Detection of an Apparent Homozygous 3120G&gt;A Cystic Fibrosis Mutation on a Routine Carrier Screen

Heaney, Denise LaMarche; Flume, Patrick A.; Hamilton, Lauren; Lyon, Elaine; Wolff, Daynna J.

doi:10.2353/jmoldx.2006.050065

Cited by 8 publications

(7 citation statements)

References 17 publications

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“…In Kuwaiti population, 55% of the CF patients exhibited the delF508, G542N and p.W1282X while 24% of cases showed c.1548delG, c.I1234V and 3120+1G>A [15]. In another study, the 3120+1G>A was a rare mutation, been detected in 3 patients along with another patient having an additional mutation ∆F508 on the other allele [16]. Our results showed 4 patients with the 3120+1G>A mutation only and one patient carrying both the 3120+1G>A and ∆F508 mutations.…”

Section: Discussionsupporting

confidence: 46%

“…More interestingly, a previous study including UAE and Oman populations showed that all patients were homomzygous for the single mutation p.S549R. Another study conducted for only 16 Omani patients revealed that 69% from Bedouin descent were found to have the p.S549R (T-G) mutation, while 12.5% (two), from Baluch decent had the ΔF508 mutation, and the remaining patients were negative for the mutations [4,10]. All these studies are in agreement with the findings of our present study.…”

Section: Discussionmentioning

confidence: 91%

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Novel Mutation in the CFTR Gene of Cystic Fibrosis Patients in Oman

Al-Kindy¹

2014

J Mol Biomark Diagn

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Blood samples (2-5 ml) were collected from patients and genomic DNA was isolated using QIAamp Blood Maxi kit DNA extraction according to the manufacturer's instructions (QIAGEN, USA). The full coding sequence of the CFTR gene was amplified using primers specific for each of the 27 exons. Amplification included a 4-min denaturation set up at 94°C, followed by 35 cycles each consisting of 30s denaturation at 94°C, 30s of annealing at temperatures ranging from 58 to 65°C

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Section: Discussionsupporting

confidence: 46%

Section: Discussionmentioning

confidence: 91%

Novel Mutation in the CFTR Gene of Cystic Fibrosis Patients in Oman

Al-Kindy¹

2014

J Mol Biomark Diagn

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“…The probes correspond to the normal and mutated alleles, covering 36 most frequent European CFTR mutations. The procedure was performed as indicated by the manufacturer (InnoGenetics, Ghent, Belgium; see also [35] ).…”

Section: Methodsmentioning

confidence: 99%

CFTR Mutations Spectrum and the Efficiency of Molecular Diagnostics in Polish Cystic Fibrosis Patients

Ziętkiewicz

Rutkiewicz

Pogorzelski³

et al. 2014

PLoS ONE

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Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane regulator gene (CFTR). In light of the strong allelic heterogeneity and regional specificity of the mutation spectrum, the strategy of molecular diagnostics and counseling in CF requires genetic tests to reflect the frequency profile characteristic for a given population. The goal of the study was to provide an updated comprehensive estimation of the distribution of CFTR mutations in Polish CF patients and to assess the effectiveness of INNOLiPA_CFTR tests in Polish population. The analyzed cohort consisted of 738 patients with the clinically confirmed CF diagnosis, prescreened for molecular defects using INNOLiPA_CFTR panels from Innogenetics. A combined efficiency of INNOLiPA CFTR_19 and CFTR_17_TnUpdate tests was 75.5%; both mutations were detected in 68.2%, and one mutation in 14.8% of the affected individuals. The group composed of all the patients with only one or with no mutation detected (109 and 126 individuals, respectively) was analyzed further using a mutation screening approach, i.e. SSCP/HD (single strand conformational polymorphism/heteroduplex) analysis of PCR products followed by sequencing of the coding sequence. As a result, 53 more mutations were found in 97 patients. The overall efficiency of the CF allele detection was 82.5% (7.0% increase compared to INNOLiPA tests alone). The distribution of the most frequent mutations in Poland was assessed. Most of the mutations repetitively found in Polish patients had been previously described in other European populations. The most frequent mutated allele, F508del, represented 54.5% of Polish CF chromosomes. Another eight mutations had frequencies over 1%, 24 had frequencies between 1 and 0.1%; c.2052-2053insA and c.3468+2_3468+3insT were the most frequent non-INNOLiPA mutations. Mutation distribution described herein is also relevant to the Polish diaspora. Our study also demonstrates that the reported efficiency of mutation detection strongly depends on the diagnostic experience of referring health centers.

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“…We obtained HEK293 cells stably expressing a minigene containing the full length CFTR coding sequence carrying a c.2988G>A mutation and flanking introns ( Supplementary table 3) 60 . This mutation is associated with abnormal CFTR function and causes a mild form of CF (MIM# 219700) 61 . Treatment with BPN-15477 increased exon 18 inclusion by 10%, confirming our CNN model prediction ( Fig.…”

Section: Experimental Validation Of New Therapeutic Targets For Bpn-1mentioning

confidence: 99%

A deep learning approach to identify new gene targets of a novel therapeutic for human splicing disorders

Gao

Morini

Salani

et al. 2020

Preprint

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Pre-mRNA splicing is a key control point in human gene expression. Disturbances in splicing due to mutation or aberrant splicing regulatory networks lead to dysregulated protein expression and contribute to a substantial fraction of human disease. Several classes of active and selective splicing modulator compounds have been recently identified, thus proving that pre-mRNA splicing is a viable target for therapy. We describe herein the identification of BPN-15477, a novel splicing modulator compound, that restores correct splicing of exon 20 in the Elongator complex protein 1 (ELP1) gene carrying the major IVS20+6T>C mutation responsible for familial dysautonomia. We then developed a machine learning approach to evaluate the therapeutic potential of BPN-15477 to correct splicing in other human genetic diseases. Using transcriptome sequencing from compound-treated fibroblast cells, we identified treatment responsive sequence signatures, the majority of which center at the 5' splice site of exons whose inclusion or exclusion is modulated by SMC treatment. We then leveraged this model to identify 155 human disease genes that harbor ClinVar mutations predicted to alter pre-mRNA splicing as potential targets for BPN-15477 treatment. Using in vitro splicing assays, we validated representative predictions by demonstrating successful correction of splicing defects caused by mutations in genes responsible for cystic fibrosis (CFTR), cholesterol ester storage disease (LIPA), Lynch syndrome (MLH1) and familial frontotemporal dementia (MAPT). Our study shows that deep learning techniques can identify a complex set of sequence signatures and predict response to pharmacological modulation, strongly supporting the use of in silico approaches to expand the therapeutic potential of drugs that modulate splicing.

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Detection of an Apparent Homozygous 3120G>A Cystic Fibrosis Mutation on a Routine Carrier Screen

Cited by 8 publications

References 17 publications

Novel Mutation in the CFTR Gene of Cystic Fibrosis Patients in Oman

Novel Mutation in the CFTR Gene of Cystic Fibrosis Patients in Oman

CFTR Mutations Spectrum and the Efficiency of Molecular Diagnostics in Polish Cystic Fibrosis Patients

A deep learning approach to identify new gene targets of a novel therapeutic for human splicing disorders

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