WS03.3 Clinical and genetic characteristics of Russian cystic fibrosis patients with the first time described pathogenic variants in the CFTR gene

The variety of clinical manifestations of cystic fibrosis is driven by the diversity of the CFTR gene nucleotide sequence. Descriptions of the clinical manifestations in patients with the newly identified genetic variants are of particular interest.The aim of this study was to describe clinical manifestations of the disease with the newly identified genetic variants.Methods. Data from Registry of patients with cystic fibrosis in the Russian Federation (2018) were used. The data review included three steps — the search for frequent mutations, Sanger sequencing, and the search for extensive rearrangements by MLPA. 38 pathogenic variants were identified that were not previously described in the international CFTR2 database. We selected and analyzed full case histories of 15 patients with 10 of those 38 pathogenic variants: p.Tyr84*, G1047S, 3321delG, c.583delC, CFTRdele13,14del18, CFTRdele19-22, c.2619+1G>A, c.743+2T>A, p.Glu1433Gly, and CFTRdel4-8del10-11.Results. A nonsense variant p.Tyr84* was found in 5 patients (0.08 %). Two missense variants c.3139G>A were found in 2 siblings (0.03 %). The c.4298A>G was found in 1 patient. Other variants were detected in a single patient (0.02 %) each. They included two variants of a deletion with a shift of the reading frame 3321delG and c.583delC, two splicing disorders c.2619+1G>A and c.743+2T>A, three extended rearrangements CFTRdele19-22, CFTRdele13,14del18, and CFTRdel4-8del10-11. The last two variants include 2 rearrangements on one allele, which cause the severe course in two young children. 8 of the 10 variants are accompanied by pancreatic insufficiency (PI). Among patients with p.Tyr84*, one had ABPA, one had liver transplantation, and all had Pseudomonas aeruginosa infection. Nasal polyps were diagnosed in 2 patients with p.Tyr84*, 1 with G1047S, 1 with CFTRdel4-8del10-11, and 1 patient with 3321delG, who also had osteoporosis and cystic fibrosis-related diabetes (CFRD). 2 patients with PI with 3321delG and CFTRdel4-8del10-11 genetic variants, and 1 with PI with p.Glu1433Gly genetic variant had severe protein-energy malnutrition (PEM).Conclusion. Clinical manifestations of previously undescribed CFTR genetic variants were described. 5/10 genetic variants should be attributed to class I, 3/10 – to class 7 of the function classification of pathogenic CFTR gene variants associated with transcription and translation disruptions. Class of the identified missense variants c.3139G>A and c.4298A>G has not been established and requires further functional, cultural, and molecular genetic studies.

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Clinical and genetic features of cystic fibrosis patients with novel pathogenic variant CFTR c.1083G> A (p.Trp361*) and functional assessment of the activity of the chloride channel

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2019.09.9-18 ◽

2019 ◽

pp. 9-18

Author(s):

Е.И. Кондратьева ◽

Ю.Л. Мельяновская ◽

А.С. Ефремова ◽

Н.В. Булатенко ◽

Т.Б. Бухарова ◽

...

Keyword(s):

