The first paper in The Lancet series on Renal Medicine is written by professor Friedhelm Hildebrandt, Howard Hughes Medical Institute at the University of Michigan Health System, Ann Arbor, MI, USA. It discusses genetic kidney diseases, and highlights that lately many such diseases have been shown to be single gene defects. According to the author, knowledge of a disease-causing mutation in a single-gene disorder represents one of the strongest diagnostic examples of personalised medicine. This is because the mutation conveys an almost 100 percent risk of developing the disease by a defined age.

Mutation analysis reveals the primary cause of the disease because of the strong genotype-phenotype correlation of almost 100 percent that is noted in recessive single-gene renal disorders. It allows prenatal diagnostic tests to be done, and has a high diagnostic and prognostic value. Mutations convey an almost 100 percent risk of developing, for instance, autosomal recessive polycystic kidney disease.

Single-gene defect kidney diseases are grouped according to main diagnostic features.

• Glomerular diseases affect the kidney’s filtering apparatus and include steroid-resistant nephrotic syndrome. It usually manifests as focal segmental glomerulosclerosis, a replacement of the filtering units by scar tissue. In children, this is associated with a 30 percent risk of recurrence in a kidney transplant. Facial swelling, low blood proteins, abnormal blood fats, and high blood pressure can all be symptoms.

• Renal cystic ciliopathies are kidney diseases involving cysts, rounded hollow spaces in the kidney. For example, autosomal dominant polycystic kidney disease (ADPKD) is the most frequent lethal heritable dominant disease in the USA and Europe. It affects about 1 in 1,000 people. Chronic kidney disease develops by age 60 to 70 years. 90 percent of ADPKD cases can now be diagnosed by mutation testing. This is helpful for clinical decision making, especially in living-related donor transplantation.

• Renal tubular disorders affect reuptake of water, salt, and sugars from the glomerular filtrate which is the fluid in the kidney post-filtration. In such disorders, the primary genetic defect causes loss of function of a specific renal transport protein or signalling molecule. For instance, sodium reabsorption abnormalities cause Bartter’s syndrome leading to loss of salt from the kidneys.

Congenital abnormalities of kidney and urinary tract are responsible for nearly 50 percent of cases of end-stage kidney disease in children. These abnormalities arise in about three to six per 1,000 live births. They represent 20 to 30 percent of all anomalies identified in newborn babies. A wide range of conditions can be caused by such abnormalities.

The author explain: “An important feature of monogenic diseases is that the mutation represents the primary cause of the disease, and therefore provides opportunities for diagnosis, treatment, and insights into pathogenesis … New drugs can be developed – eg, by analysis of animals in which the gene of interest has been deactivated.”

Disease-causing genes of recessive single-gene disorders are more uncommon than polygenic disorders. They manifest early in life and cause disease in almost every individual with the genetic defect. They are rarely associated with environmental effects, and are usually detected by gene mapping. By contrast, multi-gene (polygenic) disorders are more common. They manifest later in life and exert weak causality on the disease phenotype. They are commonly associated with environment effects. Also, they are usually detected by genome-wide association studies. Many such studies have been published in the most recent years.

In closing professor Hildebrandt discusses the new technique of exome capture. It will significantly assist the rapid discovery of causative genes for single-gene disorders. Exome capture allows selecting only the segments of the human DNA coding for proteins. Thereby, it reduces gene discovery to the relevant part of the genome. Combined with large-scale gene sequencing, Professor Hildebrandt remarks that exome capture ‘will assist disease gene discovery in the future. This approach will further help molecular genetic diagnosis, enhance our understanding of disease mechanisms, and thus enable the development of new targeted drugs. It will also provide guides for mutation-specific prognosis and treatment’.

“Genetic kidney diseases”
Friedhelm Hildebrandt
Lancet 2010; 375: 1287- 95
The Lancet

Written by Stephanie Brunner (B.A.)