Penetrance

Last updated
Illustration of the degree of Penentrance Penetrance1.0.pdf
Illustration of the degree of Penentrance

Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (genotype) that also expresses an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation that exhibit clinical symptoms among all individuals with such mutation. [1]  For example: If a mutation in the gene responsible for a particular autosomal dominant disorder has 75% penetrance, then 75% of those with the mutation will go on to develop the disease, showing its phenotype, whereas 25% will not.  

Contents

Illustration of different degrees of penetrance and variable expressivity PenetranceVE.pdf
Illustration of different degrees of penetrance and variable expressivity

Penetrance only refers to whether an individual with a specific genotype exhibits any phenotypic signs or symptoms, and is not to be confused with variable expressivity which is to what extent or degree the symptoms for said disease are shown (the expression of the phenotypic trait). Meaning that, even if the same disease-causing mutation affects separate individuals, the expressivity will vary. [1] [2] [3]

Degrees of Penetrance

Complete penetrance

If 100% of individuals carrying a particular genotype express the associated trait, the genotype is said to show complete penetrance. [1] Neurofibromatosis type 1 (NF1), is an autosomal dominant condition which shows complete penetrance, consequently everyone who inherits the disease-causing variant of this gene will develop some degree of symptoms for NF1. [4]

Reduced penetrance

The penetrance is said to be reduced if less than 100% of individuals carrying a particular genotype express associated traits, and is likely to be caused by a combination of genetic, environmental and lifestyle factors. [1] [3]   BRCA1 is an example of a genotype with reduced penetrance. By age 70, the mutation is estimated to have a breast cancer penetrance of around 65% in women. Meaning that about 65% of women carrying the gene will develop breast cancer by the time they turn 70. [5]

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. [1] [3]

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. [1]

A specific hexanucleotide repeat expansion within the C9orf72 gene said to be a major cause for developing 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. [1] [7]

Illustration of BRCA1 and BRCA2 mutations and cancer risk. BRCA1 and BRCA2 mutations and absolute cancer risk.jpg
Illustration of BRCA1 and BRCA2 mutations and cancer risk.

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. [1] [3] [9] 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. [9]

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. [3] [9] [10]

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. [11] 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 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. [1] [3]

Environmental modifiers

Exposure to environmental and lifestyle factors such as chemicals, diet, alcohol intake, drugs and stress are some of the factors that might influence disease penetrance. [1] [12] For example, several studies of BRCA1 and BRCA2 mutations, associated with an elevated risk of breast and ovarian cancer in women, have examined associations with environmental and behavioral modifiers such as pregnancies, history of breast feeding, smoking, diet, and so forth. [13]

Epigenetic regulation

Illustration of epigenetic related methylation of histone tail. Giving cause to alterations. Epigenetic mechanisms.png
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 epigenetic alterations such as DNA methylation or histone modifications. Epigenetic differences may therefore be one of the factors contributing to reduced penetrance. [1] [6] [14]  A study done on a pair of genetically identical monozygotic twins, where one twin got diagnosed with leukemia and later on 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 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. [15]    

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. [16] 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 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. These studies may contain a healthy-participant-bias which can lead to lower penetrance estimates. [16] [17] [18]

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 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. [6]      

For example, new research on Hypertrophic Cardiomyopathy (HCM) based on a technique called 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. [19]  

Subjects not yet covered

Related Research Articles

An allele, or allelomorph, is a variant of the sequence of nucleotides at a particular location, or locus, on a DNA molecule.

<span class="mw-page-title-main">Genetic disorder</span> Health problem caused by one or more abnormalities in the genome

A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development, or it can be inherited from two parents who are carriers of a faulty gene or from a parent with the disorder. When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA.

The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a specific gene depends on the number of copies of each chromosome found in that species, also referred to as ploidy. In diploid species like humans, two full sets of chromosomes are present, meaning each individual has two alleles for any given gene. If both alleles are the same, the genotype is referred to as homozygous. If the alleles are different, the genotype is referred to as heterozygous.

