Alport Syndrome Gene Panel
Alport syndrome is a genetic glomerular disease which frequently leads to end-stage renal disease. In addition to renal disease, the syndrome classically is associated with sensorineural hearing loss and ocular abnormalities.(1) The clinical kidney findings usually consist of hematuria and proteinuria with eventual renal dysfunction though there is a wide spectrum that can be seen in the clinical presentation. It most commonly has an x-linked inheritance pattern due to involvement of the COL4A5 gene but can also be autosomal recessive or autosomal dominant, depending on the gene involved in disease. The most classic and well known morphologic findings are those seen in the glomerular basement membranes by electron microscopy. However, the morphologic presentation is a spectrum that can range from classic Alport changes to thin glomerular basement membranes(2) to focal segmental glomerulosclerosis.(3)
Inherited nephropathies involving many different genes often have overlapping clinical and morphologic findings. Therefore, testing for these genetic conditions stands to greatly benefit from sequencing techniques which enable evaluation of numerous genes simultaneously. The Alport panel utilizes next generation sequencing to detect variants in 8 genes which are described to have clinical and/or morphologic findings which raise the differential disease of Alport syndrome (see a full list of genes below). The genes for all four alpha chains of collagen IV known to be associated with Alport syndrome are evaluated. The LMX1B and MYH9 genes are also included because variants in these genes are known to show overlapping ultrastructural findings with Alport syndrome. FN1 encodes an extracellular matrix protein and mutations in this gene have been described in association with fibronectin glomerulopathy.(4) MYO1E variants have previously been shown to augment the severity of Alport syndrome when COL4A5 mutation.(5)
Arkana is a laboratory with specialized expertise in the classification of renal disease. Therefore, if the patient has had a renal biopsy performed and it can be sent along with the DNA sample, the physicians at Arkana Laboratories will incorporate evaluation of the clinicopathologic findings into the report. This will enable us to provide a complete diagnosis of the patient’s kidney disease including genotype-phenotype correlation by an expert in the field.
Reasons for Testing:
Detection of variant leading to disease when there is clinical and/or morphologic suspicion for the diagnosis of Alport syndrome, Nail-Patella syndrome, MYH9-related disorders, or fibronectin glomerulopathy.
Method: Next generation sequencing and/or direct (Sanger) sequencing
Test performed: bi-weekly
Turnaround time: 3 months
Genes interrogated include:
COL4A3, COL4A4, COL4A5, COL4A6, FN1, LMX1B, MYH9, MYO1E
Acceptable specimens include:
Peripheral blood (preferred): At least 2 ml in Lavender top (EDTA) tube shipped overnight at room temperature
Previously extracted DNA: 10ul suspended in TE buffer at 100ng/ul, Transport overnight in frozen state (dry-ice) M-Th
Samples must have two patient identifiers, preferably the patient’s name and date of birth.
Each sample must be accompanied by a requisition form with the declaration signed by the ordering provider.
Please call Arkana Laboratories to request a kit.
Arkana Laboratories Molecular Division
10810 Executive Center Drive, Suite 100
Little Rock, AR 72211
Co-Director: Chris Larsen, MD
Co-Director: Jon D. Wilson, MD
Lab Manager: Marjorie Beggs, PhD
Miner JH, Baigent C, Flinter F, et al. The 2014 international workshop on Alport Syndrome. Kidney Int 2014; 86: 679-684.
Savige J, Gregory M, Gross O, Kashtan C, Ding J, Flinter F. Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol 2013; 24: 364-375.
Deltas C, Savva I, Voskarides K, Papazachariou L, Pierides A. Carriers of Autosomal Recessive Alport Syndrome with Thin Basement Membrane Nephropathy Presenting as Focal Segmental Glomerulosclerosis in Later Life. Nephron 2015; 130: 271-280.
Castelletti F, Donadelli R, Banterla F, et al. Mutations in FN1 cause glomerulopathy with fibronectin deposits. PNAS 2008; 105: 2538-2543.
Lennon R, Stuart HM, Bierzynska A, et al. Coinheritance of COL4A5 and MYO1E mutations accentuate the severity of kidney disease. Pediatr Nephrol. 2015 Sep;30(9):1459-65.