ECE2023 Poster Presentations Pituitary and Neuroendocrinology (123 abstracts)
Genetic Analyses Of 20 Turkish FIPA Families Utilizing Whole Exome Sequencing: Preliminary Results Of A Multicenter Collaborative Study
Melek Eda Ertorer 1 , Feyza Tuncer 2 , Sema Ciftci 3 , Seher Tanrikulu 4 , Ozlem Soyluk Selcukbiricik 5 , Ömercan Topaloğlu 6 , Mehtap Evran 7 , Pinar Kadioglu 8 , Sevcan Aydin 2 , Bulent Can 9 , Canan Sehit 10 , Zafer Pekkolay 11 , Gonca Oruk 12 , Berrin Cetinarslan 13 & Sema Yarman 5
1Baskent University Faculty of Medicine, Endocrinology and Metabolism, Adana, Turkey; 2Istanbul University, Aziz Sancar Institute of Experimental Medicine, Genetics, Istanbul, Turkey; 3University of Health Sciences, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Endocrinology and Metabolism, Istanbul, Turkey; 4Istanbul Haydarpasa Training and Research Hospital, Endocrinology and Metabolism, Istanbul, Turkey; 5Istanbul University Faculty of Medicine, Endocrinology and Metabolism, Istanbul, Turkey; 6Zonguldak Bulent Ecevit University Faculty of Medicine, Endocrinology and Metabolism; 7Cukurova University Faculty of Medicine, Endocrinology and Metabolism, Adana, Turkey; 8Cerrahpasa University Faculty of Medicine, Endocrinology and Metabolism, Istanbul, Turkey; 9Istanbul Medeniyet University Faculty of Medicine, Endocrinology and Metabolism, Istanbul, Turkey; 10Erciyes University Faculty of Medicine, Endocrinology and Metabolism, Kayseri, Turkey; 11Dicle University Faculty of Medicine, Endocrinology and Metabolism, Diyarbakir, Turkey; 12İzmir KatiPÇelebi Üniversitesi Atatürk Eğitim ve Araştırma Hastanesi, Endocrinology and Metabolism, İzmir, Turkey; 13Kocaeli University Faculty of Medicine, Endocrinology and Metabolism, Kocaeli, Turkey
Objective: Hereditary pituitary adenomas (PAs) are rare and occur either isolated or as part of a syndrome. Familial isolated pituitary adenoma (FIPA) is the presence of only PA in at least two members of a family, where “Aryl hydrocarbon receptor interacting protein-AIP” gene mutations have been identified in 10-20% of cases. However, the cause of tumorigenesis in the majority is unknown. We aimed to identify novel genetic variants in a cohort of FIPA patients from Turkiye.
Materials and Methods: Twelve centers in various geographical regions of the country were included. FIPA cohort involving 20 index cases and 17 affected relatives were recruited. Whole exome sequencing was performed on 20 cases on Illumina NextSeq550 system. Bioinformatic analyses and variant prioritization at MAF<1% were performed, where variants for PA-related genes followed by novel candidate genes were filtered. Affected relatives were utilized in confirmation of candidate variants by Sanger sequencing.
Results: Our cohort consisted of 10 homogeneous (index cases: 4 prolactinomas/6 acromegaly) and 10 heterogeneous (index cases: 4 prolactinomas,3 Cushing’s disease and 3 acromegaly ) FIPAs. The gender distribution of indexes in each group is equal (5F/5M). The mean age at diagnosis of index cases was 38.44±13.25 years for acromegaly (n=9), 36.25±17.13 for prolactinoma (n=8), 44.67±2.31 for Cushing’s disease (n=3). Eight out of 20 index cases of FIPA families were found to carry variations in PA-related genes, where a novel AIP variant (c.646-1G>C) was identified (Table 1). Confirmation and familial segregation are ongoing for variants in heterogeneous FIPAs.
| Index case,(no) | Age at diagnosis (years/sex) | FIPA type, (PA phenotype) | PA-related gene | Chromosomal position | Variation | Amino acid change | Novelty |
| 1 | 30/M | Heterogeneous Prolactinoma | USP8 SDHB | 15:50,769,152 1:17,354,257 | c.956C>T c.527A>G | p.(Pro319Leu) p.(Glu176Gly) | Novel Novel |
| 2 | 37/M | Heterogeneous Somatotrophinoma | AIP DICER1 | 11:67,257,786 14:95,584,087 | c.646-1G>C c.1381A>G | Splice acceptor p.(Ile461Val) | Novel Novel |
| 3 | 27/M | Heterogeneous Somatotrophinoma | AIP | 11:67,254,618 | c.241C<T | p.(Arg81Ter) | Pathogenic* |
| 4 | 44/F | Homogeneous Somatotropinoma | AIP | 11:67,258,381 | c.910C>T | p.(Arg304Ter) | Pathogenic* |
| 5 | 32/M | Homogeneous Somatotropinoma | TSC1 | 9:135,781,415 | c.1550G>A | p.(Arg517Gln) | Novel |
| 6 | 47/F | Heterogeneous Corticotrphinoma | CDH23 | 10:73,570,263 | c.2294C>T | p.(Ala765Val) | Novel |
| 7 | 22/F | Heterogeneous Prolactinoma | NF1 | 17:29,562,948 | c.3883A>G | p.(Thr1295Ala) | Novel |
| 8 | 18/F | Heterogeneous Prolactinoma | MSH2 | 2:47,703,697 | c.2197G>A | p.(Ala733Thr) | Novel |
| (*)Clinvar database (https://www.ncbi.nlm.nih.gov/clinvar/). | |||||||
Conclusion: Consistent with the literature, our preliminary results detected AIP mutation frequency as 15% in the FIPA cohort. Novel variants in our study highlight the genetic heterogeneity and phenotypic diversity of FIPA patients, which complicate the diagnosis.
Funding: Turkish Society of Endocrinology and Metabolism (project no: KA21/247).
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Endocrine Abstracts
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