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{{short description|Situation in which some gamete-producing cells are affected by a mutation}}
'''Germline mosaicism''', also called '''gonadal mosaicism''', is a type of [[genetic mosaicism]] where more than one set of genetic information is found specifically within the [[gamete]] cells; conversely, [[somatic mosaicism]] is a type of genetic mosaicism found in [[Somatic cell|somatic cells]]. [[Germ line|Germline]] mosaicism can be present at the same time as somatic mosaicism or individually, depending on when the conditions occur. Pure germline mosaicism refers to mosaicism found exclusively in the gametes and not in any somatic cells. Germline mosaicism can be caused either by a mutation that occurs after conception,<ref>{{cite journal|last1=Orva|first1=Rosa|last2=Orva|first2=David|date=April 1998|title=Germ line Mosaicism|journal=Human Genetics|volume=102|issue=4|pages=381–6|doi=10.1007/s004390050708|pmid=9600231|s2cid=22007840 }}</ref><ref>Nussbuam, McInnes, Willard. Genetics In Medicine. Elsevier. pp. 123–125. {{ISBN|978-1-4377-0696-3}}.</ref> or by [[epigenetic regulation]],<ref>{{cite journal|last1=Laurentino|first1=S.|last2=Beygo|first2=J.|last3=Nordhoff|first3=V.|last4=Kliesch|first4=S.|last5=Wistuba|first5=J.|last6=Borgmann|first6=J.|last7=Buiting|first7=K.|last8=Horsthemke|first8=B.|last9=Gromoll|first9=J.|date=21 October 2014|title=Epigenetic germline mosaicism in infertile men|url=http://journals1.scholarsportal.info/pdf/09646906/v24i0005/1295_egmiim.xml|journal=Human Molecular Genetics|volume=24|issue=5|pages=1295–1304|doi=10.1093/hmg/ddu540|pmid=25336341|doi-access=free}}</ref> alterations to DNA such as [[methylation]] that do not involve changes in the DNA coding sequence.

A mutation in an [[allele]] acquired by a somatic cell early in its development can be passed on to its daughter cells, including those that later specialize to gametes. With such mutation within the gamete cells, a pair of medically typical individuals may have repeated succession of children who suffer from certain genetic disorders such as [[Duchenne muscular dystrophy]] and [[osteogenesis imperfecta]] because of germline mosaicism. It is possible for parents unaffected by [[germline mutation]]s to produce an offspring with an [[autosomal dominant]] (AD) disorder due to a random new mutation within one’s gamete cells known as [[sporadic mutation]]; however, if these parents produce more than one child with an AD disorder, germline mosaicism is more likely the cause than a sporadic mutation.<ref>{{cite web|url=http://hihg.med.miami.edu/code/http/modules/education/Design/CoursePageContent.asp?ID=14|title=Germline Mosaicism|website=John P. Hussman Institute for Human Genomics module|date=25 March 2024 }}</ref>{{Reliable source?|date=August 2019}} In the first documented case of its kind, two offspring of a French woman who had no phenotypic expression of the AD disorder [[hypertrophic cardiomyopathy]], inherited the disease.<ref>{{cite journal|title=First description of germline mosaicism in familial hypertrophic cardiomyopathy|journal = Journal of Medical Genetics|volume = 37|issue = 2|last1=Forissier|first1=J. F.|last2=Richard|first2=P.|date=2000|pages=132–134|doi=10.1136/jmg.37.2.132|pmid = 10662815|pmc = 1734529|last3=Briault|first3=S.|last4=Ledeuil|first4=C.|last5=Dubourg|first5=O.|last6=Charbonnier|first6=B.|last7=Carrier|first7=L.|last8=Moraine|first8=C.|last9=Bonne|first9=G.|last10=Komajda|first10=M.|last11=Schwartz|first11=K.|last12=Hainque|first12=B.}}</ref>

