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Génétique des fibroses pulmonaires familiales de l’adulte

Abstract : About 10% of patients with idiopathic pulmonary fibrosis (IPF) have at least one relative with interstitial lung disease (ILD). Mutations had been reported on the genes encoding for the proteins involved in the surfactant metabolism and in the telomerase complex In adults, TERT mutations were the most frequent (˜15%), mutations of TERC, DKC1 and TINF2 more rarely found. Approximately 80% of the familial forms of pulmonary fibroses in adults were unidentified. The objectives of this work were: 1) to identify a new gene involved in unexplained adult familial pulmonary fibrosis, 2) to better characterize the phenotype of patients with mutations of TERT, TERC or the new gene detected. We selected 35 families with familial pulmonary fibrosis for which the TERT, TERC, ABCA3, SFTPB and SFTPC mutation search was negative, to perform exome sequencing. Four of the 35 families analyzed showed a very rare variant on RTEL1 in the heterozygous state. The presence of the variants was confirmed by Sanger sequencing. These variants were absent from the control databases. In silico predictions were in favor of the pathogenicity of these variants.In families, the variants co-segregated with the disease. In 3D modeling, analysis of the variants suggested a functional impact at the ATP or DNA binding site. The telomere length of carriers of the mutations was shortened compared to controls in the same age group. In 2014, 237 patients with pulmonary fibrosis (153 with familial pulmonary fibrosis, 84 with telomere syndrome) were sequenced for TERC and TERT. The variants were classified as pathogenic in 40 patients (16.8%). An early age of diangosis, macrocytosis, or thrombocytopenia were significantly associated with the presence of a mutation.The probability of a mutation was greatest for patients aged 40-60 years. The median survival without transplantation was lower for patients with TERT or TERC mutations.We performed a sequencing of the exoma in 40 other families and showed 5 new variants of RTEL1 probably pathogenic in silico. We also demonstrated 3 other mutations of RTEL1 in a cohort of ILD associated with rheumatoid arthritis. We collected data from 35 patients with ILD carriers of RTEL1 heterozygous mutations. Twenty patients had IPF (57%) and 10 a secondary ILD (25.7%). Unlike mutations within TERT or TERC, RTEL1 mutations were associated with fewer hematological abnormalities.Furthermore, the pulmonary expression of the RTEL1 protein evaluated by immunohistochemistry and mRNA by PCR was equivalent in patients carriers of RTEL1 or TERT mutations or IPF without mutation. We identified and confirmed the implication of a new gene, RTEL1, in about 10% of familial pulmonary fibroses. The presence of macrocytosis, thrombocytopenia or a young age is predictive of the presence of a mutation within TERT or TERC. The penetrance of hematological diseases appears to be lower for RTEL1 mutation carriers than for TERT or TERC mutation carriers in our cohort of ILD patient. Mutations of TERT or RTEL1 are frequently associated with secondary ILD
Keywords : RTEL1 TERT TERC
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Raphaël Borie. Génétique des fibroses pulmonaires familiales de l’adulte. Génétique humaine. Université Sorbonne Paris Cité, 2017. Français. ⟨NNT : 2017USPCC208⟩. ⟨tel-02115539⟩

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