<span class="mw-page-title-main">Phenotype</span> Composite of the organisms observable characteristics or traits

In genetics, the phenotype is the set of observable characteristics or traits of an organism. The term covers the organism's morphology, its developmental processes, its biochemical and physiological properties, its behavior, and the products of behavior. An organism's phenotype results from two basic factors: the expression of an organism's genetic code and the influence of environmental factors. Both factors may interact, further affecting the phenotype. When two or more clearly different phenotypes exist in the same population of a species, the species is called polymorphic. A well-documented example of polymorphism is Labrador Retriever coloring; while the coat color depends on many genes, it is clearly seen in the environment as yellow, black, and brown. Richard Dawkins in 1978 and then again in his 1982 book The Extended Phenotype suggested that one can regard bird nests and other built structures such as caddisfly larva cases and beaver dams as "extended phenotypes".

<span class="mw-page-title-main">Genotype–phenotype distinction</span> Distinction made in genetics

The genotype–phenotype distinction is drawn in genetics. The "Genotype" is an organism's full hereditary information. The "Phenotype" is an organism's actual observed properties, such as morphology, development, or behavior. This distinction is fundamental in the study of inheritance of traits and their evolution.

<span class="mw-page-title-main">Dominance (genetics)</span> One gene variant masking the effect of another in the other copy of the gene

Dominance, in genetics, is defined as the interactions between alleles at the same locus on homologous chromosomes and the associated phenotype. In the case of complete dominance, one allele in a heterozygote individual completely overrides or masks the phenotypic contribution of the other allele. The overriding allele is referred to as dominant and the masked one recessive. Complete dominance, also referred to as Mendelian inheritance, follow Mendel’s laws of segregation. The first law states that each allele in a pair of genes is separated at random and have an equal probability of being transferred to the next generation, while the second law states that the distribution of allele variants is done independently of each other. However, this is not always the case as not all genes segregate independently and violations of this law are often referred to as “non-Mendelian inheritance”.

A quantitative trait locus (QTL) is a locus that correlates with variation of a quantitative trait in the phenotype of a population of organisms. QTLs are mapped by identifying which molecular markers correlate with an observed trait. This is often an early step in identifying the actual genes that cause the trait variation.

Genetic architecture is the underlying genetic basis of a phenotypic trait and its variational properties. Phenotypic variation for quantitative traits is, at the most basic level, the result of the segregation of alleles at quantitative trait loci (QTL). Environmental factors and other external influences can also play a role in phenotypic variation. Genetic architecture is a broad term that can be described for any given individual based on information regarding gene and allele number, the distribution of allelic and mutational effects, and patterns of pleiotropy, dominance, and epistasis.

<span class="mw-page-title-main">Pleiotropy</span> Influence of a single gene on multiple phenotypic traits

Pleiotropy occurs when one gene influences two or more seemingly unrelated phenotypic traits. Such a gene that exhibits multiple phenotypic expression is called a pleiotropic gene. Mutation in a pleiotropic gene may have an effect on several traits simultaneously, due to the gene coding for a product used by a myriad of cells or different targets that have the same signaling function.

In genetics, expressivity is the degree to which a phenotype is expressed by individuals having a particular genotype. Alternatively, it may refer to the expression of a particular gene by individuals having a certain phenotype. Expressivity is related to the intensity of a given phenotype; it differs from penetrance, which refers to the proportion of individuals with a particular genotype that share the same phenotype.

<span class="mw-page-title-main">Haploinsufficiency</span> Concept in genetics

Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type phenotype. Haploinsufficiency may arise from a de novo or inherited loss-of-function mutation in the variant allele, such that it yields little or no gene product. Although the other, standard allele still produces the standard amount of product, the total product is insufficient to produce the standard phenotype. This heterozygous genotype may result in a non- or sub-standard, deleterious, and (or) disease phenotype. Haploinsufficiency is the standard explanation for dominant deleterious alleles.

<span class="mw-page-title-main">Gene–environment interaction</span> Response to the same environmental variation differently by different genotypes

Gene–environment interaction is when two different genotypes respond to environmental variation in different ways. A norm of reaction is a graph that shows the relationship between genes and environmental factors when phenotypic differences are continuous. They can help illustrate GxE interactions. When the norm of reaction is not parallel, as shown in the figure below, there is a gene by environment interaction. This indicates that each genotype responds to environmental variation in a different way. Environmental variation can be physical, chemical, biological, behavior patterns or life events.

In genetics, concordance is the probability that a pair of individuals will both have a certain characteristic given that one of the pair has the characteristic. Concordance can be measured with concordance rates, reflecting the odds of one person having the trait if the other does. Important clinical examples include the chance of offspring having a certain disease if the mother has it, if the father has it, or if both parents have it. Concordance among siblings is similarly of interest: what are the odds of a subsequent offspring having the disease if an older child does? In research, concordance is often discussed in the context of both members of a pair of twins. Twins are concordant when both have or both lack a given trait. The ideal example of concordance is that of identical twins, because the genome is the same, an equivalence that helps in discovering causation via deconfounding, regarding genetic effects versus epigenetic and environmental effects.