== Inheritance ==
Germline mosaicism disorders are usually inherited in a pattern that suggests that the condition is dominant in either or both of the parents. That said, diverging from Mendelian gene inheritance patterns, a parent with a recessive allele can produce offspring expressing the phenotype as dominant through germline mosaicism. A situation may also arise in which the parents have milder phenotypic expression of a mutation yet produce offspring with more expressive phenotypic variance and a more frequent sibling recurrences of the mutation.<ref>{{Cite journal|last1=Nancy B. Spinner|last2=Biesecker|first2=Leslie G.|date=2013|title=A genomic view of mosaicism and human disease|journal=Nature Reviews Genetics|language=en|volume=14|issue=5|pages=307–320|doi=10.1038/nrg3424|pmid=23594909|s2cid=4494815 |issn=1471-0064}}</ref><ref>{{Cite journal|title=Familiarity, recessivity and germline mosaicism|journal = Annals of Human Genetics|volume = 53|issue = 1|pages = 33–47|last=Edwards|first=J. H.|date=1989-01-01|language=en|doi=10.1111/j.1469-1809.1989.tb01120.x|pmid = 2658737| s2cid=28036553 }}</ref><ref>{{Cite journal|last=Zlotogora|first=Joël|date=1998-04-01|title=Germ line mosaicism|journal=Human Genetics|language=en|volume=102|issue=4|pages=381–386|doi=10.1007/s004390050708|pmid=9600231|s2cid=22007840 |issn=1432-1203}}</ref>

Diseases caused by germline mosaicism can be difficult to diagnose as genetically-inherited because the [[mutant]] [[alleles]] are not likely to be present in the somatic cells. Somatic cells are more commonly used for [[genetic analysis]] because they are easier to obtain than gametes. If the disease is a result of pure germline mosaicism, then the disease causing mutant allele would never be present in the somatic cells. This is a source of uncertainty for [[genetic counselling]]. An individual may still be a carrier for a certain disease even if the disease causing mutant allele is not present in the cells that were analyzed because the causative mutation could still exist in some of the individual's gametes.<ref name=":0">{{Cite journal|url = http://www.annclinlabsci.org/content/45/1/106.full|title = A Case Report of a Fetus with Mosaic Autosomal Variegated Aneuploidies and Literature Review|last = Chi Hyan|first = Cho|date = 2015|journal = Annals of Clinical & Laboratory Science| volume=45 | issue=1 | pages=106–109 | pmid=25696020 |access-date = December 3, 2015|display-authors=etal}}</ref>

Germline mosaicism may contribute to the inheritance of many genetic conditions. Conditions that are inherited by means of germline mosaicism are often mistaken as being the result of [[Mutation#By inheritance|de novo mutations]]. Various diseases are now being re-examined for presence of mutant alleles in the germline of the parents in order to further our understanding of how they can be passed on.<ref>{{Cite journal|title = Paternal germline mosaicism in collagen VI related myopathies|journal = European Journal of Paediatric Neurology|date = 2015-09-01|pages = 533–536|volume = 19|issue = 5|doi = 10.1016/j.ejpn.2015.04.002|pmid = 25978941|first1 = Annarita|last1 = Armaroli|first2 = Cecilia|last2 = Trabanelli|first3 = Chiara|last3 = Scotton|first4 = Anna|last4 = Venturoli|first5 = Rita|last5 = Selvatici|first6 = Giacomo|last6 = Brisca|first7 = Luciano|last7 = Merlini|first8 = Claudio|last8 = Bruno|first9 = Alessandra|last9 = Ferlini|hdl = 11392/2330840|hdl-access = free}}</ref> The frequency of germline mosaicism is not known due to the sporadic nature of the mutations causing it and the difficulty in obtaining the gametes that must be tested to diagnose it.