Cystic Fibrosis ◽

Russian Federation ◽

Genetic Variant ◽

Clinical Manifestations ◽

Pathogenic Variant ◽

Cftr Gene ◽

Genetic Characteristics ◽

Intestinal Organoids ◽

The Russian Federation ◽

First Time

В статье впервые представляется клинико-генетическая характеристика мутации c.1083G>A (p.Trp361*) в гене CFTR. Патогенный генетический вариант c.1083G>A (p.Trp361*) гена CFTR относится к нонсенс-мутациям (I класс) и впервые был внесён в базу данных CFTR1 (http://www.genet.sickkids.on.ca) в середине 2019 г. без описания клинической картины муковисцидоза. Методы. Проведен анализ амбулаторных карт и историй болезни двух пациентов из неродственных семей с редким генетическим вариантом c.1083G>A (p.Trp361*). Для определения разности кишечных потенциалов (ОРКП) и проведения форсколинового теста на кишечных органоидах использовали биопсийный материал слизистой прямой кишки пациентов. ДНК для секвенирования выделяли из лейкоцитов венозной крови пациентов. Результаты. Анализ клинических проявлений заболевания у детей 6 и 9 лет показал наличие хронической панкреатической недостаточности, более выраженной у одного ребенка с синдромом дистальной интестинальной обструкции кишечника в анамнезе. Клиническая картина второго пациента характеризовалась развитием в раннем возрасте транзиторной гипербилирубинемии, синдрома псевдо-Барттера, а в дальнейшем - повторными эпизодами бронхиальной обструкции и развитием полипозного риносинусита. ОРКП и форсколиновый тест на кишечных органоидах показали, что генетический вариант c.1083G>A (p.Trp361*) относится к вариантам гена CFTR с отсутствием функции хлорного канала. Выводы. Впервые представлены описание клинической картины муковисцидоза у двух пациентов из неродственных семей с патогенным вариантом c.1083G>A (p.Trp361*) в компаунде с вариантом c.1521_1523delCTT (p.Phe508del) (ранее называемом F508del) и результаты оценки функции белка CFTR методом ОРКП и форсколиновым тестом на кишечных органоидах. In this article we continue to describe the pathogenic variants of the CFTR gene identified among Russian cystic fibrosis (CF) patients. For the first time the clinical and genetic characteristics of the mutation c.1083G> A (p.Trp361 *) are presented. The pathogenic genetic variant c.1083G> A (p.Trp361 *) of the CFTR gene belongs to the nonsense mutations (class I) and was listed for the first time in the CFTR1 database (http://www.genet.sickkids.on.ca) by Professor Milan Macek et al. in mid-2019 without any description of clinical manifestations of cystic fibrosis. Methods. The data of the National Register of Patients with Cystic Fibrosis of the Russian Federation 2017 were analyzed. Outpatient records and case histories of two patients from unrelated families carrying a rare genetic variant c.1083G> A (p.Trp361 *) were analyzed. To determine the Intestinal current measurement (ICM) and Forskolin-induced swelling (FIS) in intestinal organoids, rectal biopsy material of CF patients was used. DNA for sequencing was isolated from leukocytes of venous blood of the patients. Results. Variant c.1083G> A (p.Trp361 *) was found in two patients from unrelated families from different regions of the Russian Federation, according to the Register of Cystic Fibrosis Patients in the Russian Federation 2017. Analysis of clinical manifestations of the disease in children 6 and 9 years old showed the presence of chronic pancreatic insufficiency, more expressed in one child with a history of distal intestinal obstruction syndrome. The clinical manifestation of the second patient was characterized by the development of transient hyperbilirubinemia, Pseudo-Bartter’s syndrome at an early age, and subsequently repeated episodes of bronchial obstruction and the development of polypoid rhinosinusitis. The ICM method and the FIS in intestinal organoids showed that the genetic variant c.1083G> A (p.Trp361 *) refers to the variants of the CFTR gene with the absence of chlorine channel function. Conclusion. The clinical picture of cystic fibrosis in two patients from unrelated families with the pathogenic variant c.1083G> A (p.Trp361 *) in the compound with variant c.1521_1523delCTT (p.Phe508del) (variant legacy name F508del) and results of the evaluation of the CFTR protein functions, obtained by the method of ICM and using the FIS assay in intestinal organoids, are presented for the first time. Patients continue to be under the control in Russian CF centers.

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Newborn cystic fibrosis screening in southeastern Mexico: Birth prevalence and novel CFTR gene variants

Journal of Medical Screening ◽

10.1177/0969141317722808 ◽

2017 ◽

Vol 25 (3) ◽

pp. 119-125 ◽

Cited By ~ 1

Author(s):

Isabel Ibarra-González ◽

Felix-Julián Campos-Garcia ◽

Luz del Alba Herrera-Pérez ◽

Patricia Martínez-Cruz ◽

Claudia-Margarita Moreno-Graciano ◽

...

