Invitae Progressive Renal Disease Panel


Test description

The Invitae Progressive Renal Disease Panel analyzes 17 genes that are associated with progressive renal disorders such as Alport syndrome, focal segmental glomerulosclerosis (FSGS) and nephrotic syndrome. Nephrotic syndrome and FSGS are genetically heterogeneous disorders representing a spectrum of hereditary renal conditions. The genetic heterogeneity associated with these renal conditions can make it difficult to use phenotype as the sole criterion to select a definitive cause. Broad panel testing allows for an efficient evaluation of several potential genes based on a single clinical indication.

Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. 

This assay does not currently include the PKD1 gene. Pathogenic variants in the PKD1 gene account for the majority (~78%) of autosomal dominant polycystic kidney disease, type 1 (PKD1). Additional testing for PKD1 should be considered, if not yet performed and clinically appropriate.

This test is specifically designed for heritable germline mutations and has assay limitations that are different from most of our other diagnostic panels. Please see the Assay section below for more details.


Test meta-description

Genetic testing for 17 genes that are associated with progressive renal disorders including Alport syndrome, focal segmental glomerulosclerosis (FSGS) and nephrotic syndrome.

Genes tested


ACTN4, ANLN, CD2AP, COL4A3, COL4A4, COL4A5, CRB2, HNF1A, INF2, LMX1B, MYO1E, NPHS1, NPHS2, PAX2, PKD2, PKHD1, TRPC6

DISORDERS TESTED

Gene

Condition

ACTN4

Focal Segmental Glomerulosclerosis 

ANLN

Focal Segmental Glomerulosclerosis 

CD2AP

Focal Segmental Glomerulosclerosis 

COL4A3

Alport syndrome

COL4A4

Alport syndrome

COL4A5

Alport syndrome

CRB2

Focal Segmental Glomerulosclerosis 

HNF1A

Maturity-onset diabetes of the young (MODY), type 3

INF2

Focal Segmental Glomerulosclerosis 

LMX1B

Focal Segmental Glomerulosclerosis 

MYO1E

Focal Segmental Glomerulosclerosis 

NPHS1

Congenital Nephrotic syndrome, type 1

NPHS2

Congenital Nephrotic syndrome, type 2

PAX2

Papillorenal syndrome

PKD2

Autosomal dominant polycystic kidney disease (ADPKD), type 2

PKHD1

Autosomal recessive polycystic kidney disease (ARPKD)

TRPC6

Focal Segmental Glomerulosclerosis 

CLINICAL DESCRIPTION

Alport syndrome can be inherited in different ways. X-linked Alport syndrome is characterized by renal disease with microscopic hematuria, hearing loss, and ocular abnormalities including anterior lenticonus and maculopathy (PMID: 10752524). Affected males with X-linked Alport syndrome have up to a 90% risk of end stage renal disease (ESRD) and deafness by age 40 years (PMID: 10752524). Affected females typically have a milder disease course, with a 10% risk of deafness and a 12% risk of ESRD by age 40 years (PMID: 14514738). Autosomal recessive Alport syndrome is characterized by childhood onset progressive hematuric nephropathy typically progressing to end stage renal disease by the end of the second decade, juvenile onset sensorineural deafness, and ocular findings including anterior lenticonus and cataract (PMID: 24033287, 24854265, 25649157). In contrast, autosomal dominant Alport syndrome has a later age of onset of renal disease and deafness, and ocular findings are rare (PMID: 24854265). Benign familial hematuria typically presents in childhood as persistent microscopic hematuria. The condition rarely progresses to renal disease but cannot be clinically differentiated from the early stages of Alport syndrome at onset (PMID: 8787673, 11961012).

Focal Segmental Glomerulosclerosis (FSGS) is characterized by a distinct histological pattern of renal damage typically clinically manifesting in late adolescence with proteinuria and progressive decline in renal function, often with progression to end stage renal disease (PMID: 9461087, 16932363, 22187987). A majority of affected individuals have nephrotic syndrome at diagnosis, typically presenting with proteinuria, hypoalbuminemia, hypercholesterolemia, and peripheral edema (PMID: 22187987).

