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6 CFTR dele2,3 (21 kb) mutation in cystic fibrosis patients in Latvia
S46
1. Genetics
5 Phenotypic characteristics of p.E92K mutation in adults with cystic fibrosis (CF) in Russia M. Usacheva1 , S. Krasovskiy1 , A. Stepanova2 , A. Polyakov2 , E. Amelina1 . 1 Research Institute of Pulmonology, Moscow, Russian Federation; 2 Research Centre for Medical Genetics, Moscow, Russian Federation The main reason for development of CF for the Chuvash − the fifth in population number (1.5 mln) nationality in Russia is of the “mild” p.E92K mutation (p.Glu92Lys, c.274G>A). Objective: To identify the clinical and functional characteristics of the course of CF in the patients-carriers of p.E92K mutation. Materials and Methods: Group 1: 26 adult CF patients homozygous or heterozygous for E92K, group 2: 103 adult patients homozygous for F508del. Age, age diagnosis, BMI, level of chloride in sweat, spirometry parameters, frequency of some complications [CF related diabetes (CFRD), liver cirrhosis with portal hypertension (LCPH), distal intestinal obstruction syndrome (DIOS)/meconium ileus (MI) in past medical history, cholelithiasis, urolithiasis, pulmonary hypertension (PH), asthma] were estimated. Results are described as mean±SD/median (IQR). Results: The median age group 1 was: 26.0 (5.95) years, higher than in the group 2 − 23.6 (6.5) years (p = 0.007); age diagnosis of patients with E92K was: 13.3 (9.2), higher than among homozygous for F508del − 1.9 (4.5) years (p < 0.001). There was no significant difference in the level of chloride in sweat (101±30.5 mmol/l vs 103±32 mmol/l respectively) in the two groups. The spirometry parameters, BMI, the frequency of LCPH, DIOS/MI, cholelithiasis, urolithiasis, asthma and PH had not significant difference. CFRD had frequency in the group of the patients homozygous for F508del, and CFRD in group p.E92K was never once identified (p = 0.046). Conclusion: p.E92K mutation in patients-carriers is associated with late onset age, significant low frequency of CERD, what is likely connected with the “mildness” of this mutation.
6 CFTR dele2,3 (21 kb) mutation in cystic fibrosis patients in Latvia G. Taurina1,2 , L. Piekuse1 , I. Kempa1 , Z. Krumina2 , I. Micule2 , V. Svabe3 , A. Krumina4 . 1 Riga Stradins University, Scientific Laboratory of Molecular Genetics, Riga, Latvia; 2 Children’s Clinical University Hospital, Medical Genetics Clinic, Riga, Latvia; 3 Children’s Clinical University Hospital, Department of Pulmonology and Allergology, Riga, Latvia; 4 Latvian Biomedical Research and Study Center, Riga, Latvia Background: Cystic fibrosis (CF) is one of the most common severe autosomal recessive diseases in Latvia with frequency 1:3,300. It is classified as I class mutation causing a premature stop codon formation in exon 4. The phenotype is associated with early onset of disease and exocrine pancreatic insufficiency. So far only few cases with homozygous dele2,3 mutations have been described. Methods: CFTR mutation screening was performed by standard molecular methods for 62 patients with clinical symptoms of CF. Results: CFTR dele2,3 mutation was detected in 3 patients. The first was a girl with dF508/dele2,3 mutation who was diagnosed with CF at the age of 1 year due to poor weight gain, recurrent lung infections and positive sweat test. On therapy there was a symptom free period of several years. She died at the age of 13 years due to pulmonary and heart insufficiency. The second was a boy with P67L/dele2,3 mutation presented with meconium ileus and had died at the age of 3 months. The third patient, a girl, presented with meconium ileus and positive sweat test in first days of her life. The molecular testing revealed her to be homozygous for dele2,3 mutation. At the age of 1 year and 6 months, even having pancreatic enzyme replacement therapy, her height and weight is still below 3rd percentile. Conclusion: CFTR dele2,3 (21 kb) mutation represents 3.2% of all CF alleles becoming the second most frequent severe CFTR mutation in Latvia. This mutation should be included in first step CF mutation screening together with dF508 mutation. The study confirms that dele2,3 mutation has severe phenotype − early presentation, exocrine pancreas insufficiency and recurrent lung infections.