Keyword(s):

Cystic Fibrosis ◽

Screening Program ◽

Cftr Gene ◽

Sweat Test ◽

Gene Variants ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

Birth Prevalence ◽

Pathogenic Variants ◽

Immunoreactive Trypsinogen

Objective To use the results of the first five years of a cystic fibrosis newborn screening program to estimate the cystic fibrosis birth prevalence and spectrum of cystic fibrosis transmembrane conductance regulator ( CFTR) gene variants in Yucatan, Mexico. Methods Screening was performed from 2010 to 2015, using two-tier immunoreactive trypsinogen testing, followed by a sweat test. When sweat test values were >30 mmol/L, the CFTR gene was analyzed. Results Of 96,071 newborns screened, a second sample was requested in 119 cases. A sweat test was performed in 30 newborns, and 9 possible cases were detected (seven confirmed cystic fibrosis and two inconclusive). The most frequently detected CFTR pathogenic variant (5/14 cystic fibrosis alleles, 35.7%) was p.(Phe508del); novel p.(Ala559Pro) and p.(Thr1299Hisfs*29) pathogenic variants were found. Conclusions Cystic fibrosis birth prevalence in southeastern Mexico is 1:13,724 newborns. Immunoreactive trypsinogen blood concentration is influenced by gestational age and by the time of sampling. The spectrum of CFTR gene variants in Yucatan is heterogeneous.

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P020 Combinations of pathogenic variants of the nucleotide sequence in the CFTR gene at formation the “mild” genotype in cystic fibrosis

Journal of Cystic Fibrosis ◽

10.1016/s1569-1993(19)30315-7 ◽

2019 ◽

Vol 18 ◽

pp. S62

Author(s):

E. Kondratyeva ◽

S. Krasovskiy ◽

E. Furman ◽

V. Shadrina

Keyword(s):

Cystic Fibrosis ◽

Nucleotide Sequence ◽

Cftr Gene ◽

Pathogenic Variants

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The spectrum of CFTR gene pathogenic variants in Northern Ossetia

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2020.07.57-59 ◽

2020 ◽

pp. 57-59

Author(s):

Н.В. Балинова ◽

Н.В. Петрова ◽

З.К. Гетоева ◽

Н.Ю. Каширская ◽

Т.А. Васильева ◽

...

Keyword(s):

Cystic Fibrosis ◽

Chloride Channel ◽

Autosomal Recessive ◽

Autosomal Recessive Disease ◽

Cftr Gene ◽

Gene Variants ◽

Healthy Individuals ◽

Pathogenic Variants ◽

The Republic ◽

North Ossetia

Муковисцидоз (МВ) - аутосомно-рецессивное заболевание, обусловленное нарушением функции эпителиального хлорного канала, кодируемого геном CFTR. Спектр и частота вариантов последовательности гена CFTR, как и частота МВ различаются в разных странах и этнических группах. Изучено распределение частот вариантов гена CFTR у больных МВ и у здоровых индивидов в Республике Северной Осетия-Алания. Спектр патогенных вариантов у осетинских больных МВ отличается своеобразием: наиболее частыми являются два варианта W1282X (50%) и F508del (20%), тогда как в общероссийской выборке пациентов самыми частыми являются варианты F508del (52,8%) и CFTRdele2,3 (6,2%), а вариант W1282X (1,90%) относительно редок. В выборке здоровых осетин частоты выявленных вариантов W1282X и F508del составляют 0,0032 и 0,0016, соответственно. Cystic fibrosis (CF) is an autosomal recessive disease caused by impaired function of the epithelial chloride channel encoded by the CFTR gene. The spectrum and frequency of CFTR gene variants, as well as the CF incidence, vary in different countries and ethnic groups. The frequency distribution of CFTR gene variants in CF patients and in healthy individuals in the Republic of North Ossetia-Alania was studied. The spectrum of pathogenic variants in Ossetian CF patients is specific: the most frequent are two variants W1282X (50%) and F508del (20%), while in the all-Russian CF patients the most frequent are variants - F508del (52.8%) and CFTRdele2.3 (6.2%), and the variant W1282X (1.90%) is relatively rare. In healthy Ossetians, the frequencies of detected variants W1282X and F508del are 0.0032 and 0.0016, respectively. The most common CFTR gene variants are W1282X and F508del, found both in CF patients and healthy individuals from the Ossetian population of the Republic of North Ossetia-Alania.

