Genetic insight into Birt-Hogg-Dubé syndrome in Indian patients reveals novel mutations at FLCN.

Autor: Ray A; Human Genetics Unit, Indian Statistical Institute, Kolkata, India., Chattopadhyay E; Human Genetics Unit, Indian Statistical Institute, Kolkata, India.; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Singh R; Human Genetics Unit, Indian Statistical Institute, Kolkata, India.; Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA., Ghosh S; Human Genetics Unit, Indian Statistical Institute, Kolkata, India., Bera A; Department of Pulmonary Medicine, RG Kar Medical College and Hospital, Kolkata, India.; Respiratory Medicine and Critical Care, Medica Superspeciality Hospital, Kolkata, India., Sarma M; Department of Chest Medicine, Calcutta National Medical College, Kolkata, India.; Narayana Superspeciality Hospital, Guwahati, India., Munot M; Department of Pulmonary Medicine, TNMC and BYL Nair Hospital, Mumbai, India., Desai U; Department of Pulmonary Medicine, TNMC and BYL Nair Hospital, Mumbai, India., Rajan S; Department of Chest Medicine, Bombay Hospital Institute of Medical Sciences, Mumbai, India., Prabhudesai P; Lilavati Hospital and Research Centre, Mumbai, India., Prakash AK; Department of Respiratory and Sleep Medicine, Medanta- The Medicity, Gurgram, India., Roy Chowdhury S; Apollo Hospital Kolkata, Pulmonology, India.; Fortis Hospital Kolkata, Pulmonology, India., Bhowmick N; Department of General Medicine, IPGMER&SSKM Hospital, Kolkata, India., Dhar R; CMRI, C K Birla Group of Hospitals, Kolkata, India., Udwadia ZF; P.D. Hinduja Hospital and Research Center, Mumbai, India., Dey A; Department of Pulmonary Medicine, RG Kar Medical College and Hospital, Kolkata, India., Mitra S; Department of Chest Medicine, Calcutta National Medical College, Kolkata, India., Joshi JM; Department of Pulmonary Medicine, TNMC and BYL Nair Hospital, Mumbai, India., Maitra A; National Institute of Biomedical Genomics, Kalyani, India., Roy B; Human Genetics Unit, Indian Statistical Institute, Kolkata, India. bidyutroy8933@gmail.com.
Jazyk: angličtina
Zdroj: Orphanet journal of rare diseases [Orphanet J Rare Dis] 2022 Apr 27; Vol. 17 (1), pp. 176. Date of Electronic Publication: 2022 Apr 27.
DOI: 10.1186/s13023-022-02326-5
Abstrakt: Background: Birt-Hogg-Dubé syndrome (BHDS) is a rare monogenic condition mostly associated with germline mutations at FLCN. It is characterized by either one or more manifestations of primary spontaneous pneumothorax (PSP), skin fibrofolliculomas and renal carcinoma (chromophobe). Here, we comprehensively studied the mutational background of 31 clinically diagnosed BHDS patients and their 74 asymptomatic related members from 15 Indian families.
Results: Targeted amplicon next-generation sequencing (NGS) and Sanger sequencing of FLCN in patients and asymptomatic members revealed a total of 76 variants. Among these variants, six different types of pathogenic FLCN mutations were detected in 26 patients and some asymptomatic family members. Two of the variants were novel mutations: an 11-nucleotide deletion (c.1150_1160delGTCCAGTCAGC) and a splice acceptor mutation (c.1301-1G > A). Two variants were Clinvar reported pathogenic mutations: a stop-gain (c.634C > T) and a 4-nucleotide duplication (c.1329_1332dupAGCC). Two known variants were: hotspot deletion (c.1285delC) and a splice donor mutation (c.1300 + 1G > A). FLCN mutations could not be detected in patients and asymptomatic members from 5 families. All these mutations greatly affected the protein stability and FLCN-FNIP2 interaction as observed by molecular docking method. Family-based association study inferred pathogenic FLCN mutations are significantly associated with BHDS.
Conclusion: Six pathogenic FLCN mutations were detected in patients from 10 families out of 15 families in the cohort. Therefore, genetic screening is necessary to validate the clinical diagnosis. The pathogenic mutations at FLCN affects the protein-protein interaction, which plays key roles in various metabolic pathways. Since, pathogenic mutations could not be detected in exonic regions of FLCN in 5 families, whole genome sequencing is necessary to detect all mutations at FLCN and/or any undescribed gene/s that may also be implicated in BHDS.
(© 2022. The Author(s).)
Databáze: MEDLINE
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