Classifications of Monogenic Diseases

The inheritance pattern of nuclear monogenic diseases can be classified into three main categories1,2

  1. Autosomal Dominant
  2. Autosomal Recessive
  3. X-Linked
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Autosomal Dominant

A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease3

Dominant mutations often lead to a gain of function, but may also be associated with a loss of function, or have a dominant-negative effect4*

Examples3,5,6

Huntington disease: Gain-of-function mutation in the HTT gene

Marfan syndrome: Evidence for haploinsufficiency† or dominant-negative effect of the FBN1 gene

FBN1, fibrillin-1; HTT, huntingtin.
*Dominant-negative mutations are defined as those that lead to a structural change in the protein encoded by the mutant allele that then interferes with the function of the wild-type protein 
encoded by the other allele; †Haploinsufficient genes are those that require two copies of a gene for normal function and removing a single copy leads to a mutant phenotype2.

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Figure from Centrum Voor Medische Genetica. Inheritance. Available at: http://www.brusselsgenetics.be/monogenic-inheritance. © CMG, UZBrussels, Belgium 7

Autosomal Recessive

Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype3,4

Recessive mutations inactivate the affected gene and lead to a loss of function4

Examples3,8,9

Cystic fibrosis: Loss-of-function mutations in the CFTR gene

Spinal muscular atrophy: Bi-allelic deletion or mutation in the SMN1 gene, which leads to insufficient SMN protein

CFTR, cystic fibrosis transmembrane conductance regulator; SMN, survival motor neuron.
A carrier is defined as an individual who carries one copy of the mutated gene for an autosomal recessive disorder but is often not affected with the condition6.

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Figure from Centrum Voor Medische Genetica. Inheritance. Available at: http://www.brusselsgenetics.be/monogenic-inheritance. © CMG, UZBrussels, Belgium7

X-Linked Dominant

In females, a mutation in one of the two copies of the gene on either of the two X chromosomes is sufficient to cause an X-linked dominant disorder; in males, a mutation in the only copy of the gene on the single X chromosome causes the disorder3

Males are usually more severely affected than female heterozygotes because they carry only one X chromosome3,11

Examples12

Rett syndrome: Loss-of-function mutations in the MECP2 gene

MECP2, methyl CpG binding protein 2.

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Figure from Centrum Voor Medische Genetica. Inheritance. Available at: http://www.brusselsgenetics.be/monogenic-inheritance. © CMG, UZBrussels, Belgium7

X-Linked Recessive

Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder3

In males who have only one X chromosome, a mutation in the only copy of the gene is sufficient to cause the disorder; in females who have two X chromosomes, a mutation needs to occur in both copies of the gene to cause the disorder3

Because it is unlikely that females will have two altered copies of the gene, males are more frequently affected than females3

Examples3,13,14

Hemophilia: Loss-of-function mutations in the F8 or F9 gene*

Fabry disease: Loss-of-function mutations in the GLA gene

*F8 and F9 genes encode for coagulation factor VIII and factor IX, respectively; GLA, alpha-galactosidase.

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Figure from Centrum Voor Medische Genetica. Inheritance. Available at: http://www.brusselsgenetics.be/monogenic-inheritance. © CMG, UZBrussels, Belgium

References

  1. World Health Organization. Genes and human disease. Available at: http://www.who.int/genomics/public/geneticdiseases/en/index2.html. Accessed January 29, 2019.
  2. Warshawky I. Cell and Tissue Based Molecular Pathology. 2009. Pages 3-9. Available at: https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/monogenic-inheritance. Accessed April 1, 2019.
  3. NIH. What are the different ways in which a genetic condition can be inherited? Available at: https://ghr.nlm.nih.gov/primer/inheritance/inheritancepatterns. Accessed February 19, 2019.
  4. Lodish H, et al. Mutations: Types and causes. Molecular Cell Biology. 4th edition. 2000. Available at: https://www.ncbi.nlm.nih.gov/books/NBK21578/.
  5. Imarisio S, et al. Biochem J 2008;412(2):191–209.
  6. Kumar A, Agarwal S. Meta Gene 2014;2:96–105.
  7. Centrum Voor Medische Genetica. Inheritance. Available at: http://www.brusselsgenetics.be/monogenic-inheritance. Accessed May 17, 2019.
  8. NIH. Cystic Fibrosis. Available at: https://ghr.nlm.nih.gov/condition/cystic-fibrosis#genes. Accessed February 20, 2019.
  9. UpToDate. Spinal muscular atrophy. Available at: https://www.uptodate.com/contents/spinal-muscular-atrophy/print. Accessed May 02, 2019.
  10. Medline Plus. Autosomal Recessive. Available at: https://medlineplus.gov/ency/article/002052.htm. Accessed February 28, 2019.
  11. King TC. Genetic and Perinatal Disease. Elsevier’s Integrated Pathology. 2007. Pages 89–110. Available at: https://www.sciencedirect.com/topics/neuroscience/x-linked-dominant-disorders. Accessed April 1, 2019.
  12. NIH. Rett syndrome. Available at: https://ghr.nlm.nih.gov/condition/rett-syndrome#inheritance. Accessed April 1, 2019.
  13. NIH. Hemophilia. Available at: https://ghr.nlm.nih.gov/condition/hemophilia#inheritance. Accessed February 20, 2019.
  14. NIH. Fabry Disease. Available at: https://ghr.nlm.nih.gov/condition/fabry-disease#inheritance. Accessed February 20, 2019.