Elsevier

The Lancet

Volume 375, Issue 9722, 10–16 April 2010, Pages 1287-1295
The Lancet

Series
Genetic kidney diseases

https://doi.org/10.1016/S0140-6736(10)60236-XGet rights and content

Summary

Knowledge of the primary cause of a disease is essential for elucidation of its mechanisms, and for adequate classification, prognosis, and treatment. Recently, the causes of many kidney diseases have been shown to be single-gene defects—eg, steroid-resistant nephrotic syndrome, which is caused by podocin mutations in about 25% of children and nearly 15% of adults with the disease. Knowledge of a disease-causing mutation in a single-gene disorder represents one of the most robust diagnostic examples of personalised medicine because the mutation conveys an almost 100% risk of developing the disease by a defined age. Whereas single-gene diseases are rare disorders, polygenic risk alleles arise in common adult-onset diseases. In this Review, I will discuss prominent renal single-gene kidney disorders, and polygenic risk alleles of common disorders. I delineate how emerging techniques of total exome capture and large-scale sequencing will assist molecular genetic diagnosis, prognosis, and specific treatment, and lead to an improved elucidation of disease mechanisms, thus enabling development of new targeted drugs.

Section snippets

Genetic disease causality

In single-gene disorders, also known as monogenic diseases, a mutation in one gene (of about 25 000 genes) is sufficient to cause the disease. Conversely, polygenic disorders are caused by mutations in several different genes. The mode of inheritance determines the degree of genetic causality (table 1). At one end of the range there is tight genotype-phenotype correlation in monogenic recessive diseases, so that the disease phenotype is almost exclusively determined by the single-gene causative

Mutation analysis

Because of the strong genotype-phenotype correlation of almost 100% that is noted in recessive single-gene renal disorders, mutation analysis shows the primary cause of the disease, allows prenatal diagnostic tests to be done, and has a high diagnostic and prognostic value. Identification of a mutation in a known recessive disease gene might be seen as the most robust diagnostic example of personalised medicine, because the recessive mutation conveys an almost 100% risk that the patient will

Common and polygenic renal disorders

In single-gene disorders, the penetrance is close to 100% (table 1), with the exception of age-dependent penetrance, and, in dominant diseases, with the exceptions of incomplete penetrance (skipping of a generation) and variable expression (different extent and severity of organ involvement). By contrast, in polygenic diseases, several mutated alleles in different genes have to act in concert to cause disease (table 1).

The clear-cut lines between single-gene and polygenic diseases have become

Future directions

The causative genes have been identified in only about 2600 of nearly 5400 known Mendelian disorders in man, whereas the disease-causing gene is still elusive in roughly 2800 disorders. Two novel techniques were developed that might greatly assist the rapid discovery of causative genes for single-gene disorders. One of these techniques is total human exome capture, in which hybridisation is used to capture the entire exome of roughly 180 000 protein-encoding human exons.97 Exome capture is

Search strategy and selection criteria

In a continuous review of the literature during the past 10 years, I searched PubMed for review articles published in English with the terms “kidney” and “molecular genetics”. Additionally, I searched OMIM for “renal tubular AND number sign”. Recent review articles about the topic were considered.

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