RESUMEN
RATIONALE: The American Thoracic Society recommended switching to race-neutral spirometry reference equations, as race is a social construct and to avoid normalizing disparities in lung function due to structural racism. Understanding the impact of the race-neutral equations on percent predicted forced expiratory volume in one second (ppFEV1) in people with cystic fibrosis (PwCF) will help prepare patients and providers to interpret pulmonary function test results. OBJECTIVE(S): To quantify the impact of switching from Global Lung Initiative (GLI) 2012 race-specific to GLI 2022 Global race-neutral reference equations on the distribution of ppFEV1 among PwCF of different races. METHODS: Cross-sectional analysis of FEV1 among PwCF ages ≥6 years in the 2021 U.S. Cystic Fibrosis Foundation Patient Registry. We describe the absolute difference in ppFEV1 between the two reference equations by reported race and the effect of age and height on this difference. RESULTS: With the switch to GLI Global, ppFEV1 will increase for White (median increase 4.7, (IQR: 3.1; 6.4)) and Asian (2.6 (IQR: 1.6; 3.7)) individuals and decrease for Black individuals (-7.7, (IQR: -10.9; -5.2)). Other race categories will see minimal changes in median ppFEV1. Individuals with higher baseline ppFEV1 and younger age will see a greater change in ppFEV1 (i.e., a greater improvement among White and Asian individuals and a greater decline among Black individuals). CONCLUSIONS: Switching from GLI 2012 race-specific reference equations to GLI 2022 Global race-neutral equations will result in larger reductions in ppFEV1 among Black individuals with CF than increases among White and Asian people with CF.
Asunto(s)
Fibrosis Quística , Espirometría , Humanos , Fibrosis Quística/fisiopatología , Fibrosis Quística/etnología , Masculino , Volumen Espiratorio Forzado , Femenino , Estudios Transversales , Adulto , Adolescente , Espirometría/métodos , Niño , Estados Unidos/epidemiología , Adulto Joven , Valores de Referencia , Sistema de RegistrosRESUMEN
PURPOSE: Cystic fibrosis (CF) is not well-characterized in Asians, potentially resulting in delayed diagnosis and poor prognosis. We characterized CF in Asian subgroups to address these disparities. METHODS: De-identified ethnicity and CFTR variant data were obtained from the United States, United Kingdom, and Canadian CF registries. We measured the prevalence of CF, CFTR variant allele frequencies, effectiveness of screening panels, and eligibility for modulator therapies. RESULTS: The prevalence of CF was 1 in 74,982 people (Canada) to 1 in 13,340 people (United Kingdom) for South Asians and 1 in 256,541 (Canada) to 1 in 52,563 (United Kingdom) for other Asians, suggesting 26,000 to 146,000 patients with CF in South Asia. p.(F508del) variant was markedly less frequent in Asians than in non-Hispanic Whites. Splicing and nonsense variants occurred at high allelic frequencies in Asians, resulting in 41% to 49% of South Asians and 21% to 39% of other Asians being ineligible for CFTR modulator therapies. Hologic/EU2v1 panels failed to identify 37% to 47% of South Asian and 23% to 46% of other Asian patients with CF. CONCLUSIONS: Among Asians, CF appears to be more common in South Asians. A significant CF population may exist in South Asia. CFTR variants in South and other Asians markedly differ from non-Hispanic Whites causing inequities in newborn screening, diagnosis, and treatment. New strategies are necessary to mitigate these health care disparities.