Nephrotic syndrome type I is the primary cause of congenital nephrotic syndrome in Finnish patients, but has also been seen in other ethnicities (PMID: 20507940, 11317351). It is typically characterized by massive proteinuria at birth (or in utero), a large placenta, marked edema, hypoalbuminemia, hyperlipidemia, and recurrent infections presenting in early infancy with rapid progression to end stage renal disease by 2 or 3 years of age (PMID: 20507940, 11317351, 11854170, 26961288). This condition is typically resistant to steroid treatment but affected individuals can be treated by nephrectomy, dialysis, and renal transplantation (PMID: 11317351, 20507940, 16752799). A classic histological feature is irregular microcystic dilation of the proximal tubules (PTD) (20507940). A subset of patients with a more mild clinical presentation have been reported (PMID: 20507940, 11854170). Genotype-phenotype correlations have been described (PMID: 20507940, 11854170).

Nephrotic syndrome type 2, also known as steroid resistant nephrotic syndrome, is typically characterized by infant or childhood onset of heavy proteinuria, hypoalbuminemia, hypercholesterolemia, and edema with progression to end stage renal disease in the first two decades of life (PMID: 24227627, 16752799, 25112471, 20507940). Disease progression and age of onset can be highly variable and genotype/ phenotype correlations have been described (PMID: 20507940, 24227627). The histological features are nonspecific and most display minimal glomerular changes or focal segmental glomerulosclerosis (FSGS) (PMID: 20507940, 16752799). Affected individuals can be treated by nephrectomy, dialysis, and renal transplantation (PMID: 16752799, 26420286).

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of cysts in the kidneys. This disorder typically begins to manifest in adulthood and can present with variable symptoms and levels of severity. Cysts can develop in a variety of organs outside of the kidneys including in the liver, pancreas, seminal vesicles and arachnoid membranes. Additional clinical features include vascular abnormalities, mitral valve prolapse and abdominal wall hernias. The majority of individuals with ADPKD will develop end stage kidney failure during their lifetime, requiring dialysis and an eventual kidney transplant (PMID: 19455193).

Autosomal recessive polycystic kidney disease (ARPKD) is a multisystemic disorder characterized by cyst formation in the kidneys and liver abnormalities associated with congenital hepatic fibrosis. Symptoms may include nephromegaly, hepatomegaly, dilated biliary ducts, and abnormal fetal pulmonary development during pregnancy. Age of onset, disease course, and severity are variable. Approximately one third of affected individuals present prenatally or in infancy, one third in childhood, and one third present in adulthood (PMID: 16523049).

Papillorenal syndrome is characterized by renal hypodysplasia and ocular anomalies (optic nerve dysplasia/coloboma and retinal anomalies) (PMID: 26571382, 22213154, 21654726). Other associated renal anomalies include multicystic dysplastic kidneys, oligomeganephronia and vesicoureteral reflux (PMID: 8588587, 21654726). Sensorineural hearing loss is also associated with this syndrome (PMID: 22213154). The clinical manifestations and severity of this condition can be variable.

Maturity-onset diabetes of the young type 3 (MODY3) is one of the most common types of familial noninsulin-dependent diabetes mellitus and is characterized by onset of diabetes in late adolescence or early adulthood. Patients with MODY3 have decreased renal absorption of glucose and glycosuria.

Inheritance

Progressive renal disorders can occur in several inheritance patterns including autosomal dominant, autosomal recessive and X-linked.

Clinical sensitivity

The clinical sensitivity of this test is dependent on the individual’s underlying genetic condition. For many rare conditions not listed in the table, the clinical sensitivity is unknown or not well-established.

 

Percent of disorders attributed to pathogenic variants in specific genes

Disorder

% Pathogenic variants in genes

Alport syndrome

COL4A5 80-85%

COL4A3 12-15%

COL4A4 5-8%

Congenital Nephrotic syndrome

NPHS1 40%

NPHS2 ~10%

Polycystic kidney disease

PKD2 ~15% of autosomal dominant disease

PKHD1 ~75% of autosomal recessive disease

MODY3

HNF1A 100%

Considerations for testing

This test may be appropriate for individuals with:

 
  • A clinical diagnosis of Alport syndrome OR a combination of the following features:
    • persistent hematuria 
    • family history of hematuria
    • irregular splitting and thickening with multi-lamellation of the glomerular basement membrane on EM
    • characteristic eye lesions (anterior lenticonus or perimacular flecks)
    • sensorineural hearing loss
 