<span class="mw-page-title-main">Canalisation (genetics)</span> Measure of the ability of a population to produce the same phenotype

Canalisation is a measure of the ability of a population to produce the same phenotype regardless of variability of its environment or genotype. It is a form of evolutionary robustness. The term was coined in 1942 by C. H. Waddington to capture the fact that "developmental reactions, as they occur in organisms submitted to natural selection...are adjusted so as to bring about one definite end-result regardless of minor variations in conditions during the course of the reaction". He used this word rather than robustness to consider that biological systems are not robust in quite the same way as, for example, engineered systems.

<span class="mw-page-title-main">Transgenerational epigenetic inheritance</span> Epigenetic transmission without DNA primary structure alteration

Transgenerational epigenetic inheritance is the transmission of epigenetic markers and modifications from one generation to multiple subsequent generations without altering the primary structure of DNA. Thus, the regulation of genes via epigenetic mechanisms can be heritable; the amount of transcripts and proteins produced can be altered by inherited epigenetic changes. In order for epigenetic marks to be heritable, however, they must occur in the gametes in animals, but since plants lack a definitive germline and can propagate, epigenetic marks in any tissue can be heritable.

Locus heterogeneity occurs when mutations at multiple genomic loci are capable of producing the same phenotype, and each individual mutation is sufficient to cause the specific phenotype independently. Locus heterogeneity should not be confused with allelic heterogeneity, in which a single phenotype can be produced by multiple mutations, all of which are at the same locus on a chromosome. Likewise, it should not be confused with phenotypic heterogeneity, in which different phenotypes arise among organisms with identical genotypes and environmental conditions. Locus heterogeneity and allelic heterogeneity are the two components of genetic heterogeneity.

Genocopy is a trait that is a phenotypic copy of a genetic trait but is caused by a different genotype. When a genetic mutation or genotype in one locus results in a phenotype similar to one that is known to be caused by another mutation or genotype in another locus, it is said to be a genocopy. However, genocopies may also be referred to as "genetic mimics", in which the same mutation or specific genotype can result in two unique phenotypes in two different patients. The term “Genocopy” was coined by Dr. H. Nachstheim in 1957, in which he discusses “false” phenocopies. In comparison to when a phenotype is the result of an environmental condition that had the same effect as a previously known genetic factor such as mutation. While offspring may inherit specific mutations or genotypes that result in genocopies, phenocopies are not heritable. Two types of elliptocytosis that are genocopies of each other, but are distinguished by the fact that one is linked to the Rh blood group locus and the other is not. The way to distinguish a recessive genocopy from a phenotype caused by a different allele would be by carrying out a test cross, breeding the two together, if they F1 hybrid segregates 1:2:1 then we can determine that it was a genocopy.

Oligogenic inheritance describes a trait that is influenced by a few genes. Oligogenic inheritance represents an intermediate between monogenic inheritance in which a trait is determined by a single causative gene, and polygenic inheritance, in which a trait is influenced by many genes and often environmental factors.

<span class="mw-page-title-main">Genotype-first approach</span>

The genotype-first approach is a type of strategy used in genetic epidemiological studies to associate specific genotypes to apparent clinical phenotypes of a complex disease or trait. As opposed to “phenotype-first”, the traditional strategy that has been guiding genome-wide association studies (GWAS) so far, this approach characterizes individuals first by a statistically common genotype based on molecular tests prior to clinical phenotypic classification. This method of grouping leads to patient evaluations based on a shared genetic etiology for the observed phenotypes, regardless of their suspected diagnosis. Thus, this approach can prevent initial phenotypic bias and allow for identification of genes that pose a significant contribution to the disease etiology.

