Abstract: TH-PO453
The Role of Whole-Exome Sequencing in Diagnosis of Genetic Disorders: A Case Report of a Novel Mutation in the Fibrinogen A-Alpha Chain Gene
Session Information
- Genetic Diseases: Glomerulopathies - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Jurubita, Roxana Adriana, Fundeni Clinical Institute, Bucharest, Romania
- Obrisca, Bogdan, Fundeni Clinical Institute, Bucharest, Romania
- Adrian Catalin, Lungu I., Fundeni Clinical Institute, Bucharest, Romania
- Ismail, Gener, Fundeni Clinical Institute, Bucharest, Romania
Introduction
Hereditary fibrinogen amyloidosis (AFib) was first characterized in 1993 in a Peruvian kindred. Patients with AFib present with renal disease and typically progress to ESRD. We describe a case of Afib with a novel mutation in the FGA gene identified by whole-exome sequencing (WES).
Case Description
A 51-year-old male patient presented to the nephrology clinic for the evaluation of a nephrotic range-proteinuria (5.4 g/day) and decreased eGFR (35 ml/min/1.73m2). His family history was notable for stage V CKD of unknown cause (patient’s mother). His past medical history is remarkable for a ruptured spleen and splenectomy following a minor trauma, two years prior to current evaluation. The initial work-up was negative for autoimmune disorders, hepatitis serology, malignancy screening, monoclonal gammopathy. The kidney biopsy revealed severe amyloid deposition with striking glomerular enlargement and almost complete obliteration of the normal architecture, without vascular or interstitial involvement. The reevaluation of splenic tissue did also reveal extensive amiloyd deposition. The bone marrow biopsy was negative and the patient didn’t have any prior history of a chronic inflammatory process (serum amyloid A protein was slightly increased, 19 mg/L). Typing of amyloid by immunohistochemistry (IHC) could not reliably differentiate between AA amyloidosis and AFib. Because the initial genetic testing for hereditary amyloidosis (including testing for SAA1 promoter gene) was negative, a WES was further performed. The patients was identified to be heterozygous for two variants of uncertain significance (VUS) of FGA gene, c.1676A>T, p. (Glu559Val) and c. 967C>G, p. (Pro323Ala).
Discussion
This case report illustrates the limitations of amyloid typing by IHC and the role of WES in identifying novel mutations in hereditary amyloidosis. The patient was heterozygous for two VUS of FGA gene, of which the c.1676A>T, p. (Glu559Val) has been previously reported in two German sisters with AFib, while the c. 967C>G, p. (Pro323Ala) has not been reported in the medical literature. Despite that both variants were reported to be VUS, the correlation with the patient’s family history and the severity of renal and splenic involvement further outlines that these variants are clinically significant.