5mrhhvloz2o3alli7gq
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... le linkage signal has been identified at chromosome 14q12 with a multipoint LOD score of 4.69. Disruption of this locus is known to cause FOXG1 syndrome (or congenital Rett syndrome; OMIM #613454 and *164874), in which 84% of affected individuals present with strabismus. With the incorporation of next generation sequencing and in-depth bioinformatic analyses, a 4bp non-coding deletion was prioritized as the top candidate for the observed strabismus phenotype. The deletion is predicted to disrupt regulation of FOXG1, which encodes a transcription factor of the Forkhead family. Suggestive of an auto-regulation effect, the disrupted sequence matches the consensus FOXG1 and Forkhead family transcription factor binding site and has been observed in previous ChIP-seq studies to be bound by Foxg1 in early mouse brain development. The findings of this study indicate that the strabismus phenotype commonly observed within FOXG1 syndrome is separable from the more severe syndromic characteristics. Future study of this specific deletion may shed light on the regulation of FOXG1 expression and may enhance our understanding of the mechanisms contributing to strabismus and FOXG1 syndrome.
A novel recurrent mutation in ATP1A3 causes CAPOS syndrome
2014
Orphanet Journal of Rare Diseases
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We undertook genetic analysis of three affected families to identify the cause of dominantly-inherited CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss) syndrome. Methods: We used whole-exome sequencing to analyze two families affected with CAPOS syndrome, including the original family reported in 1996, and Sanger sequencing to assess familial segregation of rare variants identified in the probands and in a third, apparently unrelated family with
doi:10.1186/1750-1172-9-15
pmid:24468074
pmcid:PMC3937150
fatcat:lml3kxobzfbkvkwnrvbygjs5nq
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... syndrome. Results: We found an identical heterozygous missense mutation, c.2452G > A (p.(Glu818Lys)), in the Na + /K + ATPase α 3 (ATP1A3) gene in the proband and his affected sister and mother, but not in either unaffected maternal grandparent, in the first family. The same mutation was also identified in the proband and three other affected members of the second family and in all three affected members of the third family. This mutation was not found in more than 3600 chromosomes from unaffected individuals. Conclusion: Other mutations in ATP1A3 have previously been demonstrated to cause rapid-onset dystonia-parkinsonism (also called dystonia-12) or alternating hemiplegia of childhood. This study shows that an allelic mutation in ATP1A3 produces CAPOS syndrome. We obtained informed consent and assent, when appropriate, from participating family members. Ethical review
Dynamic software design for clinical exome and genome analyses: insights from bioinformaticians, clinical geneticists, and genetic counselors
2015
JAMIA Journal of the American Medical Informatics Association
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Key matters that were repeatedly referred to in the focus groups were typed on a laptop by the moderator (Casper Shyr (CS)) and projected on a big screen via a projector. ...
doi:10.1093/jamia/ocv053
pmid:26117142
pmcid:PMC4784553
fatcat:6moa6v3yszew5purfv6hdaxpga
The genotypic and phenotypic spectrum of PIGA deficiency
2015
Orphanet Journal of Rare Diseases
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Phosphatidylinositol glycan biosynthesis class A protein (PIGA) is one of the enzymes involved in the biosynthesis of glycosylphosphatidylinositol (GPI) anchor proteins, which function as enzymes, adhesion molecules, complement regulators and co-receptors in signal transduction pathways. Until recently, only somatic PIGA mutations had been reported in patients with paroxysmal nocturnal hemoglobinuria (PNH), while germline mutations had not been observed, and were suspected to result in
doi:10.1186/s13023-015-0243-8
pmid:25885527
pmcid:PMC4348372
fatcat:llsmzcudlrb4fmz2rc6hcwjk7y
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... . However, in just two years, whole exome sequencing (WES) analyses have identified germline PIGA mutations in male patients with XLIDD (X-linked intellectual developmental disorder) with a wide spectrum of clinical presentations. Methods and results: Here, we report on a new missense PIGA germline mutation [g.15342986C>T (p.S330N)] identified via WES followed by Sanger sequencing, in a Chinese male infant presenting with developmental arrest, infantile spasms, a pattern of lesion distribution on brain MRI resembling that typical of maple syrup urine disease, contractures, dysmorphism, elevated alkaline phosphatase, mixed hearing loss (a combination of conductive and sensorineural), liver dysfunction, mitochondrial complex I and V deficiency, and therapy-responsive dyslipidemia with confirmed lipoprotein lipase deficiency. X-inactivation studies showed skewing in the clinically unaffected carrier mother, and CD109 surface expression in patient fibroblasts was 57% of that measured in controls; together these data support pathogenicity of this mutation. Furthermore, we review all reported germline PIGA mutations (1 nonsense, 1 frameshift, 1 in-frame deletion, five missense) in 8 unrelated families. Conclusions: Our case further delineates the heterogeneous phenotype of this condition for which we propose the term 'PIGA deficiency'. While the phenotypic spectrum is wide, it could be classified into two types (severe and less severe) with shared hallmarks of infantile spasms with hypsarrhythmia on EEG and profound XLIDD. In severe PIGA deficiency, as described in our patient, patients also present with dysmorphic facial features, multiple CNS abnormalities, such as thin corpus callosum and delayed myelination, as well as hypotonia and elevated alkaline phosphatase along with liver, renal, and cardiac involvement; its course is often fatal. The less severe form of PIGA deficiency does not involve facial dysmorphism and multiple CNS abnormalities; instead, patients present with milder IDD, treatable seizures and generally a longer lifespan.
