Editing Hereditary multiple exostoses (section)

==Genetics==
HME is an [[dominance (genetics)|autosomal dominant]] hereditary disorder. This means that individuals with HME have a 50% chance of transmitting this disorder to their  children. Most individuals with HME have a parent who also has the condition; however, approximately 10–20% of individuals with HME have the condition as a result of a spontaneous mutation and are thus the first person in their family to be affected.{{citation needed|date=September 2020}}

HME has thus far been linked with mutations in three genes:
* [[EXT1]] which maps to chromosome 8q24.1<ref name="pmid8317501">{{cite journal | vauthors = Cook A, Raskind W, Blanton SH, Pauli RM, Gregg RG, Francomano CA, Puffenberger E, Conrad EU, Schmale G, Schellenberg G | title = Genetic heterogeneity in families with hereditary multiple exostoses | journal = American Journal of Human Genetics | volume = 53 | issue = 1 | pages = 71–79 | date = July 1993 | pmid = 8317501 | pmc = 1682231 }}</ref>
* [[EXT2 (gene)|EXT2]] which maps to 11p13<ref name="pmid8162019">{{cite journal | vauthors = Wu YQ, Heutink P, de Vries BB, Sandkuijl LA, van den Ouweland AM, Niermeijer MF, Galjaard H, Reyniers E, Willems PJ, Halley DJ | title = Assignment of a second locus for multiple exostoses to the pericentromeric region of chromosome 11 | journal = Human Molecular Genetics | volume = 3 | issue = 1 | pages = 167–171 | date = January 1994 | pmid = 8162019 | doi = 10.1093/hmg/3.1.167 }}</ref>
* [[EXT3 (gene)|EXT3]] which maps to the short arm of chromosome 19 (though its exact location has yet to be precisely determined)<ref name="pmid8081357">{{cite journal | vauthors = Le Merrer M, Legeai-Mallet L, Jeannin PM, Horsthemke B, Schinzel A, Plauchu H, Toutain A, Achard F, Munnich A, Maroteaux P | title = A gene for hereditary multiple exostoses maps to chromosome 19p | journal = Human Molecular Genetics | volume = 3 | issue = 5 | pages = 717–722 | date = May 1994 | pmid = 8081357 | doi = 10.1093/hmg/3.5.717 | citeseerx = 10.1.1.1028.5356 }}</ref>

Mutations in these genes typically lead to the synthesis of a truncated EXT protein which does not function normally.  It is known that EXT proteins are important enzymes in the synthesis of [[heparan sulfate|heparan sulfate proteoglycans]]; however, the exact mechanism by which altered synthesis of heparan sulfate that could lead to the abnormal bone growth associated with HME is unclear.  It is thought that normal [[chondrocyte]] proliferation and differentiation may be affected, leading to abnormal bone growth.<ref name="pmid12417417">{{cite journal | vauthors = Zak BM, Crawford BE, Esko JD | title = Hereditary multiple exostoses and heparan sulfate polymerization | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1573 | issue = 3 | pages = 346–355 | date = December 2002 | pmid = 12417417 | doi = 10.1016/S0304-4165(02)00402-6 }}</ref><ref name="pmid15850368">{{cite journal | vauthors = Stieber JR, Dormans JP | title = Manifestations of hereditary multiple exostoses | journal = The Journal of the American Academy of Orthopaedic Surgeons | volume = 13 | issue = 2 | pages = 110–120 | year = 2005 | pmid = 15850368 | doi = 10.5435/00124635-200503000-00004 | s2cid = 29077708 }}</ref> Since the HME genes are involved in the synthesis of a glycan ([[heparan sulfate]]), HME may be considered a [[congenital disorder of glycosylation]] according to the new CDG nomenclature suggested in 2009.<ref name="pmid19765534">{{cite journal | vauthors = Jaeken J, Hennet T, Matthijs G, Freeze HH | title = CDG nomenclature: time for a change! | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1792 | issue = 9 | pages = 825–826 | date = September 2009 | pmid = 19765534 | pmc = 3917312 | doi = 10.1016/j.bbadis.2009.08.005 }}</ref>

For individuals with HME who are considering starting a family, preimplantation [[genetic testing]] and prenatal diagnosis are available to determine if their unborn child has inherited the disease. HME has a 96% penetrance, which means that if the affected gene is indeed transmitted to a child, the child will have a 96% of actually manifesting the disease, and 4% chance of having the disease but never manifesting it. The 96% penetrance figure comes from only one study.<ref name="pmid9272707"/> Other studies have observed both incomplete and variable penetrance but without calculating the % penetrance, e.g.<ref>{{cite journal | vauthors = Faiyaz-Ul-Haque M, Ahmad W, Zaidi SH, Hussain S, Haque S, Ahmad M, Cohn DH, Tsui LC | title = Novel mutations in the EXT1 gene in two consanguineous families affected with multiple hereditary exostoses (familial osteochondromatosis) | journal = Clinical Genetics | volume = 66 | issue = 2 | pages = 144–151 | date = August 2004 | pmid = 15253765 | doi = 10.1111/j.1399-0004.2004.00275.x | s2cid = 10431219 }}</ref> In both the aforementioned studies the symptomless individuals carrying the faulty gene were predominantly female, leading to speculation that incomplete penetrance is more likely to be exhibited in females. Indeed, other work has shown that males tend to have worse disease than females, as well as that the number of exostoses in affected members of the same family can vary greatly.<ref name=pmid15446535>{{cite journal | vauthors = Porter DE, Lonie L, Fraser M, Dobson-Stone C, Porter JR, Monaco AP, Simpson AH | title = Severity of disease and risk of malignant change in hereditary multiple exostoses. A genotype-phenotype study | journal = The Journal of Bone and Joint Surgery. British Volume | volume = 86 | issue = 7 | pages = 1041–1046 | date = September 2004 | pmid = 15446535 | doi = 10.1302/0301-620x.86b7.14815 | hdl-access = free | s2cid = 7129239 | hdl = 20.500.11820/8754788e-ceea-4613-8e65-60d34fcf9edc }}</ref> It is also possible for females to be severely affected. Severity of symptoms varies between individuals, even in the same family.{{citation needed|date=August 2021}}

Symptoms are more likely to be severe if the mutation is on the ''ext1'' gene rather than ''ext2'' or ''ext3''; ''ext1'' is also the most commonly affected gene in patients of this disorder.<ref name=pmid15446535/>