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monogenic diseases

Friday 14 January 2005

All mendelian diseases are the result of expressed mutations in single genes of large effect. Most of these are recessive and therefore do not have serious phenotypic effects. About 80% to 85% of these mutations are familial. The remainder represent new mutations acquired de novo by an affected individual

The identification of genes associated with hereditary disorders has contributed to improving medical care and to a better understanding of gene functions, interactions, and pathways.

More than 1,800 known monogenic hereditary disorders have been described. However, there are well over 1500 Mendelian disorders whose molecular basis remains unknown.

Some autosomal mutations produce partial expression in the heterozygote and full expression in the homozygote.

Although gene expression is usually described as dominant or recessive, in some cases, both of the alleles of a gene pair may be fully expressed in the heterozygote, a condition called codominance. Histocompatibility and blood group antigens are good examples of codominant inheritance.

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.

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 (full penetrance), with a high predictive power of mutation analysis.

Diseases caused by recessive genes usually manifest prenatally, or in childhood or adolescence. Those caused by dominant genes typically manifest in adulthood (eg, autosomal dominant polycystic kidney disease).

The tightness of genotype-phenotype correlation is reduced when compared with diseases caused by recessive genes, because those caused by dominant genes—eg, glomerulocystic kidney disease, might show incomplete penetrance (ie, skipping of the disease phenotype in a generation) and variable expression (ie, different degrees of organ involvement).

A single mutant gene may lead to many end effects, termed pleiotropism. Sickle cell anemia may serve as an example of pleiotropism. Conversely, mutations at several genetic loci may produce the same trait (genetic heterogeneity).

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.

Unequivocal molecular genetic diagnostic tests can be done to avoid invasive procedures—eg, the diagnosis of nephronophthisis can be made without the need for a renal biopsy. Prenatal diagnosis is possible—eg, for diagnosis of the lethal perinatal Meckel-Gruber’s syndrome.

Specific prognostic outcomes can be delineated for specific mutations—eg, in mutations of PKD1 or PKD2, which cause early-onset or late-onset autosomal dominant polycystic kidney disease, respectively.

Subgroups of diseases can be classified for differential treatment—eg, mutations in NPHS2, which convey resistance to steroid treatment in nephrotic syndrome.

Mechanisms of disease can be studied in related monogenic animal models—eg, mouse models provided the first insights into pathogenesis of renal cystic ciliopathies.

New drugs can be developed—eg, by analysis of animals in which the gene of interest has been deactivated.

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.

Exome capture is followed up with large-scale sequencing (also known as next-generation sequencing). Because about 85% of all disease-causing mutations in Mendelian disorders are within coding exons, exome capture with consecutive large-scale sequencing will assist disease gene discovery in the future (exome sequencing).

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.

However, modern techniques of exome capture, and large-scale sequencing (exome sequencing, whole genome sequencing) will produce a high number of sequence variants, which renders identification of the true disease-causing mutation difficult.

Therefore, the main clinical features that indicate which candidate genes should be assessed preferentially for disease-causing mutations should guide the assessment of exome capture and large-scale screening.


- autosomal dominant diseases
- autosomal recessive diseases
- X-linked diseases


- enzyme deficiency (enzyme defects)

  • accumulation of the substrate (storage diseases)
  • metabolic block with decreased amount of end product
  • failure to inactivate a tissue-damaging substrate

- defects in receptor proteins
- defects in transport systems
- genetically determined adverse reactions to drugs
- alterations in structure, function, or quantity of nonenzyme proteins

  • defects in structural proteins
  • defects in cell growth regulating proteins


- Mutations involving single genes typically follow one of three patterns of inheritance: autosomal dominant, autosomal recessive, and X-linked. The general rules that govern the transmission of single-gene disorders are well known and are not repeated here.

- Mendelian disorders result from alterations involving single genes. The genetic defect may lead to the formation of an abnormal protein or a reduction in the output of the gene product. Gene mutations may affect protein synthesis by affecting transcription, mRNA processing, or translation.

- The phenotypic effects of a mutation may result directly, from abnormalities in the protein encoded by the mutant gene, or indirectly, owing to interactions of the mutant protein with other normal proteins. For example, all forms of Ehlers-Danlos syndrome (EDS) are associated with abnormalities of collagen. In some forms (e.g., vascular type), there is a mutation in one of the collagen genes, whereas in others (e.g., kyphoscoliosis type), the collagen genes are normal, but there is a mutation in the gene that encodes lysyl hydroxylase, an enzyme essential for the cross-linking of collagen. In these patients, collagen weakness is secondary to a deficiency of lysyl hydroxylase.

- Virtually any type of protein may be affected in single-gene disorders and by a variety of mechanisms. To some extent, the pattern of inheritance of the disease is related to the kind of protein affected by the mutation.

The mechanisms involved in single-gene disorders can be classified into four categories:
- (1) enzyme defects and their consequences;
- (2) defects in membrane receptors and transport systems;
- (3) alterations in the structure, function, or quantity of nonenzyme proteins;
- (4) mutations resulting in unusual reactions to drugs

See also

- genic diseases


- Brinkman RR, Dube MP, Rouleau GA, Orr AC, Samuels ME. Human monogenic disorders - a source of novel drug targets. Nat Rev Genet. 2006 Apr;7(4):249-60. PMID: 16534513

- O’Connor TP, Crystal RG. Genetic medicines: treatment strategies for hereditary disorders. Nat Rev Genet. 2006 Apr;7(4):261-76. PMID: 16543931

- Antonarakis SE, Beckmann JS. Mendelian disorders deserve more attention. Nat Rev Genet. 2006 Apr;7(4):277-82. PMID: 16534515