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A Novel Pathogenic Variant of the CFTR Gene in a Patient with Cystic Fibrosis Phenotype—c.4096A > T

Journal of Pediatric Genetics ◽

10.1055/s-0039-1694964 ◽

2019 ◽

Vol 09 (01) ◽

pp. 040-043

Author(s):

Ahmet Burak Arslan ◽

Ayşe Gül Zamani ◽

Sevgi Pekcan ◽

Mahmut Selman Yıldırım

Keyword(s):

Cystic Fibrosis ◽

The United States ◽

Clinical Findings ◽

World Health ◽

Cftr Gene ◽

Sequencing Analysis ◽

Nucleotide Exchange ◽

Pathogenic Variants ◽

Health Organization ◽

Additional Value

AbstractCystic fibrosis is a chronic multisystemic disease originating from functional alterations in CFTR (cystic fibrosis transmembrane conductance regulator) protein. To date, more than 300 pathogenic variants have been described in the literature. However, the diagnosis of CF, which was thought to become easier after the CFTR gene was identified, became more complicated due to the enormous amount of variations. In this study, we present a patient whose clinical findings were consistent with cystic fibrosis (CF) and showed a homozygous missense change that is not previously reported in the CFTR gene as pathogenic. In the next-generation sequencing analysis, homozygous c.4096A > T single-nucleotide exchange (I1366F [p.Ile1366Phe], missense) was shown in both alleles of the patient' CFTR gene. According to our database analysis, this variant has not yet been previously reported (VarSome, ClinVar, MutationTaster, Ensembl, dbSNP, PubMed). We do consider the change as pathogenic since the patient's findings were compatible with CF and the data analysis was in favor of pathogenicity. The most recent consensus report published in 2017 emphasized the importance of CFTR gene analysis, and this study emphasizes the difficulties of associating CFTR gene variations with a clinical picture and constitutes a new data on the genotype–phenotype correlation of CFTR variants. Also, considering the frequency of CF (according to World Health Organization data, every 1 out of 2,000–3,000 infants is born with CF in European Union countries and every 1 out of 3,500 in the United States) as well as the increasing rate of molecular studies performed on CF patients worldwide, reporting novel variation has an additional value.

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Prenatal Ultrasound Suspicion of Cystic Fibrosis in a Multiethnic Population: Is Extensive CFTR Genotyping Needed?

Genes ◽

10.3390/genes12050670 ◽

2021 ◽

Vol 12 (5) ◽

pp. 670

Author(s):

Chadia Mekki ◽

Abdel Aissat ◽

Véronique Mirlesse ◽

Sophie Mayer Lacrosniere ◽

Elsa Eche ◽

...

Keyword(s):

Cystic Fibrosis ◽

Gene Mutations ◽

Cftr Gene ◽

Intestinal Loop ◽

Fetal Ultrasound ◽

Pathogenic Variants ◽

Frequent Mutations ◽

Multiethnic Population ◽

Exhaustive Study ◽

Cf Transmembrane Conductance Regulator

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.

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A retrospective study of cases diagnosed with cystic fibrosis at a single care center in Syria

Egyptian Journal of Medical Human Genetics ◽

10.1186/s43042-021-00178-5 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Raghad Al-Baba ◽

Almoutassem Billah Zetoune

Keyword(s):

