Editing Penetrance (section)

== Factors affecting penetrance ==
Many factors such as age, sex, environment, epigenetic modifiers, and modifier genes are linked to penetrance. These factors can help explain why certain individuals with a specific genotype exhibit symptoms or signs of disease, whilst others do not. <ref name=":0" /><ref name=":1" />

=== Age-dependent penetrance ===
If clinical signs associated with a specific genotype appear more frequently with increasing age, the penetrance is said to be age dependent. Some diseases are non-penetrant up until a certain age and then the penetrance starts to increase drastically, whilst others exhibit low penetrance at an early age and continue to increase with time. For this reason, many diseases have a different estimated penetrance dependent on the age.<ref name=":0" /> 

A specific hexanucleotide repeat expansion within the [[C9orf72]] gene said to be a major cause for developing [[ALS|amyotrophic lateral sclerosis]] (ALS) and [[frontotemporal dementia]] (FTD) is an example of a genotype with age dependent penetrance. The genotype is said to be non-penetrant until the age of 35, 50% penetrant by the age of 60, and almost completely penetrant by age 80. <ref name=":0" /><ref>{{Cite journal |last1=Murphy |first1=Natalie A. |last2=Arthur |first2=Karissa C. |last3=Tienari |first3=Pentti J. |last4=Houlden |first4=Henry |last5=Chiò |first5=Adriano |last6=Traynor |first6=Bryan J. |date=18 May 2017 |title=Age-related penetrance of the C9orf72 repeat expansion |journal=Scientific Reports |language=en |volume=7 |issue=1 |pages=2116 |doi=10.1038/s41598-017-02364-1 |issn=2045-2322 |pmc=5437033 |pmid=28522837 |bibcode=2017NatSR...7.2116M }}</ref>

=== Gender-related penetrance ===
[[File:BRCA1 and BRCA2 mutations and absolute cancer risk.jpg|thumb|Illustration of BRCA1 and BRCA2 mutations and cancer risk.<ref>{{Citation |last1=Petrucelli |first1=Nancie |title=BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer |date=1993 |work=GeneReviews® |editor-last=Adam |editor-first=Margaret P. |url=http://www.ncbi.nlm.nih.gov/books/NBK1247/ |access-date=15 February 2024 |place=Seattle (WA) |publisher=University of Washington, Seattle |pmid=20301425 |last2=Daly |first2=Mary B. |last3=Pal |first3=Tuya |editor2-last=Feldman |editor2-first=Jerry |editor3-last=Mirzaa |editor3-first=Ghayda M. |editor4-last=Pagon |editor4-first=Roberta A. |archive-date=8 March 2021 |archive-url=https://web.archive.org/web/20210308001246/https://www.ncbi.nlm.nih.gov/books/NBK1247/ |url-status=live }}</ref>]]
For some mutations, the phenotype is more frequently present in one [[sex]] and in rare cases mutations appear completely non-penetrant in a particular gender. This is called gender-related penetrance or sex-dependent penetrance and may be the result of allelic variation, disorders in which the expression of the disease is limited to organs only found in one sex such as testis or ovaries, or sex steroid-responsive genes.<ref name=":0" /><ref name=":1" /><ref name=":4">{{Citation |last1=Koellner |first1=Christine M. |title=Chapter 5 - Basic Concepts in Human Molecular Genetics |date=1 January 2018 |work=Molecular Pathology (Second Edition) |pages=99–120 |editor-last=Coleman |editor-first=William B. |url=https://www.sciencedirect.com/science/article/pii/B9780128027615000055 |access-date=13 February 2024 |publisher=Academic Press |doi=10.1016/b978-0-12-802761-5.00005-5 |isbn=978-0-12-802761-5 |last2=Mensink |first2=Kara A. |last3=Highsmith |first3=W. Edward |editor2-last=Tsongalis |editor2-first=Gregory J. |url-access=subscription }}</ref> Breast cancer caused by the BRCA2 mutation is an example of a disease with gender-related penetrance. The penetrance is determined to be much higher in women than men. By age 70, around 86% of females in contrast to 6% of males with the same mutation is estimated to develop breast cancer.<ref name=":4" /> 

In cases where clinical symptoms or the phenotype related to a genetic mutation are present only in one sex, the disorder is said to be sex-limited. [[Familial male-limited precocious puberty]] (FMPP) caused by a mutation in the LHCGR gene, is an example of a genotype only penetrant in males. Meaning that males with this particular genotype exhibit symptoms of the disease whilst the same genotype is nonpenetrant in females.<ref name=":1" /><ref name=":4" /><ref>{{Cite journal |last1=Gurnurkar |first1=Shilpa |last2=DiLillo |first2=Emily |last3=Carakushansky |first3=Mauri |date=1 June 2021 |title=A Case of Familial Male-limited Precocious Puberty with a Novel Mutation |url=http://cms.galenos.com.tr/Uploads/Article_39964/JCRPE-13-239-En.pdf |journal=Journal of Clinical Research in Pediatric Endocrinology |volume=13 |issue=2 |pages=239–244 |doi=10.4274/jcrpe.galenos.2020.2020.0067 |issn=1308-5727 |pmc=8186329 |pmid=32757547 |access-date=15 February 2024 |archive-date=27 February 2024 |archive-url=https://web.archive.org/web/20240227080346/https://cms.galenos.com.tr/Uploads/Article_39964/JCRPE-13-239-En.pdf |url-status=live }}</ref>

