Editing Fragile X syndrome (section)

=== Inheritance ===
Fragile X syndrome has traditionally been considered an [[X-linked recessive inheritance|X-linked recessive]] condition with variable expressivity and possibly reduced [[penetrance]].<ref name=Garber/> The likelihood of transmission depends on the parent's sex, the X chromosome carrying the mutation, and the number of CGG repeats in the premutation.

Due to [[genetic anticipation]] and [[X-inactivation]] in females, the inheritance of Fragile X syndrome does not follow the usual pattern of X-linked dominant inheritance, and scholars from [[The University of Chicago Medical Center]] and [[Groningen University Hospital]] have had an abstract published in the [[American Journal of Medical Genetics]] that proposes discontinuing labeling X-linked disorders as dominant or recessive.<ref>{{cite journal | vauthors = Dobyns WB, Filauro A, Tomson BN, Chan AS, Ho AW, Ting NT, Oosterwijk JC, Ober C | display-authors = 6 | title = Inheritance of most X-linked traits is not dominant or recessive, just X-linked | journal = American Journal of Medical Genetics. Part A | volume = 129A | issue = 2 | pages = 136–143 | date = August 2004 | pmid = 15316978 | doi = 10.1002/ajmg.a.30123 | s2cid = 42108591 }}</ref> Males with a full mutation are usually affected and infertile, while carrier females have a 50% chance of passing the mutation.

Before the ''FMR1'' gene was discovered, analysis of pedigrees showed the presence of male carriers who were asymptomatic, with their grandchildren affected by the condition at a higher rate than their siblings suggesting that [[genetic anticipation]] was occurring.<ref name=Santoro/> This tendency for future generations to be affected at a higher frequency became known as the [[Sherman paradox]] after its description in 1985.<ref name=Santoro/><ref>{{cite journal | vauthors = Sherman SL, Jacobs PA, Morton NE, Froster-Iskenius U, Howard-Peebles PN, Nielsen KB, Partington MW, Sutherland GR, Turner G, Watson M | display-authors = 6 | title = Further segregation analysis of the fragile X syndrome with special reference to transmitting males | journal = Human Genetics | volume = 69 | issue = 4 | pages = 289–299 | year = 1985 | pmid = 3838733 | doi = 10.1007/BF00291644 | s2cid = 23299935 }}</ref> Due to this, male children often have a greater degree of symptoms than their mothers.<ref name=Marco>{{cite journal | vauthors = Marco EJ, Skuse DH | title = Autism-lessons from the X chromosome | journal = Social Cognitive and Affective Neuroscience | volume = 1 | issue = 3 | pages = 183–193 | date = December 2006 | pmid = 18985105 | pmc = 2555419 | doi = 10.1093/scan/nsl028 }}</ref>

The explanation for this phenomenon is that male carriers pass on their premutation to all of their daughters, with the length of the ''FMR1'' CGG repeat typically not increasing during [[meiosis]], the cell division that is required to produce sperm.<ref name=Santoro/><ref name=Peprah/> Incidentally, males with a full mutation only pass on premutations to their daughters.<ref name=Peprah/> However, females with a full mutation are able to pass this full mutation on, so theoretically there is a 50% chance that a child will be affected.<ref name=Peprah/><ref name=guidelines/> In addition, the length of the CGG repeat frequently does increase during meiosis in female premutation carriers due to instability and so, depending on the length of their premutation, they may pass on a full mutation to their children who will then be affected. [[trinucleotide repeat expansion|Repeat expansion]] is considered to be a consequence of [[strand slippage]] either during [[DNA replication]] or [[DNA repair]] synthesis.<ref name="pmid25608779">{{cite journal | vauthors = Usdin K, House NC, Freudenreich CH | title = Repeat instability during DNA repair: Insights from model systems | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 50 | issue = 2 | pages = 142–167 | date = 2015 | pmid = 25608779 | pmc = 4454471 | doi = 10.3109/10409238.2014.999192 }}</ref>

==== Mosaicism ====
Mosaicism refers to cases where individuals have both full mutation and premutation copies. Mosaicism can result from instability in the CGG repeats, and affected individuals may show classic symptoms, although some evidence suggests higher intellectual abilities compared to those with a full mutation.<ref>{{Cite journal |last1=Mineur |first1=Yann S. |last2=Sluyter |first2=Frans |last3=de Wit |first3=Sanne |last4=Oostra |first4=Ben A. |last5=Crusio |first5=Wim E. |date=2002 |title=Behavioral and neuroanatomical characterization of the ''Fmr1'' knockout mouse |url=http://dx.doi.org/10.1002/hipo.10005 |journal=Hippocampus |volume=12 |issue=1 |pages=39–46 |doi=10.1002/hipo.10005 |pmid=11918286 |s2cid=35472224 |issn=1050-9631}}</ref>