Genetic Syndromes

Advances in technology with next-generation sequencing has reduced the cost of sequencing a human genome from $2.7 billion (e.g., the Human Genome Project) to approximately US$1,000 in 2018. Genetic causes of renal disease are varied and can manifest in a multitude of phenotypes (e.g., congenital anomalies of the kidneys and urinary tract [CAKUT], steroid-resistant nephrotic syndrome, cystic kidney diseases, tubulopathies, or as part of a syndrome). Genetic testing has also identified an increasing number of monogenic causes of kidney disease.

Clinical diagnoses in which to suspect renal involvement in addition to nonrenal manifestations:

Williams syndrome: Monitor for renovascular hypertension.
Neurofibromatosis: Monitor for renovascular hypertension.
Tuberous sclerosis: Angiomyolipomas can develop in the kidneys and over time cause decline in renal function.
Ciliopathies: Renal involvement may be part of a larger syndrome involving the liver, brain, skeleton/bone, skin, and eyes.
Turner syndrome: Renal manifestations include horseshoe kidney and hypertension.
Sickle cell disease: Monitor for proteinuria and hypertension (secondary to papillary necrosis from chronic sickling).
Beckwith-Wiedemann syndrome: Monitor for Wilms tumor with ultrasound every 3 months until age 8 years.
Alport syndrome: Renal involvement may accompany disease of the eyes and ears.
Nephrolithiasis: Some causes of kidney failure with kidney stones (e.g., cystinuria) are accompanied by crystal deposition in other organs.
Inborn errors of metabolism: Many diseases (e.g., Fabry disease) involving abnormal breakdown of metabolic products can cause damage to the kidney as well as other organs.

Research

Landmark clinical trials and other important studies

Research

Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract

van der Ven AT et al. J Am Soc Nephrol 2018.

Using whole-exome sequencing (WES) technology, individuals from 232 families with congenital anomalies of the kidney and urinary tract (CAKUT) were sequenced and evaluated for mutations in single genes known to cause CAKUT. Families with multiple affected individuals or with consanguinity were also analyzed for novel gene mutations. In total, 14% (30 families) had the causative gene identified for their clinical presentation of CAKUT.

Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis

Braun DA et al. Clin J Am Soc Nephrol 2016.

Using multiplex polymerase-chain-reaction (PCR) technology, 143 individuals younger than 18 years with nephrolithiasis or nephrocalcinosis were sequenced for mutations in 30 genes known to cause kidney stones or nephrocalcinosis. Results of this study demonstrated that 16.8% of patients (24 out of 143) had the causative mutation identified in a gene (14 of 30 genes analyzed with mutations found).

Rapid Detection of Monogenic Causes of Childhood-Onset Steroid-Resistant Nephrotic Syndrome

Lovric S et al. Clin J Am Soc Nephrol 2014.

In this pilot study, 48 people were sequenced using multiplex polymerase-chain-reaction (PCR) technology to query 21 genes known to cause SRNS. This study paved the way for future sequencing technology to be applied in patients with steroid-resistant nephrotic syndrome.