Optic atrophy, cataracts, lipodystrophy/lipoatrophy, and peripheral neuropathy caused by a de novo OPA3 mutation
2016
Molecular Case Studies
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align the FASTQ reads to the human genome reference version 19 (GRCh37.75) and to identify and assess the predicted effect of rare (<3% allelic frequency from dbSNPv146) variants on protein function (Shyr ...
doi:10.1101/mcs.a001156
pmid:28050599
pmcid:PMC5171695
fatcat:j5kfhon2qbhchbigztpgns7zqq
Further Validation of the SIGMAR1 c.151+1G>T Mutation as Cause of Distal Hereditary Motor Neuropathy
2016
Child Neurology Open
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Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis
2010
Nucleic Acids Research
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The Nrf2 (nuclear factor E2 p45-related factor 2) transcription factor responds to diverse oxidative and electrophilic environmental stresses by circumventing repression by Keap1, translocating to the nucleus, and activating cytoprotective genes. Nrf2 responses provide protection against chemical carcinogenesis, chronic inflammation, neurodegeneration, emphysema, asthma and sepsis in murine models. Nrf2 regulates the expression of a plethora of genes that detoxify oxidants and electrophiles and
doi:10.1093/nar/gkq212
pmid:20460467
pmcid:PMC2943601
fatcat:kigebjmawrcb5c7apbbmrcn7yy
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... repair or remove damaged macromolecules, such as through proteasomal processing. However, many direct targets of Nrf2 remain undefined. Here, mouse embryonic fibroblasts (MEF) with either constitutive nuclear accumulation (Keap1 À/À ) or depletion (Nrf2 À/À ) of Nrf2 were utilized to perform chromatin-immunoprecipitation with parallel sequencing (ChIP-Seq) and global transcription profiling. This unique Nrf2 ChIP-Seq dataset is highly enriched for Nrf2-binding motifs. Integrating ChIP-Seq and microarray analyses, we identified 645 basal and 654 inducible direct targets of Nrf2, with 244 genes at the intersection. Modulated pathways in stress response and cell proliferation distinguish the inducible and basal programs. Results were confirmed in an in vivo stress model of cigarette smoke-exposed mice. This study reveals global circuitry of the Nrf2 stress response emphasizing Nrf2 as a central node in cell survival response.
RMND1 deficiency associated with neonatal lactic acidosis, infantile onset renal failure, deafness and multiorgan involvement
2015
European Journal of Human Genetics
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RMND1 is an integral inner membrane mitochondrial protein that assembles into a large 240 kDa complex to support translation of the 13 polypeptides encoded on mtDNA, all of which are essential subunits of the oxidative phosphorylation (OXPHOS) complexes. Variants in RMND1 produce global defects in mitochondrial translation and were first reported in patients with severe neurological phenotypes leading to mortality in the first months of life. Using whole-exome sequencing, we identified compound
doi:10.1038/ejhg.2014.293
pmid:25604853
pmcid:PMC4592087
fatcat:bjcrp5ra7bbdzpgikyav3e3dnq
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... heterozygous RMND1 variants in a 4-year-old patient with congenital lactic acidosis, severe myopathy, hearing loss, renal failure, and dysautonomia. The levels of mitochondrial ribosome proteins were reduced in patient fibroblasts, causing a translation defect, which was rescued by expression of the wild-type cDNA. RMND1 was almost undetectable by immunoblot analysis in patient muscle and fibroblasts. BN-PAGE analysis showed a severe combined OXPHOS assembly defect that was more prominent in patient muscle than in fibroblasts. Immunofluorescence experiments showed that RMND1 localizes to discrete foci in the mitochondrial network, juxtaposed to RNA granules where the primary mitochondrial transcripts are processed. RMND1 foci were not detected in patient fibroblasts. We hypothesize that RMND1 acts to anchor or stabilize the mitochondrial ribosome near the sites where the mRNAs are matured, spatially coupling post-transcriptional handling mRNAs with their translation, and that loss of function variants in RMND1 are associated with a unique constellation of clinical phenotypes that vary with the severity of the mitochondrial translation defect.