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Pueblo Asiatico , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Fibrosis Quística , Pueblo Asiatico/genética , Canadá/epidemiología , Fibrosis Quística/diagnóstico , Fibrosis Quística/etnología , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Genotipo , Humanos , Recién Nacido , Mutación , Sistema de Registros , Reino Unido/epidemiología , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Cystic fibrosis, a pulmonary disease which is an autosomal recessive, inherited, multisystemic genetic disease commonly seen in the Caucasian race, is the most frequent cause of mortality and morbidity. So far, more than 2000 disease-causing gene variants have been found and this number has been increasing with the studies conducted. Although there is not yet enough data that include the Turkish population, the recent increase of studies is noteworthy. AIMS: To discover the genetic variation in patients diagnosed with cystic fibrosis in the Central Anatolian region. STUDY DESIGN: Cross-sectional study. METHODS: The study was carried out in the Central Anatolian region in 3 pediatric pulmonology departments (Kayseri, Konya, and Ankara) in Turkey between July 2014 and December 2017. The Sanger and Next Generation Sequence analyses were used for exon and exon-intron boundaries in the cystic fibrosis transmembrane conductance regulatory (CFTR) gene, and in selected patients, mutation analysis was performed using the Multiplex Ligation-dependent Probe Amplification technique for large deletions and duplications. RESULTS: CFTR gene analysis was performed for 316 patients and 215 of them were genetically diagnosed with cystic fibrosis. Sixtythree different variants were defined in these patients and 7 of these were large deletions/duplications detected with the MLPA method. The most frequent variants were F508del (29.6%), G85E (8.2%), N1303K (8.2%), Y515* (7.5%), and G542* (3.4%). CONCLUSION: Using sequencing and Multiplex Ligation-dependent Probe Amplification methods, the identification of seven new mutations that were not previously reported in the literature contributes to a better understanding of the heterogeneous nature of CFTR mutations in the Turkish population. When no mutations are detected (pathogenic/probably pathogenic) in clinically compatible cases, Multiplex Ligationdependent Probe Amplification analysis contributes significantly to the diagnosis.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/diagnóstico , Mutación/genética , Niño , Estudios Transversales , Fibrosis Quística/etnología , Fibrosis Quística/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Reacción en Cadena de la Polimerasa Multiplex , Turquía/epidemiologíaRESUMEN
BACKGROUND: Due to the COVID-19 pandemic, there was an uptake of telehealth in cystic fibrosis care. Previous studies show disparities in telehealth use based on socioeconomic status (SES). We aimed to: (1) understand telehealth use and perceptions and (2) identify the facilitators and barriers to telehealth use among people with CF and their families (PwCF) from diverse racial/ethnic and socioeconomic backgrounds. METHODS: We conducted an analysis of the 2020 Cystic Fibrosis State of Care surveys completed by PwCF (PFSoC), CF Care Programs (SoC1) and the CF Foundation Patient Registry (CFFPR). RESULTS: A total of 424 PwCF and 286 programs responded to the PFSoC and SoC1. Among PwCF, 90% self-identified as White, 6% as Hispanic/Latino, and 2% as Black. Racial/ethnic minorities were less likely to have had a telehealth visit (p=.015). This difference was pronounced among the Hispanic/Latino population (p<.01). Telehealth use did not differ by health insurance and was similarly offered independent of financial status. Compared to PwCF who denied financial constraints, those who reported financial difficulties found telehealth more difficult to use (p=.018) and were less likely to think that their concerns (p=.010) or issues that mattered most to them (p=.020) were addressed during telehealth. Programs perceived lack of technology, language barriers, and home conditions as barriers to telehealth in vulnerable populations. CONCLUSION: PFSoC and SoC1 identified differences in telehealth use and care perceptions by ethnicity, race, and socioeconomic characteristics. Further studies are needed to understand how telehealth can change access to CF care in diverse subpopulations.
Asunto(s)
COVID-19 , Barreras de Comunicación , Fibrosis Quística , Salud de las Minorías , Telemedicina , COVID-19/epidemiología , COVID-19/prevención & control , Control de Enfermedades Transmisibles/métodos , Fibrosis Quística/economía , Fibrosis Quística/etnología , Fibrosis Quística/psicología , Fibrosis Quística/terapia , Estrés Financiero/etnología , Accesibilidad a los Servicios de Salud/organización & administración , Accesibilidad a los Servicios de Salud/tendencias , Disparidades en Atención de Salud/etnología , Disparidades en Atención de Salud/normas , Humanos , Salud de las Minorías/etnología , Salud de las Minorías/normas , Salud de las Minorías/estadística & datos numéricos , Evaluación de Necesidades , Innovación Organizacional , SARS-CoV-2 , Factores Socioeconómicos , Telemedicina/organización & administración , Telemedicina/normas , Estados Unidos/epidemiología , Poblaciones Vulnerables/estadística & datos numéricosRESUMEN
In families without a Cystic Fibrosis (CF) history, fetal ultrasound bowel abnormalities can unexpectedly reveal the disease. Isolated or in association, the signs can be fetal bowel hyperechogenicity, intestinal loop dilatation and non-visualization of fetal gallbladder. In these cases, search for CF transmembrane conductance regulator (CFTR) gene mutations is part of the recommended diagnostic practices, with a search for frequent mutations according to ethnicity, and, in case of the triad of signs, with an exhaustive study of the gene. However, the molecular diagnosis remains a challenge in populations without well-known frequent pathogenic variants. We present a multiethnic cohort of 108 pregnancies with fetal bowel abnormalities in which the parents benefited from an exhaustive study of the CFTR gene. We describe the new homozygous p.Cys1410* mutation in a fetus of African origin. We did not observe the most frequent p.Phe508del mutation in our cohort but evidenced variants undetected by our frequent mutations kit. Thanks to the progress of sequencing techniques and despite the difficulties of interpretation occasionally encountered, we discuss the need to carry out a comprehensive CFTR study in all patients in case of fetal bowel abnormalities.
