Editing Penetrance (section)

== Determining penetrance ==
It can be challenging to estimate the penetrance of a specific genotype due to all the influencing factors. In addition to the factors mentioned above there are several other considerations that must be taken into account when penetrance is determined: 

=== Ascertainment bias ===
Penetrance [[estimates]] can be affected by ascertainment [[bias]] if the sampling is not systematic.<ref name=":5">{{Cite journal |last1=Spargo |first1=Thomas P. |last2=Opie-Martin |first2=Sarah |last3=Bowles |first3=Harry |last4=Lewis |first4=Cathryn M. |last5=Iacoangeli |first5=Alfredo |last6=Al-Chalabi |first6=Ammar |date=15 December 2022 |title=Calculating variant penetrance from family history of disease and average family size in population-scale data |journal=Genome Medicine |volume=14 |issue=1 |pages=141 |doi=10.1186/s13073-022-01142-7 |doi-access=free |issn=1756-994X |pmc=9753373 |pmid=36522764 }}</ref> Traditionally a phenotype-driven approach focusing on individuals with a given condition and their family members has been used to determine penetrance. However, it may be difficult to transfer these estimates over to the general population because family members may share other genetic and/or environmental factors that could influence manifestation of said disease, leading to ascertainment bias and an overestimation of the penetrance. Large-scale population-based studies, which use both [[DNA sequencing|genetic sequencing]] and phenotype data from large groups of people, is a different method for determining penetrance. This method offers less upward bias compared to family-based studies and is more accurate the larger the sample population is. However, these studies may contain a healthy-participant-bias which can lead to lower penetrance estimates.<ref name=":5" /><ref>{{Cite journal |last1=Goodrich |first1=Julia K. |last2=Singer-Berk |first2=Moriel |last3=Son |first3=Rachel |last4=Sveden |first4=Abigail |last5=Wood |first5=Jordan |last6=England |first6=Eleina |last7=Cole |first7=Joanne B. |last8=Weisburd |first8=Ben |last9=Watts |first9=Nick |last10=Caulkins |first10=Lizz |last11=Dornbos |first11=Peter |last12=Koesterer |first12=Ryan |last13=Zappala |first13=Zachary |last14=Zhang |first14=Haichen |last15=Maloney |first15=Kristin A. |date=9 June 2021 |title=Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes |journal=Nature Communications |language=en |volume=12 |issue=1 |pages=3505 |doi=10.1038/s41467-021-23556-4 |issn=2041-1723 |pmc=8190084 |pmid=34108472 |bibcode=2021NatCo..12.3505G }}</ref><ref>{{Cite journal |last1=Turner |first1=Heather |last2=Jackson |first2=Leigh |date=14 January 2020 |title=Evidence for penetrance in patients without a family history of disease: a systematic review |journal=European Journal of Human Genetics |language=en |volume=28 |issue=5 |pages=539–550 |doi=10.1038/s41431-019-0556-5 |issn=1476-5438 |pmc=7170932 |pmid=31937893 }}</ref> 

=== Phenocopies ===
A genotype with complete penetrance will always display the clinical phenotypic traits related to its mutation (taking into consideration the expressivity), but the signs or symptoms displayed by a specific affected individual can often be similar to other unrelated phenotypical traits. Taking into consideration the effect that environmental or behavioral modifiers have, and how they can impact the cause of a mutation or epigenetic alteration, we now have the cause as to how different paths lead to the same phenotypic display. When similar phenotypes can be observed but by different causes, it is called ''[[Phenocopy|phenocopies]].'' Phenocopies is when environmental and/or behavioral modifiers causes an illness which mimics the phenotype of a genetic inherited disease. Because of phenocopies, determining the degree of penetrance for a genetic disease requires full knowledge of the individuals attending the studies, and the factors that may or may not have caused their illness.<ref name=":3" />       

For example, new research on ''[[Hypertrophic cardiomyopathy|Hypertrophic Cardiomyopathy]] (''HCM'')'' based on a technique called [[Cardiac magnetic resonance imaging|''Cardiac Magnetic Resonance'']] (CMR), describes how various genetic illnesses that showcase the same phenotypic traits as HCM, are actually phenocopies. Previously these phenocopies were all diagnosed and treated, thought to arrive from the same cause, but because of new diagnostic methods, they can now be separated and treated more efficiently.<ref>{{Cite journal |last1=Pieroni |first1=Maurizio |last2=Ciabatti |first2=Michele |last3=Saletti |first3=Elisa |last4=Tavanti |first4=Valentina |last5=Santangeli |first5=Pasquale |last6=Martinese |first6=Lucia |last7=Liistro |first7=Francesco |last8=Olivotto |first8=Iacopo |last9=Bolognese |first9=Leonardo |date=1 November 2022 |title=Beyond Sarcomeric Hypertrophic Cardiomyopathy: How to Diagnose and Manage Phenocopies |url=https://doi.org/10.1007/s11886-022-01778-2 |journal=Current Cardiology Reports |language=en |volume=24 |issue=11 |pages=1567–1585 |doi=10.1007/s11886-022-01778-2 |pmid=36053410 |s2cid=251982622 |issn=1534-3170 |url-access=subscription }}</ref>