Unit:
Faculty of MedicineLibrary of the School of Health Sciences
Author:
Karamanakos Anastasios
Dissertation committee:
Σφηκάκης Π. Πέτρος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Γερμενής Αναστάσιος, Ομότιμος Καθηγητής, Ιατρική Σχολή, Πανεπιστήμιο Θεσσαλίας
Τεκτονίδου Μαρία, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Κόκκινος Αλέξανδρος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Λυμπερόπουλος Ευάγγελος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Μαυραγάνη Κλειώ, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Φραγκούλης Γεώργιος, Επίκουρος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Original Title:
Genetic analysis of patients with clinical features of autoinflammatory disorders plus pyrin gene mutations using next generation sequencing (NGS)
Translated title:
Genetic analysis of patients with clinical features of autoinflammatory disorders plus pyrin gene mutations using next generation sequencing (NGS)
Summary:
Objective: To assess the possible impact conferred by co-existing variants in MEditerranean FeVer (MEFV) and other genes on systemic autoinflammatory disease (SAID) phenotype.
Methods: Consecutive patients (n = 42) who underwent screening for SAIDs by next generation sequencing (NGS) targeting 26 genes, and carried at least one MEFV gene variant, were retrospectively studied. A total of 63 MEFV gene variants mainly located in exon 10 (n = 29) and exon 2 (n = 19) were identified in 21 patients with juvenile-and 21 with adult-onset disease.
Results: The candidate clinical diagnosis was Familial Mediterranean Fever (FMF) in 11, polygenic SAIDs (PFAPA, Still’s disease, atypical SAPHO and inflammatory bowel disease) in 9, whereas the disease could not be clinically defined in 22 patients. Notably, 33 out of the 42 patients (79%) had at least one co-existing variants in 19 genes other than MEFV. NGS confirmed all clinical diagnoses and helped defining diagnosis in 59% of the remaining cases. Patients with undefined SAIDs (n = 9) or atypical FMF phenotype (n = 12) carried significantly more disease-causing variants in genes other than MEFV compared to patients with typical FMF (n = 9). More than one variants in these genes were significantly associated with adult-onset disease, while disease–causing variants in the same genes were also associated with an overall more severe SAID phenotype.
Conclusion: Co-existing variants in SAID-related genes may explain the phenotypic variability of these diseases. Further studies should validate combined molecular and clinical data in order to better understand the cumulative gene dosage effect and improve the classification of these patients.
Main subject category:
Health Sciences
Keywords:
Genetic analysis, Autoinflammatory disorders, Next generation sequencing
Number of references:
255
File:
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Karamanakos_Anastasios_PhD.pdf
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