- Genetic etiology comprises a significant proportion of renal disease in childhood, and genome sequencing has helped identify numerous single-gene causes of early-onset of kidney disease*.
- These can be relatively common to rare disorders, from benign to those with a high morbidity and mortality.
Precision in diagnosis, including the identification of disease subtypes, directly influences treatment and patient outcomes. Understanding of pathology at a molecular level is critical for identification of many diseases and their subtypes.
Presenting ACTIA from MedGenome, delivering ACTIONABLE insights to enable happier outcomes. Actia provides an end-to-end integrated solution to clinical genomics in India and is highly focussed on the Indian population.
Renal disorders in children
Renal disorders in adults
- Several genetic disorders can be present in adult patients with renal insufficiency.
- Genetic renal disease other than ADPKD accounts for ESRD in the adult population and molecular genetics can be of aid in the diagnostic process.
*Fletcher, J., McDonald, S., Alexander, S.I. et al. Pediatr Nephrol (2013) 28: 251-256.
Genetic Renal Disorders
The prevalence of renal diseases is rising and reaching 5-15% of the adult population. Studies indicate that renal diseases are influenced not only by environmental but also by genetic factors .
An estimated 20% of cases of CKD are thought to be due to genetic forms of renal disease, as evidenced by familial clustering and differing prevalence rates across ethnic groups .
The prevalence of renal disease in children, including those with a GFR of <30 ml/min/1.73 2 superscript to ESRD, ranges from 21 to 55 per million age represtentative population. In countries with high rates of consanguinity and potentially greater risks of autosomal recessive disease, approximately one fifth to one third of paediatric patients with ESRD are reported as having hereditary renal disease .
 Gluba-Brzózka A, Franczyk B, Olszewski R, et al. Int J Mol Sci. 2017 Jun 10;18(6).
 Mallett A, Patel C, Salisbury A, et al. Orphanet Journal of Rare Diseases. 2014;9:98.
 Fletcher, J., McDonald, S., Alexander, S.I. et al. Pediatr Nephrol (2013) 28: 251. [*]Hildebrandt F: Genetic kidney diseases. Lancet. 2010, 375 (9722): 1287-1295.
Prevalence of Renal Diseases
Renal Cystic & Interstitial Diseases
Defects of the cilial system are strongly related to the development of cystic kidney disease at any stage of life. The cystic kidney diseases are also known as renal cystic ciliopathies. Some of these are:
- Bartter syndrome
- Gitelman syndrome
Renal Tubular Diseases
Renal tubular function governs reabsorption of water and solutes from the glomerular filtrate. In renal tubulopathies, the primary genetic defect causes loss of function of a specific renal transport protein or signalling molecule. The following are classified under genetic renal tubular disorders.
Renal Glomerular Disorders
Glomeruli are the tiny units within the kidney where blood is cleaned. Glomerulonephritis (inflammation of the membrane tissue in the kidney that serves as a filter) and glomerulosclerosis (hardening of the tiny blood vessels within the kidney) are the two major categories of glomerular diseases. Some genetic glomerular diseases are:
- Familial atypical HUS
- Alport syndrome
- Fibronectin glomerulopathy
The heritability of renal stone formation (nephrolithiasis) has long been recognized. And the advent of the genomic era has greatly increased the potential to define its underlying genetic defects. These defects which lead to stone formation have been valuable in defining renal pathophysiology in these diseases.
- Primary Hyperoxaluria
- Hereditary Xanthinuria
- Dent disease
Congenital abnormalities of the kidney and urinary tract (CAKUT)
CAKUT account for approximately 50% of children with end-stage kidney disease. They occur in about 3 to 6 per 1,000 live births and constitute 20–30% of all anomalies identified in the neonatal period. They may present as an isolated feature or as part of clinical syndromes. Single-gene mutations in many different genes may cause a wide phenotypic spectrum of CAKUT and these are listed below
- Renal agenesis (RA)
- Renal hypodysplasia (RHD)
- Multicystic renal dysplasia (MRD)
- Vesicoureteral reflux (VUR 2)
How genomics has helped patients with Genetic Renal Disorders
Highly penetrant mutations cause a wide range of renal phenotypes including:
- Disease of renal growth (eg. polycystic kidney disease)
- Diseases of abnormal glomerular function (eg. congenital nephrotic syndrome)
- Abnormalities of blood pressure and electrolyte homeostasis (eg. Bartter syndrome)
Correct diagnosis of GRD impacts
- Specific investigations
- Affect on the treatment
- Consequences on the whole family such as identifying the affected subjects and taking decisions regarding specific therapy
1. Atypical Haemolytic Uraemic Syndrome (aHUS)
Until recently a HUS was an untreatable disease. Understanding the genetics of a HUS has revealed that most individuals carry mutations in complement genes which results in over activation of the complement system. This resulted in the successful clinical trial of the complement inhibitor Eculizumab. Proven mutations in complement genes predicts response to Eculizumab, while mutations in the noncomplement gene DGKE, is a marker of non-response in a subgroup of patients.
2. The Role of UMOD in Hypertension and Chronic Kidney Disease
Mutations in UMOD, which encodes uromodulin, are associated with Medullary Cystic Kidney Disease Type 2, a rare dominantly inherited cause of CKD. Recent GWAS studies have identified susceptibility variants for chronic kidney disease and hypertension in UMOD. Risk variants in UMOD directly increase UMOD expression, leading to salt-sensitive hypertension, secondary to activation of the renal sodium- potassium-chloride cotransporter NKCC2. Uromodulin may be a novel therapeutic target to control blood pressure and preserve renal function.
Source: Mallett A, et al. Genomics in the renal clinic - translating nephrogenetics for clinical practice. Hum Gen. 2015 Jun 24;9:13.
Why Recommend ACTIA for Patients with Genetic Renal Disorders?
With an in-depth disease understanding and incorporating the latest research into the particular genetic disorder, ACTIA has developed a broad range of pre-designed gene mutation panels.
- Polycystic kidney disease gene panel (ARPKD: PKHD1/ADPKD: PKD1 & PKD2)
- Meckel Gruber syndrome gene panel
- VHL gene analysis
- Von Hippel-Lindau syndrome (VHL) deletion/duplication analysis
- Joubert syndrome gene panel
- Bardet-Biedl syndrome gene panel
- TSC1 & TSC2 gene analysis
- Bartter syndrome gene panel
- Nephrotic syndrome gene panel
- Hemolytic uremic syndrome - HUS (CFH, CFHR1 & CFHR3) deletion duplication analysis
- Primary hyperoxaluria gene panel
- Homocystinuria gene panel
- Clinical exome
1.Next Generation Sequencing (NGS)
Using genomic DNA extracted from blood, the coding regions of all the genes are captured and sequenced simultaneously by NGS technology on an Illumina platform. The sequence data that is generated is aligned and analyzed for sequence variants.
2.Multiplex ligation-dependent probe amplification (MLPA)
Deletion and duplication analysis of genomic DNA is carried out by MLPA. This method allows for the amplification of multiple targets with only a single primer pair.
Test sample requirements
- Relevant clinical information including all the clinical presentations and symptoms
- Test request form (TRF)
- 4 weeks for NGS
- 3 weeks for MLPA
- 3 weeks for Sanger sequencing
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Best available support for your patients and families via
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