Abstract: PO1655
Variation in Phenotype in Utah Families with Autosomal Recessive Alport Syndrome
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - 2
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Al-Rabadi, Laith, University of Utah Health, Salt Lake City, Utah, United States
- Lin, Edwin, University of Utah Health, Salt Lake City, Utah, United States
- Sauer, Lydia, University of Utah Health, Salt Lake City, Utah, United States
- Vitale, Alex, University of Utah Health, Salt Lake City, Utah, United States
- Bernstein, Paul, University of Utah Health, Salt Lake City, Utah, United States
- Gregory, Martin C., University of Utah Health, Salt Lake City, Utah, United States
Background
Individuals with heterozygous COL4A3 or COL4A4 mutations usually have thin basement membrane nephropathy (TBMN), which is often considered the carrier state of autosomal recessive Alport syndrome (ARAS). Patients with ARAS usually progress to end-stage renal disease (ESRD) by the fourth decade of life. While ocular abnormalities, hearing loss and renal impairment are classically absent with TBMN, a subset of patients develop focal segmental glomerulosclerosis (FSGS) and 13-25% of patients progress to ESRD.
It is unclear why some individuals with heterozygous COL4A3 mutations follow a mild course with isolated microscopic hematuria or low-grade proteinuria while others with the same mutations develop progressive renal dysfunction. It is also unclear why some family members show hematuria while others with the same mutation do not.
Methods
This study was designed to address these clinical questions using unbiased Whole Exome Sequencing (WES) in a population of patients harboring a limited number of pathogenic heterozygous COL4A3 mutations. Our work has focused on detailed examinations of patients carrying the same mutation to assess carefully the inter and intrafamilial variability and assess the impact of mutation on pathology.
Results
Two Utah families (figure) with a unique combination of two pathogenic mutations were identified. These pathogenic mutations have been reported before. However, the compound heterozygous status in each family is unique and has not been reported before.The probands are compound heterozygotes sharing one mutation (c.2083G>A, p.Gly695Arg) but differ in the second mutation (c.4981C>G, p.Arg1661Cys vs c.4421T>C, p.Leu1474Pro).
Conclusion
This study expanded the phenotypic spectrum of COL4A3 mutation carriers. Our findings showed the significant overlap between phenotypes induced by COL4A3 variants and the considerable intra and inter-familial variability and renal disease progression in patients with COL4A3 mutations.
Family pedigrees.
Arrows : Absence of COL4A3 mutation
Funding
- Private Foundation Support