Asunto(s)
Fibrosis Quística/diagnóstico por imagen , Intestino Ecogénico/diagnóstico por imagen , Pruebas Genéticas/normas , Ultrasonografía Prenatal/normas , Fibrosis Quística/complicaciones , Fibrosis Quística/etnología , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Intestino Ecogénico/etiología , Intestino Ecogénico/genética , Etnicidad/genética , Femenino , Frecuencia de los Genes , Pruebas Genéticas/métodos , Humanos , Valor Predictivo de las Pruebas , Embarazo , Ultrasonografía Prenatal/métodosRESUMEN
BACKGROUND: Understanding how health outcomes differ for patients with advanced cystic fibrosis (CF) lung disease living in the United States compared with Canada has health policy implications. RESEARCH QUESTION: What are rates of lung transplant (LTx) and rates of death without LTx in the United States and Canada among individuals with FEV1 < 40% predicted? STUDY DESIGN AND METHODS: This was a retrospective population-based cohort study, 2005 to 2016, using the US CF Foundation, United Network for Organ Sharing, and Canadian CF registries. Individuals with CF and at least two FEV1 measurements < 40% predicted within a 5-year period, age ≥ 6 years, without prior LTx were included. Multivariable competing risk regression for time to death without LTx (LTx as a competing risk) and time to LTx (death as a competing risk) was performed. RESULTS: There were 5,899 patients (53% male) and 905 patients (54% male) with CF with FEV1 < 40% predicted living in the United States and Canada, respectively. Multivariable competing risk regression models identified an increased risk of death without LTx (hazard ratio [HR], 1.79; 95% CI, 1.52-2.1) and decreased LTx (HR, 0.66; 95% CI, 0.58-0.74) among individuals in the United States compared with Canada. More pronounced differences were seen in the patients in the United States with Medicaid/Medicare insurance compared with Canadians (multivariable HR for death without LTx, 2.24 [95% CI, 1.89-2.64]; multivariable HR for LTx, 0.54 [95% CI, 0.47-0.61]). Patients of nonwhite race were also disadvantaged (multivariable HR for death without LTx, 1.56 [95% CI, 1.32-1.84]; multivariable HR for LTx, 0.47 [95% CI, 0.36-0.62]). INTERPRETATION: There are lower rates of LTx and an increased risk of death without LTx for US patients with CF with FEV1 < 40% predicted compared with Canadian patients. Findings are more striking among US patients with CF with Medicaid/Medicare health insurance, and nonwhite patients in both countries, raising concerns about underuse of LTx among vulnerable populations.