  • A clinical diagnosis or renal biopsy confirming FSGS
  •  
  • A clinical diagnosis of nephrotic syndrome or steroid-resistant nephrotic syndrome (SRNS) OR  
    • Renal biopsy showing sclerotic glomeruli, microcystic tubular changes and tubular hypertrophy, podocyte foot process effacement, podocyte microvillous transformation, and tubuloreticular inclusions.
    • Mild to severe proteinuria  
    • Hypoalbuminemia (increased urine microalbumin excretion)
 
  • A clinical diagnosis of polycystic kidney disease (PKD) OR  
    • three or more (unilateral or bilateral) renal cysts in an individual age 15-39 years
    • two or more cysts in each kidney in an individual age 40-59 years
    • four or more cysts in each kidney in an individual age 60 years and older 
    • large echogenic kidneys without distinct macroscopic cysts in an infant/child
    • bilateral renal enlargement and cysts with or without the presence of hepatic cysts
    • End-stage renal disease (ESRD) before the age of 20 years or renal insufficiency

References

1. Mathis B, Kim S, Calabrese K et al. A locus for inherited focal segmental glomerulosclerosis maps to chromosome 19q13. Kidney Int. 1998;53(2):282-286. doi:10.1046/j.1523-1755.1998.00828.x

2. Meyrier A. Mechanisms of Disease: Focal segmental glomerulosclerosis. Nat Clin Pract Nephrol. 2005;1(1):44-54. doi:10.1038/ncpneph0025

3. D'Agati V, Kaskel F, Falk R. Focal segmental glomerulosclerosis. New Eng J Med. 2011;365(25):2398-2411. doi:10.1056/nejmra1106556

4. Okumura T, Furuichi K, Higashide T et al. Association of PAX2 and other gene mutations with the clinical manifestations of renal coloboma syndrome. PLoS ONE. 2015;10(11):e0142843. doi:10.1371/journal.pone.0142843

5. Bower M, Salomon R, Allanson J et al. Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database. Hum Mutat. 2012;33(3):457-466. doi:10.1002/humu.22020

6. Schimmenti L. Renal coloboma syndrome. Eur J Hum Genet. 2011;19(12):1207-1212. doi:10.1038/ejhg.2011.102

7. Schimmenti L, Pierpont M, Carpenter B, Kashtan C, Johnson M, Dobyns W. Autosomal dominant optic nerve colobomas, vesicoureteral reflux, and renal anomalies. Am J Med Genet. 1995;59(2):204-208. doi:10.1002/ajmg.1320590217

8. Torres V, Harris P. Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int. 2009;76(2):149-168. doi:10.1038/ki.2009.128

9. Adeva M, El-Youssef M, Rossetti S et al. Clinical and molecular characterization defines a broadened spectrum of autosomal recessive polycystic kidney disease (ARPKD). Medicine (Baltimore). 2006;85(1):1-21. doi:10.1097/01.md.0000200165.90373.9a

10. Sadowski C, Lovric S, Ashraf S et al. A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. J Am Soc Nephrol. 2014;26(6):1279-1289. doi:10.1681/asn.2014050489

11. Jais J. X-Linked Alport syndrome: Natural history and genotype-phenotype correlations in girls and women belonging to 195 families: A "European community Alport syndrome concerted action" study. J Am Soc Nephrol. 2003;14(10):2603-2610. doi:10.1097/01.asn.0000090034.71205.74

12. Jais J. X-linked Alport syndrome natural history in 195 families and genotype-phenotype correlations in males. J Am Soc Nephrol. 2000;11(4):649-657.

