OVERVIEW

The genetic causes of hereditary renal/kidney diseases are diverse, with a wide variety of clinical and genetic heterogeneity. Congenital abnormalities of the kidneys and urinary tract (CAKUT) are the main cause of chronic renal failure in newborns and children. CAKUT comprises a wide spectrum of structural and functional malformations leading to a defective morphogenesis of the kidneys and/or the urinary tract. Polycystic kidney disease manifests in utero or at birth and is associated with a shortened life expectancy. The kidney phenotype includes bilateral renal enlargement and impairment of renal function and congenital liver fibrosis. Nephrotic syndrome (NS) is associated with a dysfunction of the glomerular filter of the kidneys, leading to excessive loss of plasma proteins. NS is characterized by high proteinuria and hypalbuminemia which can occur in childhood or in adult in the context of other underlying diseases such as immunological systemic diseases, metabolic diseases, chronic infections or intoxications. Alport syndrome is a progressive hereditary nephropathy. Clinical signs are proteinuria and hematuria, but patients develop terminal renal failure as the disease progresses. In addition, non-renal manifestations such as early onset of hearing loss and ocular changes are observed. Early identification of individuals at risk can help establish the right clinical management plan.

We offer comprehensive and syndrome-specific panels testing for renal diseases. The test can offer a molecular genetic diagnosis of a renal disorder that is observed or predicted in you or a family member.

IMPORTANCE OF GETTING TESTED

If you or a family member has a risk of a renal disease, identifying the cause can help you take actions to improve the outcome of the disorder. Additionally, family members can be informed and encouraged to also get tested. Our genetic counsellors can provide medical advice.

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You have a family history
of renal diseases

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You want to estimate the risk of
passing the disease to your child

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You have a clinical diagnosis
and want to confirm

POSSIBLE OUTCOMES OF THE TEST

A molecular genetic diagnostic report outlining the results of the sequencing analysis is provided. Changes in DNA sequences (variants) can be detrimental and lead to the development of a cardiac or aortic disorder, including asymptomatic disorders that develop later in life. We will report pathogenic and likely pathogenic variants as well as variants of unknown significance.
Pathogenic and likely pathogenic variants mean the genetic cause of the observed symptoms has been identified and may help determine the right treatment and management plan.
Variants of unknown significance means there was not enough evidence to classify the variant as either pathogenic or neutral. Annual variant reclassification and testing family members is recommended.
It is important to note that a negative result does not guarantee the absence of a disorder or that the disorder does not have a genetic cause. Genetic testing is an evolving field and may not detect all variants or there may not currently be enough evidence to classify all variants that lead to an inherited disease.

MEDICAL GENETIC COUNSELLING

We provide expert medical genetic counselling as part of a genetic testing journey. Genetic counselling is a process of communication that supports patients and their relatives before and after genetic testing. It is educational, impartial and nondirective. Prior to any genetic test, genetic counsellors will obtain a detailed family history, explain the method of testing that will be used, its risks and benefits, the limitations of the diagnosis and the implications of making a genetic diagnosis (Elliott and Friedman, 2018, Nat Rev Genet 19:735).

Upon receiving the genetic test results, genetic counselling can help the specialist physician and the patient to interpret them. They can be advised of the consequences of the results including the probability of developing the genetic disorder or passing it on to children, as well as ways to prevent, avoid or reduce these risks (Yang and Kim, 2018, Ann Lab Med 38:291). Our goal of counselling is to provide the patient with greater knowledge and thus, a better understanding of the results and the ability to make a more informed decision.

ACCEPTED MATERIAL

1 ml EDTA Blood

TURNAROUND TIME

15-25 working days

TECHNOLOGY

DNA is isolated and next generation sequencing is performed on all coding exons and conserved intronic regions. Single base pair changes, small deletions and duplications and copy number variants (CNV) are identified. Sequencing runs result in a Quality Score of >30 (accuracy >99.9%) in at least 75% of all bases with a coverage of >20-fold. CNV detection sensitivity is 76.99% and precision is 62.59% (with GC limitation between 0.4 and 0.6 per target sensitivity is 77.04% and precision is 84.10%). Variant classification is performed following ACMG guidelines (Richards et al. 2015, Genet Med 17:405; Kearney et al. 2011, Genet Med 13:680).

Test Methodology
Test Methodology
Sequencing

Next generation
sequencing (Illumina)

Enrichment

Twist Human Core
Exome plus Ref Seq
Spikeln

SNV and CNV data anlaysis

Illumina DRAGEN
Bio-IT Platform

Data Evaluation

VarSeq by
GoldenHelix

Reference Genome

hg38, NCBI GR38

Quality Criteria

>30 (precision >99,9%)
in min. 75% of bases

SNV detection sensitivity

99.92-99.93%; confirmation of reported SNV with Sanger
sequencing, data analysis with
SeqPilot