Asunto(s)
Fibrosis Quística , Trasplante de Pulmón , Pruebas de Función Respiratoria , Adulto , Canadá/epidemiología , Niño , Fibrosis Quística/diagnóstico , Fibrosis Quística/etnología , Fibrosis Quística/mortalidad , Fibrosis Quística/cirugía , Progresión de la Enfermedad , Femenino , Política de Salud , Mal Uso de los Servicios de Salud , Humanos , Revisión de Utilización de Seguros , Trasplante de Pulmón/métodos , Trasplante de Pulmón/estadística & datos numéricos , Masculino , Mortalidad , Evaluación de Necesidades , Sistema de Registros/estadística & datos numéricos , Pruebas de Función Respiratoria/métodos , Pruebas de Función Respiratoria/estadística & datos numéricos , Medición de Riesgo/métodos , Medición de Riesgo/estadística & datos numéricos , Estados Unidos/epidemiología , Poblaciones VulnerablesRESUMEN
The Robert Debre Pediatric Cystic Fibrosis (CF) centre, located in the North East of Paris, a multicultural area, is in charge of a cohort of around a hundred and sixty children diagnosed with CF. Between 2000 and 2019, the proportion of children of African descent in this centre increased from 2% to 10%. We report the clinical features of 17 children of African descent diagnosed with CF: 4 (23%) were diagnosed after a meconium ileus, 14 (83%) had exocrine pancreatic insufficiency, and 7 (41%) had early Pseudomonas aeruginosa infection before the age of two. Even though the majority of patients were diagnosed through NBS, the twenty-nine-mutation testing kit proved less effective in non-Caucasian populations, with a false negative rate of 25% in this series. CF is definitely not solely a Caucasian disease and the literature reveals similar phenotypes in Caucasian and African people provided that they present the same CFTR mutations. Clinicians have to keep in mind that the diagnosis of CF in patients of African descent must be evoked in the case of symptoms and a sweat test must be performed, despite a negative result for NBS.
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Población Negra/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/diagnóstico , Mutación , Niño , Preescolar , Fibrosis Quística/etnología , Fibrosis Quística/genética , Reacciones Falso Negativas , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Tamizaje Neonatal , Paris/etnología , Fenotipo , Juego de Reactivos para Diagnóstico , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
Cystic fibrosis (CF), an autosomal recessive genetic disease, is recognized as one of the most prevalent diseases in Caucasian populations. Epidemiological data show that the incidence of CF varies between countries and ethnic groups in the same region. CF occurs due to pathogenic variants in the gene encoding cystic fibrosis transmembrane conductance regulator (CFTR), located on chromosome 7q31.2. To date, more than 2,000 variants have been registered in the CFTR database. The study of these variants leads to the diagnosis and the possibility of a specific treatment for each patient through precision medicine. In this study, complete screening of CFTR was performed through next-generation sequencing (NGS) to gain insight into the variants circulating in the population of Rio de Janeiro and to provide patient access to treatment through genotype-specific therapies. Samples from 93 patients with an inconclusive molecular diagnosis were subjected to full-length screening of CFTR using an Illumina NGS HiSeq platform. Among these patients, 46 had two pathogenic variants, whereas 12 had only one CFTR variant. Twenty-four variants were not part of our routine screening. Of these 24 variants, V938Gfs∗37 had not been described in the CF databases previously. This research achieved a molecular diagnosis of the patients with CF and identification of possible molecular candidates for genotype-specific treatments.
Asunto(s)
Cromosomas Humanos Par 7/química , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/genética , Mutación , Adolescente , Adulto , Brasil , Niño , Preescolar , Estudios de Cohortes , Fibrosis Quística/diagnóstico , Fibrosis Quística/etnología , Fibrosis Quística/patología , Femenino , Expresión Génica , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Medicina de Precisión , Población BlancaRESUMEN
Cystic fibrosis is a hereditary disease that mostly affects the sweat glands, respiratory system, digestive system, and reproductive system. Many and various types of mutations have been reported in CFTR in different ethnicities and countries/regions. Analysis of CFTR gene rearrangements is recommended in patients with unidentified mutated alleles in CFTR sequencing analysis. We collected MLPA analyses of 527 patients from Turkey who had at least one unidentified mutation in CFTR sequence analysis. Heterozygous/homozygous deletions were detected in the CFTR gene in 49 individuals (9.2%) from 35 families. Twelve different single/multi exon deletions were demonstrated, two of which were not previously reported in the literature. Mutations have previously reported in patients from various regions including Asia, Europe, and Africa, and Turkey is located at a crossroads between them. The most frequent mutation was the exon 2 deletion, accounting for 60%. Moreover, patients with exon 2 deletions, were especially originated from northern Turkey. This finding is valuable in leading and shaping planned screening programs in Turkey. Our study, the most comprehensive study for rearrangement analysis in patients from Tukey, revealed a candidate hotspot region of patients suspected of having CFTR-related disorders from Turkey.