A human disease modifier gene is a modifier gene that alters expression of a human gene at another locus that in turn causes a genetic disease. Whereas medical genetics has tended to distinguish between monogenic traits, governed by simple, Mendelian inheritance, and quantitative traits, with cumulative, multifactorial causes, increasing evidence suggests that human diseases exist on a continuous spectrum between the two.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 Cooper, David N.; Krawczak, Michael; Polychronakos, Constantin; Tyler-Smith, Chris; Kehrer-Sawatzki, Hildegard (2013-10-01). "Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease". Human Genetics. 132 (10): 1077–1130. doi:10.1007/s00439-013-1331-2. ISSN   1432-1203. PMC   3778950 . PMID   23820649.
  2. ↑ Raj, Arjun; Rifkin, Scott A.; Andersen, Erik; van Oudenaarden, Alexander (2010-02-18). "Variability in gene expression underlies incomplete penetrance". Nature. 463 (7283): 913–918. Bibcode:2010Natur.463..913R. doi:10.1038/nature08781. ISSN   1476-4687. PMC   2836165 . PMID   20164922.
  3. 1 2 3 4 5 6 Zlotogora, Joël (2003-09-01). "Penetrance and expressivity in the molecular age". Genetics in Medicine. 5 (5): 347–352. doi: 10.1097/01.GIM.0000086478.87623.69 . ISSN   1098-3600. PMID   14501829.
  4. ↑ Pacot, Laurence; Pelletier, Valerie; Chansavang, Albain; Briand-Suleau, Audrey; Burin des Roziers, Cyril; Coustier, Audrey; Maillard, Theodora; Vaucouleur, Nicolas; Orhant, Lucie; Barbance, Cécile; Lermine, Alban; Hamzaoui, Nadim; Hadjadj, Djihad; Laurendeau, Ingrid; El Khattabi, Laïla (2023-01-01). "Contribution of whole genome sequencing in the molecular diagnosis of mosaic partial deletion of the NF1 gene in neurofibromatosis type 1". Human Genetics. 142 (1): 1–9. doi:10.1007/s00439-022-02476-3. ISSN   1432-1203. PMID   35941319. S2CID   251445081.
  5. ↑ Chen, Jinbo; Bae, Eunchan; Zhang, Lingjiao; Hughes, Kevin; Parmigiani, Giovanni; Braun, Danielle; Rebbeck, Timothy R (2020-04-23). "Penetrance of Breast and Ovarian Cancer in Women Who Carry a BRCA1/2 Mutation and Do Not Use Risk-Reducing Salpingo-Oophorectomy: An Updated Meta-Analysis". JNCI Cancer Spectrum. 4 (4): pkaa029. doi:10.1093/jncics/pkaa029. ISSN   2515-5091. PMC   7353955 . PMID   32676552.
  6. 1 2 3 Korf, Bruce R.; Sathienkijkanchai, Achara (2009-01-01), Robertson, David; Williams, Gordon H. (eds.), "Chapter 19 - Introduction to Human Genetics", Clinical and Translational Science, San Diego: Academic Press, pp. 265–287, doi:10.1016/b978-0-12-373639-0.00019-4, ISBN   978-0-12-373639-0 , retrieved 2024-02-13
  7. ↑ Murphy, Natalie A.; Arthur, Karissa C.; Tienari, Pentti J.; Houlden, Henry; Chiò, Adriano; Traynor, Bryan J. (2017-05-18). "Age-related penetrance of the C9orf72 repeat expansion". Scientific Reports. 7 (1): 2116. Bibcode:2017NatSR...7.2116M. doi:10.1038/s41598-017-02364-1. ISSN   2045-2322. PMC   5437033 . PMID   28522837.
  8. ↑ Petrucelli, Nancie; Daly, Mary B.; Pal, Tuya (1993), Adam, Margaret P.; Feldman, Jerry; Mirzaa, Ghayda M.; Pagon, Roberta A. (eds.), "BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID   20301425 , retrieved 2024-02-15
  9. 1 2 3 Koellner, Christine M.; Mensink, Kara A.; Highsmith, W. Edward (2018-01-01), Coleman, William B.; Tsongalis, Gregory J. (eds.), "Chapter 5 - Basic Concepts in Human Molecular Genetics", Molecular Pathology (Second Edition), Academic Press, pp. 99–120, doi:10.1016/b978-0-12-802761-5.00005-5, ISBN   978-0-12-802761-5 , retrieved 2024-02-13