13. Fallerini C, Dosa L, Tita R et al. Unbiased next-generation sequencing analysis confirms the existence of autosomal dominant Alport syndrome in a relevant fraction of cases. Clin Genet. 2013;86(3):252-257. doi:10.1111/cge.12258

14. Morinière V, Dahan K, Hilbert P et al. Improving mutation screening in familial hematuric nephropathies through next-generation sequencing. J Am Soc Nephrol. 2014;25(12):2740-2751. doi:10.1681/asn.2013080912

15. Savige J, Sheth S, Leys A, Nicholson A, Mack H, Colville D. Ocular features in Alport syndrome: Pathogenesis and clinical significance. Clin J Am Soc Nephrol. 2015;10(4):703-709. doi:10.2215/cjn.10581014

16. Lemmink H, Nillesen W, Mochizuki T et al. Benign familial hematuria due to mutation of the type IV collagen alpha4 gene. J Clin Invest. 1996;98(5):1114-1118. doi:10.1172/jci118893

17. Badenas C. Mutations in theCOL4A4 and COL4A3 genes cause familial benign hematuria. Am Soc Nephrol. 2002;13(5):1248-1254.

18. Machuca E, Benoit G, Nevo F et al. Genotype–phenotype correlations in Non-Finnish Congenital Nephrotic Syndrome. J Am Soc Nephrol. 2010;21(7):1209-1217. doi:10.1681/asn.2009121309

19. Beltcheva O, Martin P, Lenkkeri U, Tryggvason K. Mutation spectrum in the nephrin gene (NPHS1) in congenital nephrotic syndrome. Hum Mutat. 2001;17(5):368-373. doi:10.1002/humu.1111

20. Koziell A. Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration. Hum Mol Genet. 2002;11(4):379-388. doi:10.1093/hmg/11.4.379

21. Koziell A. Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration. Hum Mol Genet. 2002;11(4):379-388. doi:10.1093/hmg/11.4.379

22. Bouchireb K, Boyer O, Gribouval O et al. NPHS2 mutations in steroid-resistant nephrotic syndrome: A mutation update and the associated phenotypic spectrum. Hum Mutat. 2013;35(2):178-186. doi:10.1002/humu.22485

23. Obeidova H. Genetic basis of nephrotic syndrome--review. Prague Med Rep. 2006;107(1):5-16.

24. Dai Y, Yang H, Gao P, Liu W. NPHS2 variation in Chinese southern infants with late steroid-resistant nephrotic syndrome. Ren Fail. 2014;36(9):1395-1398. doi:10.3109/0886022x.2014.947515

Assay

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Based on review of current medical guidelines and peer-reviewed publications, our sequence analysis covers clinically important regions of each gene, including coding exons +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. Any variants that fall outside these regions are not analyzed unless otherwise noted. Any specific limitations in the analysis of these genes are also listed in the table below.

We use our Boosted Exome assay to analyze the genes included in this panel. To ensure high sensitivity and specificity of calls, the exome is sequenced to an average depth of 150x, with all analyzed regions covered to a minimum depth of 20x unless otherwise noted. Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants and insertions and deletions <15bp in length. Sensitivity to detect insertions and deletions larger than 15bp but smaller than a full exon may be marginally reduced. This test permits reliable detection of deletions/duplications spanning four exons or more, although the resolution for detectable CNV lengths varies among genes due to sequence and coverage properties, and can also be influenced by DNA quality. Smaller events may also be detected and will be reported when sufficient resolution exists. Invitae confirms all clinically significant variants that do not meet our stringent NGS quality metrics. Confirmation technologies include any of the following: Sanger sequencing, Pacific Biosciences SMRT sequencing, MLPA, MLPA-seq, Array CGH. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. The report reflects the analysis of an extracted genomic DNA sample. In very rare cases (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion), the analyzed DNA may not represent the patient's constitutional genome.

 
Gene Transcript
reference
Sequencing 
analysis
Deleting/Duplication
analysis
Limitations
ACTN4 NM_004924.5
ANLN NM_018685.4
CD2AP NM_012120.2
COL4A3 NM_000091.4
COL4A4 NM_000092.4
COL4A5 NM_000495.4
CRB2 NM_173689.6
HNF1A NM_000545.5
INF2* NM_022489.3
LMX1B NM_002316.3
MYO1E* NM_004998.3
NPHS1 NM_004646.3
NPHS2 NM_014625.3
PAX2 NM_003988.3
PKD2 NM_000297.3
PKHD1 NM_138694.3
TRPC6* NM_004621.5

INF2: Deletion/duplication and sequencing analysis is not offered for exon 8.
MYO1E: Deletion/duplication and sequencing analysis is not offered for exon 1.
TRPC6: Deletion/duplication and sequencing analysis is not offered for exons 6-9.