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Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/genética , Exones/genética , Enfermedades Urogenitales Masculinas/genética , Conducto Deferente/anomalías , Adolescente , Adulto , Niño , Preescolar , Fibrosis Quística/etnología , Femenino , Genotipo , Humanos , Incidencia , Masculino , Enfermedades Urogenitales Masculinas/etnología , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa Multiplex , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Eliminación de Secuencia , Turquía/epidemiología , Adulto JovenRESUMEN
BACKGROUND: For unknown reasons, Hispanic patients with cystic fibrosis (CF) have more severe pulmonary disease than non-Hispanic white patients. In CF, the pulmonary pathogen Pseudomonas aeruginosa is associated with worse outcomes. We sought to determine if Hispanic patients with CF are at an increased risk of acquiring P. aeruginosa or acquire it earlier than non-Hispanic white patients. METHODS: This is a longitudinal study comparing the timing and risk of acquisition of different forms of P. aeruginosa between Hispanic and non-Hispanic white patients aged 0-21 years old with CF in the CF Foundation Patient Registry (CFFPR) in 2008-2013. The age at the initial acquisition of P. aeruginosa (initial acquisition, mucoid, chronic, multidrug-resistant) was summarized using Kaplan-Meier survival curves and analyzed using Cox proportional hazards regression models. RESULTS: Of 10,464 patients, 788 (7.5%) were Hispanic and 9,676 (92.5%) were non-Hispanic white. Hispanic patients acquired all forms of P. aeruginosa at a younger age than non-Hispanic white patients. Hispanic patients had a higher risk of acquiring P. aeruginosa than non-Hispanic white patients: the hazard ratio (HR) was 1.26 (95% CI 1.16-1.38, p<0.001) for initial P. aeruginosa, 1.59 (95% CI 1.43-1.77, p<0.001) for mucoid P. aeruginosa, 1.91 (95% CI 1.64-2.23, p<0.001) for multidrug-resistant P. aeruginosa, and 1.39 (95% CI 1.25-1.55, p<0.001) for chronic P. aeruginosa. CONCLUSIONS: Hispanic patients have an increased risk of acquiring P. aeruginosa and acquire it at an earlier age than non-Hispanic white patients in the United States. This may contribute to increased morbidity and mortality in Hispanic patients with CF.
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Fibrosis Quística/etnología , Fibrosis Quística/microbiología , Hispánicos o Latinos , Infecciones por Pseudomonas/etnología , Adolescente , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Estudios Longitudinales , Masculino , Pseudomonas aeruginosa , Sistema de Registros , Estados Unidos/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Most patients with cystic fibrosis (CF) present with respiratory or digestive symptoms. About 3% of patients have electrolyte disturbances at the time of diagnosis, but most of the described cases presenting with this manifestation have been in children. Only 3 adult patients are identified in the literature who first presented with hypokalemia. We describe a morbidly obese African American adult who presented with severe hypokalemia and metabolic alkalosis, which eventually led to the diagnosis of CF after multiple hospitalizations over 4 consecutive summers. Besides being the first African American adult with this presentation, he had the highest BMI, lowest serum potassium, highest pH, and highest bicarbonate level. CASE PRESENTATION: In the summer of 2015, a 26 year-old African American man presented to the hospital for generalized weakness. His BMI was 54 kg/M2, and he had been on a special diet for a few months with a weight loss of 50 pounds. He sweated profusely while working as a chef. Laboratory tests showed severe hypokalemia and metabolic alkalosis. Further work-up pointed toward extrarenal losses of potassium. He was treated with intravenous normal saline and potassium chloride. After discharge, his potassium level remained normal through the winter while the potassium was tapered off. However, over the following three summers, he repeatedly presented to hospitals for the same problems. Cystic fibrosis was suspected and confirmed by an abnormal pilocarpine sweat test. Gene test revealed two mutations of cystic fibrosis transmembrane conductance regulator (CFTR). Thereafter, his potassium level remained normal with potassium replacement during summertime. Unexpectedly, however, his BMI rose to 83 kg/M2 after he stopped the special diet for weight reduction. The reason for the delayed diagnosis is discussed. CONCLUSION: We present an exceedingly rare case of CF in a morbidly obese African American adult male whose only manifestation of CF was hypokalemia and metabolic alkalosis. Clinicians should keep an open mind to the diagnosis of CF in ethnically diverse populations, even if it seems unlikely at first glance. For "summer hypokalemia", consider cystic fibrosis.