Posters
7 Genetic prevention of cystic fibrosis as a part of the national strategy for rare diseases in University Hospital Brno, Czech Republic (genetic counselling − DNA analysis − newborn screening − education) R. Gaillyov´a1,2,3 , I. Val´asˇkov´a1,2,3 , J. Neˇcasov´a1 , R. Spˇesˇn´a1,3 , H. Vinohradsk´a3,4 , A. Holˇc´ıkov´a5 , L. Homola5 , E. Pokojov´a6 , O. Dost´al7 . 1 University Hospital, Dept. of Medical Genetics, Brno, Czech Republic; 2 Masaryk University, Faculty of Medicine, Dept. of Biology, Brno, Czech Republic; 3 Masaryk University, Faculty of Medicine, Department of Laboratory Methods, Brno, Czech Republic; 4 University Hospital, Dept. of Clinical Biochemistry, Brno, Czech Republic; 5 University Hospital, Clinic of Pediatric Infectious Diseases, Brno, Czech Republic; 6 University Hospital, Clinic of Pulmonary Diseases and Tuberculosis, Brno, Czech Republic; 7 Masaryk University, Mendel Museum, Brno, Czech Republic “Interdepartmental and interdisciplinary working group on rare diseases” runs under the Czech Ministry of Health, and coordinates the establishment of centres for rare diseases. A team of experts from CF Centre in University Hospital Brno currently cares for 64 children and 34 adults with Cystic Fibrosis (CF). University Hospital Brno is also responsible for newborn screening for CF(NSCF) for the Moravia region. From December 2009 till the end of December 2013, 161 917 newborns were examined under the NSCF at the University Hospital Brno. DNA analysis of the CFTR gene was carried out in 1846 newborns, representing 1.14%. One or two mutations in CFTR gene were found in 10% of newborns. We detected 20 different mutations in the CFTR gene, the most frequent were the mutations F508del (113), CFTRdele2,3 (21 kb) (18) and D1152H (14). The DNA analysis of the CFTR gene we also perform within the genetic prevention for 400–500 people per year, which represent about 20% of patients examined in our laboratory of DNA diagnostics. In this group, we detected the pathological CF allele in more than 15% individuals. Centres for Orphan cooperate with patient organisations associated in the Czech Association of Rare Diseases. An important part of the work of all experts on rare diseases is an effort to raise awareness about rare diseases among specialists and the public. Lecture devoted to Cystic Fibrosis in November 2013 was a part of the activities within the European day for CF. Teaching of Clinical Genetics at Masaryk University Brno and public lectures dedicated on rare diseases in the Mendel Museum Masaryk University (www.mendelmuseum.muni.cz) illustrate activities our CF Center.
1. Genetics
5 Phenotypic characteristics of p.E92K mutation in adults with cystic fibrosis (CF) in Russia M. Usacheva1 , S. Krasovskiy1 , A. Stepanova2 , A. Polyakov2 , E. Amelina1 . 1 Research Institute of Pulmonology, Moscow, Russian Federation; 2 Research Centre for Medical Genetics, Moscow, Russian Federation The main reason for development of CF for the Chuvash − the fifth in population number (1.5 mln) nationality in Russia is of the “mild” p.E92K mutation (p.Glu92Lys, c.274G>A). Objective: To identify the clinical and functional characteristics of the course of CF in the patients-carriers of p.E92K mutation. Materials and Methods: Group 1: 26 adult CF patients homozygous or heterozygous for E92K, group 2: 103 adult patients homozygous for F508del. Age, age diagnosis, BMI, level of chloride in sweat, spirometry parameters, frequency of some complications [CF related diabetes (CFRD), liver cirrhosis with portal hypertension (LCPH), distal intestinal obstruction syndrome (DIOS)/meconium ileus (MI) in past medical history, cholelithiasis, urolithiasis, pulmonary hypertension (PH), asthma] were estimated. Results are described as mean±SD/median (IQR). Results: The median age group 1 was: 26.0 (5.95) years, higher than in the group 2 − 23.6 (6.5) years (p = 0.007); age diagnosis of patients with E92K was: 13.3 (9.2), higher than among homozygous for F508del − 1.9 (4.5) years (p < 0.001). There was no significant difference in the level of chloride in sweat (101±30.5 mmol/l vs 103±32 mmol/l respectively) in the two groups. The spirometry parameters, BMI, the frequency of LCPH, DIOS/MI, cholelithiasis, urolithiasis, asthma and PH had not significant difference. CFRD had frequency in the group of the patients homozygous for F508del, and CFRD in group p.E92K was never once identified (p = 0.046). Conclusion: p.E92K mutation in patients-carriers is associated with late onset age, significant low frequency of CERD, what is likely connected with the “mildness” of this mutation.
