Dataset Information

Homozygous Deletion of the CFTR Gene Caused by Interstitial Maternal Isodisomy in a Peruvian Child with Cystic Fibrosis.

ABSTRACT: We report the first case in Peru of cystic fibrosis caused by a homozygous deletion of the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene. A 10-month-old child who presented with meconium ileus and pancreatic insufficiency was tested for cystic fibrosis. Both parents of the child are of Peruvian background, are nonconsanguineous, and have no personal or family history of the disease. Chromosome microarray analysis revealed a homozygous deletion of the CFTR gene on chromosome 7 (7q31.2) within a maternally derived 12.8-Mb region of loss of heterozygosity with deletion of a region that includes the CFTR gene. Parental testing confirmed this finding. This case highlights the great importance of molecular testing and the study of chromosomal rearrangements in reaching a correct diagnosis and providing proper genetic counseling to the affected families.

SUBMITTER: Vasquez Sotomayor F

PROVIDER: S-EPMC6688885 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Homozygous Deletion of the CFTR Gene Caused by Interstitial Maternal Isodisomy in a Peruvian Child with Cystic Fibrosis.

Vásquez Sotomayor Flor F Abarca-Barriga Hugo Hernán HH

Journal of pediatric genetics 20190213 3

We report the first case in Peru of cystic fibrosis caused by a homozygous deletion of the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene. A 10-month-old child who presented with meconium ileus and pancreatic insufficiency was tested for cystic fibrosis. Both parents of the child are of Peruvian background, are nonconsanguineous, and have no personal or family history of the disease. Chromosome microarray analysis revealed a homozygous deletion of the CFTR gene o ...[more]

PMID: 31406621

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Project description:BackgroundCystic fibrosis is a life-limiting disease that is caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Phe508del is the most common CFTR mutation.MethodsWe conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator, in patients 12 years of age or older who had cystic fibrosis and were homozygous for the Phe508del CFTR mutation. In both studies, patients were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary end point was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24.ResultsA total of 1108 patients underwent randomization and received study drug. The mean baseline FEV1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both lumacaftor-ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV1 ranged from 2.6 to 4.0 percentage points (P<0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P<0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the lumacaftor-ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor-ivacaftor groups as well. The incidence of adverse events was generally similar in the lumacaftor-ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor-ivacaftor versus 1.6% among those who received placebo.ConclusionsThese data show that lumacaftor in combination with ivacaftor provided a benefit for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. (Funded by Vertex Pharmaceuticals and others; TRAFFIC and TRANSPORT ClinicalTrials.gov numbers, NCT01807923 and NCT01807949.).

Project description:RationaleCombination lumacaftor/ivacaftor has been shown to improve lung function and other endpoints in patients aged 12 years and older with cystic fibrosis and homozygous for F508del-CFTR, but it has not been assessed in younger patients.ObjectivesIn this open-label phase III trial, we evaluated the safety, tolerability, pharmacodynamics, and efficacy of lumacaftor/ivacaftor combination therapy in patients aged 6-11 years with cystic fibrosis who were homozygous for F508del-CFTR.MethodsPatients (N = 58) received 200 mg lumacaftor/250 mg ivacaftor orally every 12 hours for 24 weeks in addition to their existing cystic fibrosis medications.Measurements and main resultsLumacaftor/ivacaftor was well tolerated; the safety profile was generally similar to that observed in larger lumacaftor/ivacaftor trials with older patients. Four patients discontinued (two because of drug-related adverse events: elevated liver transaminases, n = 1; rash, n = 1). No safety concerns were associated with spirometry. No significant changes in percent predicted FEV1 were observed (change from baseline at Week 24, +2.5 percentage points; 95% confidence interval [CI], -0.2 to 5.2; P = 0.0671). At Week 24, significant improvements from baseline were observed in sweat chloride (-24.8 mmol/L; 95% CI, -29.1 to -20.5; P < 0.0001), body mass index z score (+0.15; 95% CI, 0.08 to 0.22; P < 0.0001), Cystic Fibrosis Questionnaire-Revised respiratory domain score (+5.4; 95% CI, 1.4 to 9.4; P = 0.0085), and lung clearance index based on lung volume turnover required to reach 2.5% of starting N2 concentration (-0.88; 95% CI, -1.40 to -0.37; P = 0.0018).ConclusionsLumacaftor/ivacaftor was well tolerated in this young population; no new safety concerns were identified. Improvements in lung clearance index, sweat chloride, nutritional status, and health-related quality of life were observed after 24 weeks of treatment. Clinical trial registered with www.clinicaltrials.gov (NCT01897233).

Dataset Information

Homozygous Deletion of the CFTR Gene Caused by Interstitial Maternal Isodisomy in a Peruvian Child with Cystic Fibrosis.

Publications

Homozygous Deletion of the <i>CFTR</i> Gene Caused by Interstitial Maternal Isodisomy in a Peruvian Child with Cystic Fibrosis.

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