Asunto(s)
Negro o Afroamericano , Fibrosis Quística/complicaciones , Diagnóstico Tardío , Hipopotasemia/etiología , Obesidad Mórbida/complicaciones , Acidosis/etiología , Adulto , Fibrosis Quística/diagnóstico , Fibrosis Quística/etnología , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Humanos , Masculino , Mutación , Potasio/sangre , Estaciones del AñoAsunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística , Tamizaje Neonatal/métodos , Fibrosis Quística/diagnóstico , Fibrosis Quística/etnología , Fibrosis Quística/genética , Diagnóstico Precoz , Pruebas Genéticas/métodos , Groenlandia/epidemiología , Humanos , Recién Nacido , Inuk , Mutación , LinajeRESUMEN
Understanding variability in cystic fibrosis (CF) health outcomes requires an understanding of factors that go far beyond Cystic Fibrosis Transmembrane Receptor (CFTR) function caused by different gene mutations. Social and environmental factors that influence health have a significant influence on the trajectory of health in CF and in other chronic diseases. In this article, we review demographic factors associated with poorer health outcomes in CF, known and postulated biological mechanisms of these outcomes, and interventions that healthcare teams can implement that may reduce outcome disparities.
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Fibrosis Quística/epidemiología , Fibrosis Quística/etnología , Fibrosis Quística/genética , Fibrosis Quística/mortalidad , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Demografía , Etnicidad , Humanos , Mutación , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). There are over 2000 different pathogenic and non-pathogenic variants described in association with a broad clinical heterogeneity. The most common types of mutations in this gene are single nucleotide substitutions or small deletions and insertions. However, large rearrangements, such as large duplications or deletions, are also a possible cause of CF; these variations are rarely tested in routine screenings, and much of them remain unidentified in some populations, especially those with high ethnic heterogeneity. METHODS: The present study utilized the Multiplex Ligation-dependent Probe Amplification (MLPA) technique for the detection of duplications and deletions in 165 CF patients from the Rio de Janeiro State (Brazil), which after extensive mutational screening, still exhibited one or two unidentified CF alleles. RESULTS: Five patients with alterations in MLPA signals were detected. After validation, we identified three copy number variations, one large duplication (CFTRdup2-3) and two large deletions (CFTRdel25-26 and CFTRdel25-27-CTTNBP2). Two detected deletions were not validated. They were false positives caused by a small deletion of 18 base pairs (232del18) and a point mutation (S168L) in the probe binding site. CONCLUSION: Our results highlight the importance of screening for large rearrangements in CF cases with no or only one CFTR mutation defined.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/patología , Preescolar , Fibrosis Quística/etnología , Fibrosis Quística/genética , ADN/química , ADN/genética , ADN/metabolismo , Variaciones en el Número de Copia de ADN , Femenino , Eliminación de Gen , Duplicación de Gen , Humanos , Lactante , Recién Nacido , Masculino , Técnicas de Amplificación de Ácido Nucleico/métodos , Mutación PuntualRESUMEN
BACKGROUND: Hispanic subjects with cystic fibrosis (CF) have increased morbidity and mortality than non-Hispanic white subjects. The ethnic disparity in mortality varies by region. Factors influencing pulmonary function vary by both ethnicity and region. OBJECTIVE: To determine if the ethnic difference in pulmonary function varies by region. METHODS: This retrospective cohort study compared differences in longitudinal pulmonary function (percent-predicted forced vital capacity [FVC], forced expiratory volume in 1 second [FEV1 ], forced expiratory flow at 25% to 75% [FEF25-75 ], FEV1 /FVC, and FEV1 decline) between Hispanic and non-Hispanic white subjects with CF by Census region of the United States (West, South, Midwest, and Northeast). Subjects were of ages 6 to 25 years and in the CF Foundation Patient Registry from 2008 to 2013. We used linear mixed effects models with subject-specific slopes and intercepts, adjusting for 14 demographic and clinical variables. RESULTS: Of 14 932 subjects, 1433 (9.6%) were Hispanic and 13 499 (90.4%) were non-Hispanic white. Hispanic subjects' FEV1 was 9.0% (8.3%-9.8%) lower than non-Hispanic white subjects in the West, while Hispanic subjects' FEV1 was only 4.0% (3.0%-5.0%) lower in the Midwest, 4.4% (3.1%-5.7%) lower in the Northeast, and 4.4% (3.2%-5.5%) lower in the South. Similarly, FVC and FEF25-75 were lower among Hispanic subjects compared to non-Hispanic white subjects in all US regions, with the biggest differences in the West. Only in the West was FEV1 /FVC significantly lower in Hispanic subjects (-0.019; -0.022 to -0.015). FEV1 decline was not significantly different between ethnicities in any region. CONCLUSIONS: In CF, Hispanic subjects have lower pulmonary function than non-Hispanic white subjects in all geographic regions with the largest difference in occurring in the West.