6 CFTR dele2,3 (21 kb) mutation in cystic fibrosis patients in Latvia G. Taurina1,2 , L. Piekuse1 , I. Kempa1 , Z. Krumina2 , I. Micule2 , V. Svabe3 , A. Krumina4 . 1 Riga Stradins University, Scientific Laboratory of Molecular Genetics, Riga, Latvia; 2 Children’s Clinical University Hospital, Medical Genetics Clinic, Riga, Latvia; 3 Children’s Clinical University Hospital, Department of Pulmonology and Allergology, Riga, Latvia; 4 Latvian Biomedical Research and Study Center, Riga, Latvia Background: Cystic fibrosis (CF) is one of the most common severe autosomal recessive diseases in Latvia with frequency 1:3,300. It is classified as I class mutation causing a premature stop codon formation in exon 4. The phenotype is associated with early onset of disease and exocrine pancreatic insufficiency. So far only few cases with homozygous dele2,3 mutations have been described. Methods: CFTR mutation screening was performed by standard molecular methods for 62 patients with clinical symptoms of CF. Results: CFTR dele2,3 mutation was detected in 3 patients. The first was a girl with dF508/dele2,3 mutation who was diagnosed with CF at the age of 1 year due to poor weight gain, recurrent lung infections and positive sweat test. On therapy there was a symptom free period of several years. She died at the age of 13 years due to pulmonary and heart insufficiency. The second was a boy with P67L/dele2,3 mutation presented with meconium ileus and had died at the age of 3 months. The third patient, a girl, presented with meconium ileus and positive sweat test in first days of her life. The molecular testing revealed her to be homozygous for dele2,3 mutation. At the age of 1 year and 6 months, even having pancreatic enzyme replacement therapy, her height and weight is still below 3rd percentile. Conclusion: CFTR dele2,3 (21 kb) mutation represents 3.2% of all CF alleles becoming the second most frequent severe CFTR mutation in Latvia. This mutation should be included in first step CF mutation screening together with dF508 mutation. The study confirms that dele2,3 mutation has severe phenotype − early presentation, exocrine pancreas insufficiency and recurrent lung infections.
Posters
7 Genetic prevention of cystic fibrosis as a part of the national strategy for rare diseases in University Hospital Brno, Czech Republic (genetic counselling − DNA analysis − newborn screening − education) R. Gaillyov´a1,2,3 , I. Val´asˇkov´a1,2,3 , J. Neˇcasov´a1 , R. Spˇesˇn´a1,3 , H. Vinohradsk´a3,4 , A. Holˇc´ıkov´a5 , L. Homola5 , E. Pokojov´a6 , O. Dost´al7 . 1 University Hospital, Dept. of Medical Genetics, Brno, Czech Republic; 2 Masaryk University, Faculty of Medicine, Dept. of Biology, Brno, Czech Republic; 3 Masaryk University, Faculty of Medicine, Department of Laboratory Methods, Brno, Czech Republic; 4 University Hospital, Dept. of Clinical Biochemistry, Brno, Czech Republic; 5 University Hospital, Clinic of Pediatric Infectious Diseases, Brno, Czech Republic; 6 University Hospital, Clinic of Pulmonary Diseases and Tuberculosis, Brno, Czech Republic; 7 Masaryk University, Mendel Museum, Brno, Czech Republic “Interdepartmental and interdisciplinary working group on rare diseases” runs under the Czech Ministry of Health, and coordinates the establishment of centres for rare diseases. A team of experts from CF Centre in University Hospital Brno currently cares for 64 children and 34 adults with Cystic Fibrosis (CF). University Hospital Brno is also responsible for newborn screening for CF(NSCF) for the Moravia region. From December 2009 till the end of December 2013, 161 917 newborns were examined under the NSCF at the University Hospital Brno. DNA analysis of the CFTR gene was carried out in 1846 newborns, representing 1.14%. One or two mutations in CFTR gene were found in 10% of newborns. We detected 20 different mutations in the CFTR gene, the most frequent were the mutations F508del (113), CFTRdele2,3 (21 kb) (18) and D1152H (14). The DNA analysis of the CFTR gene we also perform within the genetic prevention for 400–500 people per year, which represent about 20% of patients examined in our laboratory of DNA diagnostics. In this group, we detected the pathological CF allele in more than 15% individuals. Centres for Orphan cooperate with patient organisations associated in the Czech Association of Rare Diseases. An important part of the work of all experts on rare diseases is an effort to raise awareness about rare diseases among specialists and the public. Lecture devoted to Cystic Fibrosis in November 2013 was a part of the activities within the European day for CF. Teaching of Clinical Genetics at Masaryk University Brno and public lectures dedicated on rare diseases in the Mendel Museum Masaryk University (www.mendelmuseum.muni.cz) illustrate activities our CF Center.