Cystic Fibrosis ◽

Retrospective Study ◽

Mortality Rate ◽

Care Center ◽

Gastrointestinal Symptoms ◽

Statistical Correlation ◽

Pathogenic Variant ◽

Genetic Characteristics ◽

Pathogenic Variants ◽

The Relationship

Abstract Background Although there is relatively much information about the status of cystic fibrosis disease in different countries of the world, limited data are available on this disease among Syrian children. Therefore, we did a retrospective study that included 173 children diagnosed with cystic fibrosis according to the diagnostic criteria. This study was conducted to determine the diagnostic, clinical, and genetic characteristics of patients with cystic fibrosis in Syria and to assess the relationship between the genotype and the phenotype of disease in these patients. Results As a result of the early classical manifestations, CF diagnosis was established in the present study by the age of 1 year in 78.6%; the mortality rate was 23.1% (82.5% of them were in the first year of life). The prevalence of respiratory and gastrointestinal symptoms was 81.5% and 78.6%, respectively with an average age of 7.8 and 3.4 months. Consanguinity was reported in 75.7% of the families. The most common pathogenic variant in the sample was F508del (36%) followed by W1282X (17%). There was a statistical correlation between incidence of steatorrhea and the presence of class I pathogenic variants. A relationship between the mortality rate and the presence of class II pathogenic variants (pathogenic deletion variants) was also observed. There was no statistical relationship between other clinical manifestation and pathogenic variant classes. However, the incidence of most CF-related conditions was a little higher in the presence of classes I, II, and III pathogenic variants compared to their incidence in the presence of classes IV and V pathogenic variants. Conclusions The number of cases diagnosed with cystic fibrosis in Syria is less than the number of real cases, and there is a need to perform CFTR gene sequencing on large sample sizes, to determine all CFTR pathogenic variants that could exist in Syrian patients and to make a better evaluation of the relationship between genotype and phenotype of the disease.

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Variety of large rearrangements in the CFTR gene in Russian patients with Cystic Fibrosis

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2020.02.28-34 ◽

2020 ◽

pp. 28-34

Author(s):

Е.И. Кондратьева ◽

Н.В. Петрова ◽

А.Ю. Воронкова ◽

С.А. Красовский ◽

Е.Л. Амелина ◽

...

Keyword(s):

Cystic Fibrosis ◽

Russian Federation ◽

Genetic Variants ◽

Genetic Variant ◽

Cftr Gene ◽

Pathogenic Variants ◽

The Russian Federation ◽

Basic Characteristics ◽

Gland Function ◽

Large Rearrangements

Целью исследования стал анализ частоты протяженных перестроек гена CFTR и клинико-лабораторных характеристик пациентов с протяженными перестройками гена CFTR. В Регистр больных муковисцидозом РФ 2017 г. включены данные 3096 пациентов из 81 региона РФ, у которых выявлено 196 патогенных вариантов гена CFTR. Патогенные варианты обнаруживаются как в кодирующих, так и в интронных областях, и в регуляторных регионах гена CFTR. В гене CFTR относительно мало (около 2,5%) протяженных перестроек, но среди мутантных хромосом, в которых генетические варианты не были идентифицированы стандартными методами, такие перестройки составляют до 20%. По данным Регистра 2017 г. выявлен 21 пациент, несущий в своем генотипе крупные перестройки. Перестройки CFTRdele12,13del16, CFTRdele19-22(17а-19), CFTRdele8(7*), CFTRdele2-8(2-7*) ранее не были описаны в международных базах данных. Клиническая характеристика больных с протяженными перестройками не отличалась по основным признакам от пациентов с «тяжелыми» генотипами. Наличие в генотипе пациентов с протяженными перестройками варианта нуклеотидной последовательности гена CFTR, определяющего сохранную функцию поджелудочной железы, обусловило отсутствие у них панкреатической недостаточности. The aim of the study was to analyze large rearrangements in the CFTR gene in patients with cystic fibrosis in the Russian Federation in 2017. The Cystic Fibrosis Patients Registry of the Russian Federation for 2017 includes data from 3096 patients from 81 regions of the Russian Federation. To date, more than 2,000 mutations or variants of the nucleotide sequence of the CFTR gene have been described. In the Cystic Fibrosis Patients Registry of the Russian Federation for 2017, 196 pathogenic CFTR variants are given. Pathogenic variants are found both in the coding and in the intron regions, and in the regulatory regions of the CFTR gene. The CFTR gene has relatively few (about 2.5%) large rearrangements, but among mutant chromosomes in which genetic variants were not identified by standard methods, such rearrangements account for up to 20%. According to the Registry of 2017, 21 patients were identified that carried large rearrangements in their genotype. The rearrangements CFTRdele12,13del16, CFTRdele19-22 (17a-19), CFTRdele8 (7*), CFTRdele2-8 (2-7*) are not described in international databases. The clinical characteristics of patients with extensive rearrangements in the genotype did not differ in basic characteristics from patients with “severe” genotypes. The presence of a genetic variant in the genotype that determines the preserved function of the pancreas leads to the preservation of gland function in patients with large rearrangements in the genotype.

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