=== Genetic modifiers ===
Genetic modifiers are genetic variants or mutations able to modify a primary disease-causing variant's phenotypic outcome without being disease causing themselves.<ref>{{Cite journal |last1=Rahit |first1=K. M. Tahsin Hassan |last2=Tarailo-Graovac |first2=Maja |date=25 February 2020 |title=Genetic Modifiers and Rare Mendelian Disease |journal=Genes |language=en |volume=11 |issue=3 |pages=239 |doi=10.3390/genes11030239 |doi-access=free |issn=2073-4425 |pmc=7140819 |pmid=32106447 }}</ref> For instance, in single gene disorders there is one gene primarily responsible for development of the disease, but modifier genes inherited separately can affect the phenotype. Meaning that the presence of a mutation located on a [[Chromosome|loci]] different from the one with the disease-causing mutation, may either hinder manifestation of the phenotype or alter the mutations effects, and thereby influencing the penetrance.<ref name=":0" /><ref name=":1" /> 

=== Environmental modifiers ===
Exposure to environmental and lifestyle factors such as [[Chemical substance|chemicals]], [[Dieting|diet]], [[Alcoholic beverage|alcohol intake]], [[Drug|drugs]] and [[Stress (biology)|stress]] are some of the factors that might influence disease penetrance.<ref name=":0" /><ref>{{Cite journal |last1=Cavalli |first1=Giacomo |last2=Heard |first2=Edith |date=24 July 2019 |title=Advances in epigenetics link genetics to the environment and disease |url=https://www.nature.com/articles/s41586-019-1411-0 |journal=Nature |language=en |volume=571 |issue=7766 |pages=489–499 |doi=10.1038/s41586-019-1411-0 |pmid=31341302 |bibcode=2019Natur.571..489C |issn=1476-4687 |access-date=15 February 2024 |archive-date=9 February 2024 |archive-url=https://web.archive.org/web/20240209193940/https://www.nature.com/articles/s41586-019-1411-0 |url-status=live }}</ref> For example, several studies of BRCA1 and BRCA2 mutations, associated with an elevated risk of [[Breast cancer|breast]] and [[ovarian cancer]] in women, have examined associations with environmental and behavioral modifiers such as [[Pregnancy|pregnancies]], history of [[Breastfeeding|breast feeding]], [[smoking]], diet, and so forth.<ref>{{Cite journal |last1=Tryggvadottir |first1=Laufey |last2=Olafsdottir |first2=Elinborg J. |last3=Gudlaugsdottir |first3=Sigfridur |last4=Thorlacius |first4=Steinunn |last5=Jonasson |first5=Jon G. |last6=Tulinius |first6=Hrafn |last7=Eyfjord |first7=Jorunn E. |date=1 October 2003 |title=BRCA2mutation carriers, reproductive factors and breast cancer risk |journal=Breast Cancer Research |volume=5 |issue=5 |pages=R121-8 |doi=10.1186/bcr619 |doi-access=free |issn=1465-542X |pmc=314423 |pmid=12927042 }}</ref>

=== Epigenetic regulation ===
[[File:Epigenetic mechanisms.png|thumb|Illustration of epigenetic related methylation of histone tail. Giving cause to alterations. ]]
Sometimes, genetic alterations which can cause genetic disease and phenotypic traits, are not from changes related directly to the [[DNA]] sequence, but from [[Epigenetics|epigenetic]] alterations such as DNA [[methylation]] or [[Histone|histone modifications]]. Epigenetic differences may therefore be one of the factors contributing to reduced penetrance.<ref name=":0" /><ref name=":3" /><ref>{{Cite journal |last1=Safi-Stibler |first1=Sofiane |last2=Gabory |first2=Anne |date=1 January 2020 |title=Epigenetics and the Developmental Origins of Health and Disease: Parental environment signalling to the epigenome, critical time windows and sculpting the adult phenotype |url=https://www.sciencedirect.com/science/article/pii/S108495211830154X |journal=Seminars in Cell & Developmental Biology |series=SI: Chromatin dynamics in regeneration |volume=97 |pages=172–180 |doi=10.1016/j.semcdb.2019.09.008 |pmid=31587964 |s2cid=203849316 |issn=1084-9521 |url-access=subscription }}</ref> A study done on a pair of genetically identical [[Twin|monozygotic twins]], where one twin got diagnosed with [[leukemia]] and later on [[Thyroid neoplasm|thyroid carcinoma]] whilst the other had no registered illnesses, showed that the affected twin had increased methylation levels of the BRCA 1 gene. The research concluded that the family had no known [[DNA repair|DNA-repair syndrome]] or any other hereditary diseases in the last four generations, and no genetic differences between the studied pair of monozygotic twins were detected in the BRCA1 regulatory region. This indicates that epigenetic changes caused by environmental or behavioral factors had a key role in the cause of promotor hypermethylation of the BRCA1 gene in the affected twin, which caused the cancer.<ref>{{Cite journal |last1=Galetzka |first1=Danuta |last2=Hansmann |first2=Tamara |last3=El Hajj |first3=Nady |last4=Weis |first4=Eva |last5=Irmscher |first5=Benjamin |last6=Ludwig |first6=Marco |last7=Schneider-Rätzke |first7=Brigitte |last8=Kohlschmidt |first8=Nicolai |last9=Beyer |first9=Vera |last10=Bartsch |first10=Oliver |last11=Zechner |first11=Ulrich |last12=Spix |first12=Claudia |last13=Haaf |first13=Thomas |date=1 January 2012 |title=Monozygotic twins discordant for constitutive BRCA1 promoter methylation, childhood cancer and secondary cancer |journal=Epigenetics |language=en |volume=7 |issue=1 |pages=47–54 |doi=10.4161/epi.7.1.18814 |issn=1559-2294 |pmc=3329502 |pmid=22207351 }}</ref>