Linkage analysis identifies an isolated strabismus locus at 14q12 overlapping with FOXG1 syndrome region
2020
Journal of Medical Genetics
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Strabismus is a common condition, affecting 1%–4% of individuals. Isolated strabismus has been studied in families with Mendelian inheritance patterns. Despite the identification of multiple loci via linkage analyses, no specific genes have been identified from these studies. The current study is based on a seven-generation family with isolated strabismus inherited in an autosomal dominant manner. A total of 13 individuals from a common ancestor have been included for linkage analysis. Among
doi:10.1136/jmedgenet-2020-107226
pmid:33257509
pmcid:PMC8685624
fatcat:kd5h4w2pszffpewwqd6vkzdo3i
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... se, nine are affected and four are unaffected. A single linkage signal has been identified at an 8.5 Mb region of chromosome 14q12 with a multipoint LOD (logarithm of the odds) score of 4.69. Disruption of this locus is known to cause FOXG1 syndrome (or congenital Rett syndrome; OMIM #613454 and *164874), in which 84% of affected individuals present with strabismus. With the incorporation of next-generation sequencing and in-depth bioinformatic analyses, a 4 bp non-coding deletion was prioritised as the top candidate for the observed strabismus phenotype. The deletion is predicted to disrupt regulation of FOXG1, which encodes a transcription factor of the Forkhead family. Suggestive of an autoregulation effect, the disrupted sequence matches the consensus FOXG1 and Forkhead family transcription factor binding site and has been observed in previous ChIP-seq studies to be bound by Foxg1 in early mouse brain development. Future study of this specific deletion may shed light on the regulation of FOXG1 expression and may enhance our understanding of the mechanisms contributing to strabismus and FOXG1 syndrome.
JASPAR 2014: an extensively expanded and updated open-access database of transcription factor binding profiles
2013
Nucleic Acids Research
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JASPAR 2016: a major expansion and update of the open-access database of transcription factor binding profiles
2015
Nucleic Acids Research
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JASPAR (http://jaspar.genereg.net) is an openaccess database storing curated, non-redundant transcription factor (TF) binding profiles represent- ing transcription factor binding preferences as position frequency matrices for multiple species in six taxonomic groups. For this 2016 release, we expanded the JASPAR CORE collection with 494 new TF binding profiles (315 in vertebrates, 11 in nematodes, 3 in insects, 1 in fungi and 164 in plants) and updated 59 profiles (58 in vertebrates and 1 in
doi:10.1093/nar/gkv1176
pmid:26531826
pmcid:PMC4702842
fatcat:dfyf2xpuprh4pg2udndeovgxrm
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... gi). The introduced profiles represent an 83% expansion and 10% update when compared to the previous release. We updated the structural annotation of the TF DNA binding domains (DBDs) following a published hierarchical structural classification. In addition, we introduced 130 transcription factor flexible models trained on ChIP-seq data for vertebrates, which capture dinucleotide dependencies within TF binding sites. This new JASPAR release is accompanied by a new web tool to infer JASPAR TF binding profiles recognized by a given TF protein sequence. Moreover, we provide the users with a Ruby module complementing the JASPAR API to ease programmatic access and use of the JASPAR collection of profiles. Finally, we provide the JASPAR2016 R/Bioconductor
Atypical cerebral palsy: genomics analysis enables precision medicine
2018
Genetics in Medicine
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The presentation and etiology of cerebral palsy (CP) are heterogeneous. Diagnostic evaluation can be a prolonged and expensive process that might remain inconclusive. This study aimed to determine the diagnostic yield and impact on management of next-generation sequencing (NGS) in 50 individuals with atypical CP (ACP).
doi:10.1038/s41436-018-0376-y
pmid:30542205
fatcat:lhoanbolkngankvtu4xihoavpy
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