Asunto(s)
Hispánicos o Latinos , Pulmón/fisiopatología , Adolescente , Adulto , Niño , Fibrosis Quística/etnología , Fibrosis Quística/fisiopatología , Femenino , Volumen Espiratorio Forzado , Humanos , Modelos Lineales , Masculino , Pruebas de Función Respiratoria , Estudios Retrospectivos , Estados Unidos , Capacidad Vital , Población Blanca , Adulto JovenRESUMEN
BACKGROUND: Cystic fibrosis (CF; OMIM #219700) is a common autosomal recessive disease caused by pathogenic variants (henceforward mutations) in the cystic fibrosis transmembrane conductance regulator gene (CFTR). The spectrum and frequencies of CFTR mutations vary among different populations. Characterization of the specific distribution of CFTR mutations can be used to optimize genetic counseling, foster reproductive choices, and facilitate the introduction of mutation-specific therapies. Chechens are a distinct Caucasian ethnic group of the Nakh peoples that originated from the North Caucasus. Chechens are one of the oldest ethnic groups in the Caucasus, the sixth largest ethnic group in the Russian Federation (RF), and constitute the majority population of the Chechen Republic (Chechnya). The spectrum of CFTR mutations in a representative cohort of Chechen CF patients and healthy individuals was analyzed. METHODS: Molecular genetic analysis of 34 CFTR mutations (representing approx. 80-85% of mutations in multiethnic CF populations of the RF) was performed in 32 CF patients from 31 unrelated Chechen families living in Chechnya. One hundred randomly chosen healthy Chechens were analyzed for the 15 most common "Russian" mutations. The clinical symptoms in Chechen CF patients with different CFTR genotypes were investigated. RESULTS: High frequencies of c.1545_1546delTA (p.Tyr515X; 1677delTA) (52 out of 64 CFTR alleles tested; 81.3%) and c.274G > A (p.Glu92Lys, E92K) (8/64, 12.5%) mutations were found. Twenty patients were homozygous for the c.1545_1546delTA mutation, and eight were compound heterozygous for the c.1545_1546delTA and c.274G > A mutations. Three carriers of the c.1545_1546delTA mutation were also found in the cohort of 100 apparently healthy Chechens (frequency - 0.015). The c.1545_1546delTA and c.274G > A mutations are linked to the same haplotype (22-7-16-13) of intragenic Short Tandem Repeat markers, i.e., IVS1CA, IVS6aGATT, IVS8CA, and IVS17bCA. CONCLUSIONS: The distribution of CFTR mutations in the Chechen CF population is unique regarding the high frequency of mutations c.1545_1546delTA and c.274G > A (more than 90% of the mutant alleles). The c.274G > A mutation is associated with a less severe course of CF than that observed in c.1545_1546delTA homozygotes. Testing for these two variants can be proposed as the first step of CF DNA diagnosis in the Chechen population.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/genética , Mutación Puntual , Eliminación de Secuencia , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Fibrosis Quística/etnología , Diagnóstico Precoz , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Lactante , Recién Nacido , Masculino , Federación de Rusia/etnología , Índice de Severidad de la EnfermedadRESUMEN
PURPOSE OF REVIEW: Tracking patient outcomes using cystic fibrosis (CF) national data registries, we have seen a dramatic improvement in patient survival. As there are multiple ways to measure survival, it is important for readers to understand these different metrics in order to clearly translate this information to patients and their families. The aims of this review were to describe measures of survival and to review the recent literature pertaining to survival in CF to capture the changing epidemiology. RECENT FINDINGS: Although survival has improved on a population level, several individual factors continue to impact survival such as sex, age of diagnosis, ethnic background and lung function. Survival estimates, conditional on surviving to a specified age, are more relevant to individuals living with CF today and are higher than the reported overall median age of survival. There is some evidence to suggest that newborn screening (NBS) has resulted in prolonged survival in CF. SUMMARY: Prognosis in CF is often described by reporting the median age of survival, the median age of death, the median survival conditional on living to a certain age and the survival by birth cohort. Each of these metrics provide useful information depending on an individual's personal disease trajectory. The median age of survival continues to increase in CF in many countries while mortality rates are decreasing. Several factors have been associated with worse survival such as female sex, ethnicity, worse nutritional status, lower lung function and microbiology. When comparing survival between countries, one needs to ensure that similar data collection and processing techniques are used to ensure valid and robust comparisons.