== Diagnosis ==
Autosomal dominant or X-linked familial disorders often prompt prenatal testing for germline mosaicism. This diagnosis may involve minimally invasive procedures, such as blood sampling or amniotic fluid sampling.<ref name=":0" /><ref name=":1">{{Cite journal|last=Edwards|first=J. H.|date=1989|title=Familiarity, recessivity and germline mosaicism|journal=Annals of Human Genetics|language=en|volume=53|issue=1|pages=33–47|doi=10.1111/j.1469-1809.1989.tb01120.x|pmid=2658737|s2cid=28036553 |issn=1469-1809}}</ref><ref>{{Cite journal|last1=Mari|first1=F.|last2=Caselli|first2=R.|last3=Russo|first3=S.|last4=Cogliati|first4=F.|last5=Ariani|first5=F.|last6=Longo|first6=I.|last7=Bruttini|first7=M.|last8=Meloni|first8=I.|last9=Pescucci|first9=C.|date=2005|title=Germline mosaicism in Rett syndrome identified by prenatal diagnosis|journal=Clinical Genetics|language=en|volume=67|issue=3|pages=258–260|doi=10.1111/j.1399-0004.2005.00397.x|pmid=15691364|issn=1399-0004|hdl=2434/13970|s2cid=29782253 |hdl-access=free}}</ref><ref>{{Cite journal|last1=Betsalel|first1=Ofir T.|last2=van de Kamp|first2=Jiddeke M.|last3=Martínez-Muñoz|first3=Cristina|last4=Rosenberg|first4=Efraim H.|last5=de Brouwer|first5=Arjan P. M.|last6=Pouwels|first6=Petra J. W.|last7=van der Knaap|first7=Marjo S.|last8=Mancini|first8=Grazia M. S.|last9=Jakobs|first9=Cornelis|date=2008-07-01|title=Detection of low-level somatic and germline mosaicism by denaturing high-performance liquid chromatography in a EURO-MRX family with SLC6A8 deficiency|journal=Neurogenetics|language=en|volume=9|issue=3|pages=183–190|doi=10.1007/s10048-008-0125-5|pmid=18350323|s2cid=16211597 |issn=1364-6753|hdl=1765/30290|hdl-access=free}}</ref><ref name=":2">{{Cite journal|last1=Wilkie|first1=Andrew O. M.|last2=Goriely|first2=Anne|date=September 2019|title=Gonadal mosaicism and non-invasive prenatal diagnosis for 'reassurance' in sporadic paternal age effect (PAE) disorders|journal=Prenatal Diagnosis|volume=37|issue=9|pages=946–948|doi=10.1002/pd.5108|issn=0197-3851|pmc=5638092|pmid=28686291}}</ref> Collected samples can be sequenced via common DNA testing methods, such as [[Sanger sequencing|Sanger Sequencing]], [[Multiplex ligation-dependent probe amplification|MLPA]], or [[Southern blot|Southern Blot]] analysis, to look for variations on relevant genes connected to the disorder.<ref name=":2" /><ref>{{Cite journal|last1=Sgambati|first1=M. T.|last2=Stolle|first2=C.|last3=Choyke|first3=P. L.|last4=Walther|first4=M. M.|last5=Zbar|first5=B.|last6=Linehan|first6=W. M.|last7=Glenn|first7=G. M.|date=2000-01-01|title=Mosaicism in von Hippel–Lindau Disease: Lessons from Kindreds with Germline Mutations Identified in Offspring with Mosaic Parents|journal=The American Journal of Human Genetics|volume=66|issue=1|pages=84–91|doi=10.1086/302726|pmid=10631138|pmc=1288351|issn=0002-9297}}</ref>

== Recurrence rate ==
The recurrence rate of conditions caused by germline mosaicism varies greatly between subjects. Recurrence is proportional to the number of gamete cells that carry the particular mutation with the condition. If the mutation occurred earlier on in the development of the gamete cells, then the recurrence rate would be higher because a greater number of cells would carry the mutant allele.<ref name=":1" />

== Case studies ==
A Moroccan family consisting of two healthy unrelated parents and three offspring—including two with Noonan syndrome, a rare autosomal dominant disorder with varying expression and genetic heterogeneity—underwent [[genetic testing]] revealing that both of the siblings with NS share the same PTPN11 haplotype from both parents, while a distinct paternal and maternal haplotype was inherited by the unaffected sibling. <ref>Elalaoui SC, Kraoua L, Liger C, Ratbi I, CaveH, Sefiani A. 2010. Germinal mosaicism in Noonan syndrome: A family with two affected siblings of normal parents. Am J Med Genet Part A 152A:2850–2853</ref>
In the paper Germline and somatic mosaicism in transgenic mice published in 1986, Thomas M.Wilkie, Ralph L.Brinster, and Richard D.Palmiter analyzed a germline mosaicism experiment done on 262 transgenic mice and concluded that 30% of founder transgenic mice are mosaic in the germline. <ref>Thomas M. Wilkie, Ralph L. Brinster, Richard D. Palmiter. 1986. Germline and somatic mosaicism in transgenic mice, Developmental Biology, Volume 118, Issue 1, pp. 9-18. ISSN 0012-1606. </ref>

==Notes==
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[[Category:Genetics]]

Germline mosaicism - История изменений

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