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Targeted sequencing reveals complex, phenotype-correlated genotypes in cystic fibrosis

BACKGROUND: Cystic fibrosis (CF) is one of the most common life-threatening genetic disorders. Around 2000 variants in the CFTR gene have been identified, with some proportion known to be pathogenic and 300 disease-causing mutations have been characterized in detail by CFTR2 database, which complica...

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Detalles Bibliográficos
Autores principales: Ivanov, Maxim, Matsvay, Alina, Glazova, Olga, Krasovskiy, Stanislav, Usacheva, Mariya, Amelina, Elena, Chernyak, Aleksandr, Ivanov, Mikhail, Musienko, Sergey, Prodanov, Timofey, Kovalenko, Sergey, Baranova, Ancha, Khafizov, Kamil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836842/
https://www.ncbi.nlm.nih.gov/pubmed/29504914
http://dx.doi.org/10.1186/s12920-018-0328-z
Descripción
Sumario:BACKGROUND: Cystic fibrosis (CF) is one of the most common life-threatening genetic disorders. Around 2000 variants in the CFTR gene have been identified, with some proportion known to be pathogenic and 300 disease-causing mutations have been characterized in detail by CFTR2 database, which complicates its analysis with conventional methods. METHODS: We conducted next-generation sequencing (NGS) in a cohort of 89 adult patients negative for p.Phe508del homozygosity. Complete clinical and demographic information were available for 84 patients. RESULTS: By combining MLPA with NGS, we identified disease-causing alleles in all the CF patients. Importantly, in 10% of cases, standard bioinformatics pipelines were inefficient in identifying causative mutations. Class IV-V mutations were observed in 38 (45%) cases, predominantly ones with pancreatic sufficient CF disease; rest of the patients had Class I-III mutations. Diabetes was seen only in patients homozygous for class I-III mutations. We found that 12% of the patients were heterozygous for more than two pathogenic CFTR mutations. Two patients were observed with p.[Arg1070Gln, Ser466*] complex allele which was associated with milder pulmonary obstructions (FVC 107 and 109% versus 67%, CI 95%: 63-72%; FEV 90 and 111% versus 47%, CI 95%: 37-48%). For the first time p.[Phe508del, Leu467Phe] complex allele was reported, observed in four patients (5%). CONCLUSION: NGS can be a more information-gaining technology compared to standard methods. Combined with its equivalent diagnostic performance, it can therefore be implemented in the clinical practice, although careful validation is still required. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12920-018-0328-z) contains supplementary material, which is available to authorized users.