Asunto(s)
Fibrosis Quística/mortalidad , Factores de Edad , Fibrosis Quística/etnología , Fibrosis Quística/fisiopatología , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Humanos , Estado Nutricional , Factores Sexuales , Tasa de SupervivenciaRESUMEN
BACKGROUND: The Q359K/T360K mutation, described in Jewish CF patients of Georgian decent, is of questionable clinical significance. METHODS: Clinical records of patients with the Q359K/T360K mutation from three CF centers were studied for phenotypic expression and putative mechanism of dysfunction. Computer models of mutant CFTR were constructed. RESULTS: Nine patients (4 homozygous) of Georgian Jewish origin were included. Age at diagnosis was 9.4 (0.25-38.2) years, median (range). Sweat chloride was 106⯱â¯13â¯meq/L, mean⯱â¯SD. Nasal Potential Difference performed in three, was abnormal. All had pulmonary symptoms since early childhood and bronchiectasis. Median FEV1 was 88 (40-121)%. Five had chronic mucoid P. aeruginosa. Homozygous patients were pancreatic insufficient. Enzyme supplementation was initiated at 3.8 (1-14.7) years, median (range). Structural models hint at possible interference of this mutation with transmembrane chloride transport. CONCLUSION: In our cohort, the Q359K/T360K mutation resulted in a severe CF phenotype, although with residual early CFTR function. The CFTR2 database should consider defining this mutation as CF-causing.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/genética , Judíos/genética , Adolescente , Adulto , Niño , Preescolar , Fibrosis Quística/etnología , Femenino , Humanos , Lactante , Israel , Masculino , Mutación , FenotipoRESUMEN
RATIONALE: Patients of Hispanic origin with cystic fibrosis (CF) are the largest growing minority, representing 8.5% of patients with CF in the United States. No national survival analysis of this group has ever been undertaken. OBJECTIVES: We aimed to determine whether Hispanic ethnicity within the CF population is associated with worse outcomes and whether any geographic differences exist. METHODS: Using U.S. Cystic Fibrosis Foundation Patient Registry data from 2010 to 2014, we performed a retrospective cohort analysis comparing survival rates between Hispanics and non-Hispanics using Kaplan-Meier and Cox regression analysis. A subject's residence was categorized into geographic regions based on U.S. Census Bureau data: Northeast, Midwest, West, and South. MEASUREMENTS AND MAIN RESULTS: A total of 29,637 patients were included in the study; 2,493 identified themselves as Hispanic. Hispanics had a lower survival probability overall, with a mean age of death of 22.4 ± 9.9 years compared with non-Hispanics of 28.1 ± 10.0 years (P < 0.0001). Multivariate Cox proportional hazards modeling revealed that Hispanic patients with CF had a 1.27 times higher rate of death compared with non-Hispanics (95% confidence interval, 1.05-1.53) after adjusting for covariates including age, sex, genetic mutations, bacterial cultures, lung function, body mass index, use of CF respiratory therapies, low socioeconomic status, pancreatic enzyme use, and CF-related diabetes. When analyzed by region, Hispanics in the Midwest, Northeast, and West had shorter median survivals compared with non-Hispanics, which was not demonstrated in the South. CONCLUSIONS: Patients with CF of Hispanic origin have a higher mortality rate than non-Hispanic patients with CF. This pattern was seen in the Midwest, Northeast, and West but not in the South.