  10. ↑ Gurnurkar, Shilpa; DiLillo, Emily; Carakushansky, Mauri (2021-06-01). "A Case of Familial Male-limited Precocious Puberty with a Novel Mutation" (PDF). Journal of Clinical Research in Pediatric Endocrinology. 13 (2): 239–244. doi:10.4274/jcrpe.galenos.2020.2020.0067. ISSN   1308-5727. PMC   8186329 . PMID   32757547.
  11. ↑ Rahit, K. M. Tahsin Hassan; Tarailo-Graovac, Maja (2020-02-25). "Genetic Modifiers and Rare Mendelian Disease". Genes. 11 (3): 239. doi: 10.3390/genes11030239 . ISSN   2073-4425. PMC   7140819 . PMID   32106447.
  12. ↑ Cavalli, Giacomo; Heard, Edith (2019-07-24). "Advances in epigenetics link genetics to the environment and disease". Nature. 571 (7766): 489–499. Bibcode:2019Natur.571..489C. doi:10.1038/s41586-019-1411-0. ISSN   1476-4687. PMID   31341302.
  13. ↑ Tryggvadottir, Laufey; Olafsdottir, Elinborg J.; Gudlaugsdottir, Sigfridur; Thorlacius, Steinunn; Jonasson, Jon G.; Tulinius, Hrafn; Eyfjord, Jorunn E. (2003-10-01). "BRCA2mutation carriers, reproductive factors and breast cancer risk". Breast Cancer Research. 5 (5): R121-8. doi: 10.1186/bcr619 . ISSN   1465-542X. PMC   314423 . PMID   12927042.
  14. ↑ Safi-Stibler, Sofiane; Gabory, Anne (2020-01-01). "Epigenetics and the Developmental Origins of Health and Disease: Parental environment signalling to the epigenome, critical time windows and sculpting the adult phenotype". Seminars in Cell & Developmental Biology. SI: Chromatin dynamics in regeneration. 97: 172–180. doi:10.1016/j.semcdb.2019.09.008. ISSN   1084-9521. PMID   31587964. S2CID   203849316.
  15. ↑ Galetzka, Danuta; Hansmann, Tamara; El Hajj, Nady; Weis, Eva; Irmscher, Benjamin; Ludwig, Marco; Schneider-Rätzke, Brigitte; Kohlschmidt, Nicolai; Beyer, Vera; Bartsch, Oliver; Zechner, Ulrich; Spix, Claudia; Haaf, Thomas (2012-01-01). "Monozygotic twins discordant for constitutive BRCA1 promoter methylation, childhood cancer and secondary cancer". Epigenetics. 7 (1): 47–54. doi:10.4161/epi.7.1.18814. ISSN   1559-2294. PMC   3329502 . PMID   22207351.
  16. 1 2 Spargo, Thomas P.; Opie-Martin, Sarah; Bowles, Harry; Lewis, Cathryn M.; Iacoangeli, Alfredo; Al-Chalabi, Ammar (2022-12-15). "Calculating variant penetrance from family history of disease and average family size in population-scale data". Genome Medicine. 14 (1): 141. doi: 10.1186/s13073-022-01142-7 . ISSN   1756-994X. PMC   9753373 . PMID   36522764.
  17. ↑ Goodrich, Julia K.; Singer-Berk, Moriel; Son, Rachel; Sveden, Abigail; Wood, Jordan; England, Eleina; Cole, Joanne B.; Weisburd, Ben; Watts, Nick; Caulkins, Lizz; Dornbos, Peter; Koesterer, Ryan; Zappala, Zachary; Zhang, Haichen; Maloney, Kristin A. (2021-06-09). "Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes". Nature Communications. 12 (1): 3505. Bibcode:2021NatCo..12.3505G. doi:10.1038/s41467-021-23556-4. ISSN   2041-1723. PMC   8190084 . PMID   34108472.
  18. ↑ Turner, Heather; Jackson, Leigh (2020-01-14). "Evidence for penetrance in patients without a family history of disease: a systematic review". European Journal of Human Genetics. 28 (5): 539–550. doi:10.1038/s41431-019-0556-5. ISSN   1476-5438. PMC   7170932 . PMID   31937893.
  19. ↑ Pieroni, Maurizio; Ciabatti, Michele; Saletti, Elisa; Tavanti, Valentina; Santangeli, Pasquale; Martinese, Lucia; Liistro, Francesco; Olivotto, Iacopo; Bolognese, Leonardo (2022-11-01). "Beyond Sarcomeric Hypertrophic Cardiomyopathy: How to Diagnose and Manage Phenocopies". Current Cardiology Reports. 24 (11): 1567–1585. doi:10.1007/s11886-022-01778-2. ISSN   1534-3170. PMID   36053410. S2CID   251982622.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.