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
PRI03-Slide05-2alt.svg

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

inherit1.svg

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

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

inherit2.svg

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

inherit3b.svg
inherit3.svg

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

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

inherit4.svg
inherit4b.svg

7

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;