Classification of variants

Richards et al. 2015, Genet Med
17:405; Ellard et al. “ACGS Best
Practice Guidelines for Variant
Classification 2020″

in silico algorithms

MaxEntScan,
SpliceSiteFinder-like,
REVEL

Databases

HGMD Professional
release, ClinVar,
gnomAD

OUR TESTS

ALPORT SYNDROME (ATS)

Genes: COL4A3, COL4A4, COL4A5

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CONGENITAL ABNORMALITIES OF THE KIDNEYS AND URINARY TRACT (CAKUT) core panel

Genes: BMP4, DSTYK, EYA1, HNF1B, MUC1, PAX2, SALL1, SIX1, SIX2, SIX5, SOX17, UMOD, UPK3A, WNT4, WT1

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CONGENITAL ABNORMALITIES OF THE KIDNEYS AND URINARY TRACT (CAKUT) extended panel

Genes: ACE, ACTA2, ACTG2, AGT, AGTR1, ANOS1, BICC1, BMP7, CDC5L, CHD1L, CHRM3, DACH1, ETV4, ETV5, FGF20, FOXC1, FOXC2, FRAS1, FREM1, FREM2, GATA3, GDNF, GREM1, GRIP1, HPSE2, ITGA3, ITGA8, LRIG2, PAX8, REN, RET, ROBO2, TRAP1, UPK2, ZIC3

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Gitelman syndrome

Genes: SLC12A3

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HYPEROXALURIA

Genes: AGXT, GRHPR, HOGA1

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Kidney agenesis/dysgenesis (core panel)

Genes: BMP4, CDC5L, DSTYK, FGF20, HNF1B, ITGA8, PAX2, RET, SALL1, SIX2, TRAP1, UPK3A

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Kidney agenesis/dysgenesis (extended panel)

Genes: ANOS1, BMP4, CDC5L, DSTYK, FGF20, FRAS1, FREM1, FREM2, GREM1, HNF1B, ITGA8, PAX2, RET, SALL1, SIX2, TRAP1, UPK3A, WNT4

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Lower urinary tract obstruction (LUTO), congenital

Genes: ACTA2, ACTG2, BMP4, CHD1L, CHRM3, DSTYK, GATA3, HNF1B, PAX2, ROBO2

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Nephrogenic diabetes insipidus (NDI)

Genes: AQP2, AVPR2

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NEPHRONOPHTHISIS (NPHP) core panel

Genes: CEP290, GLIS2, INVS, IQCB1, NPHP1, NPHP3, NPHP4

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NEPHRONOPHTHISIS (NPHP) extended panel

Genes: AHI1, ANKS6, CC2D2A, CEP164, CEP290, CEP83, DCDC2, GLIS2, IFT172, INVS, IQCB1, MAPKBP1, NEK8, NPHP1, NPHP3, NPHP4, PAX2, RPGRIP1L, SDCCAG8, SLC41A1, TMEM216, TMEM237, TMEM67, TTC21B, WDR19, XPNPEP3, ZNF423

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NEPHROTIC SYNDROME (FOCAL SEGMENTAL GLOMERULOSCLEROSIS, NS) core panel

Genes: ACTN4, CD2AP, INF2, NPHS1, NPHS2, PLCE1, TRPC6, WT1

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NEPHROTIC SYNDROME (FOCAL SEGMENTAL GLOMERULOSCLEROSIS, NS) extended panel

Genes: ACTN4, ANLN, APOL1, ARHGAP24, ARHGDIA, CD2AP, CFH, COL4A3, COL4A4, COL4A5, COQ2, COQ6, COQ8B, CRB2, CUBN, DGKE, EMP2, GLA, INF2, ITGA3, ITGB4, KANK1, KANK2, KANK4, LAMB2, LMX1B, MYH9, MYO1E, NEIL1, NPHS1, NPHS2, PAX2, PDSS2, PLCE1, PTPRO, SCARB2, SMARCAL1, TRPC6, WT1

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POLYCYSTIC KIDNEY DISEASE, AUTOSOMAL DOMINANT (ADPKD)

Genes: DNAJB11, GANAB, HNF1B, PKD1, PKD2

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POLYCYSTIC KIDNEY DISEASE, AUTOSOMAL RECESSIVE (ARPKD)

Genes: DZIP1L, PKHD1

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Renal cysts and diabetes syndrome

Genes: HNF1B

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Renal tubular dysgenesis

Genes: ACE, AGT, AGTR1, REN

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Thin-basement-membrane nephropathy (Hematuria, benign familial)

Genes: COL4A3, COL4A4, COL4A5

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URINARY TRACT MALFORMATION core panel

Genes: ACTA2, ACTG2, BMP4, CHD1L, CHRM3, DSTYK, GATA3, HNF1B, ITGA8, PAX2, ROBO2, SOX17

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URINARY TRACT MALFORMATION extended panel

Genes: ACTA2, ACTG2, BMP4, BMP7, CHD1L, CHRM3, DACH1, DSTYK, EYA1, FRAS1, FREM1, FREM2, GATA3, HNF1B, HPSE2, ITGA8, LRIG2, PAX2, RET, ROBO2, SALL1, SOX17, TRAP1

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OUR NETWORK