Editing Genetic disorder (section)

== {{anchor|Single gene disorder}}Single-gene ==
{| class="wikitable" align="right" style="margin-left:10px;"
|+Prevalence of some single-gene disorders<ref>{{Cite web|title=Prevalence and incidence of rare diseases|url=https://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf |archive-url=https://web.archive.org/web/20081118043120/http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf |archive-date=2008-11-18|url-status=live}}</ref>
! colspan="2" |Disorder prevalence (approximate)
|-
! colspan="2" |Autosomal dominant
|-
|[[Familial hypercholesterolemia]]
|1 in 500<ref>{{Cite web|url=https://www.omim.org/entry/144010?search=familial%20hypercholesterolaemia&highlight=%22familial%20(hypercholesterolemia%7Chypercholesterolaemia)%22%20familial%20hypercholesterolaemia%20hypercholesterolemia|title=OMIM Entry #144010 – HYPERCHOLESTEROLEMIA, FAMILIAL, 2; FCHL2|website=omim.org|access-date=2019-07-01|archive-date=2021-03-09|archive-url=https://web.archive.org/web/20210309020530/https://www.omim.org/entry/144010?search=familial%20hypercholesterolaemia&highlight=%22familial%20(hypercholesterolemia%7Chypercholesterolaemia)%22%20familial%20hypercholesterolaemia%20hypercholesterolemia|url-status=live}}</ref>
|-
|-
|[[Myotonic dystrophy|Myotonic dystrophy type 1]]
|1 in 2,100<ref>{{cite journal | vauthors = Johnson NE, Butterfield RJ, Mayne K, Newcomb T, Imburgia C, Dunn D, Duval B, Feldkamp ML, Weiss RB | title = Population-Based Prevalence of Myotonic Dystrophy Type 1 Using Genetic Analysis of Statewide Blood Screening Program | journal = Neurology | volume = 96 | issue = 7 | pages = e1045-e1053 | date = February 2021 | pmid = 33472919 | pmc = 8055332 | doi = 10.1212/WNL.0000000000011425 }}</ref>
|-
|[[Neurofibromatosis type I]]
|1 in 2,500<ref>{{Cite web|url=https://www.omim.org/entry/162200?search=neurofibromatosis&highlight=neurofibromatosi|title=OMIM Entry #162200 – NEUROFIBROMATOSIS, TYPE I; NF1|website=omim.org|language=en-us|access-date=2019-07-01|archive-date=2021-03-08|archive-url=https://web.archive.org/web/20210308190537/https://www.omim.org/entry/162200?search=neurofibromatosis&highlight=neurofibromatosi|url-status=live}}</ref>
|-
|[[Hereditary spherocytosis]]
|1 in 5,000
|-
|[[Marfan syndrome]]
|1 in 4,000<ref name="PMID18506019">{{cite journal | vauthors = Keane MG, Pyeritz RE | title = Medical management of Marfan syndrome | journal = Circulation | volume = 117 | issue = 21 | pages = 2802–2813 | date = May 2008 | pmid = 18506019 | doi = 10.1161/CIRCULATIONAHA.107.693523 | doi-access =  }}</ref>
|-
|[[Huntington's disease]]
|1 in 15,000<ref name="lancet221">{{cite journal | vauthors = Walker FO | title = Huntington's disease | journal = Lancet | volume = 369 | issue = 9557 | pages = 218–228 | date = January 2007 | pmid = 17240289 | doi = 10.1016/S0140-6736(07)60111-1 | s2cid = 46151626 }}</ref>
|-
! colspan="2" |Autosomal recessive
|-
|[[Sickle cell anaemia]]
|1 in 625<ref>{{Cite web|url=https://www.omim.org/entry/603903?search=sickle%20cell%20anemia&highlight=%22sickle%20cell%20(anaemia%7Canemia)%22%20anaemia%20anemia%20cell%20sickle|title=OMIM Entry #603903 – SICKLE CELL ANEMIA|website=omim.org|language=en-us|access-date=2019-07-01|archive-date=2021-04-26|archive-url=https://web.archive.org/web/20210426193926/https://www.omim.org/entry/603903?search=sickle%20cell%20anemia&highlight=%22sickle%20cell%20(anaemia%7Canemia)%22%20anaemia%20anemia%20cell%20sickle|url-status=live}}</ref>
|-
|[[Cystic fibrosis]]
|1 in 2,000
|-
|[[Tay–Sachs disease]]
|1 in 3,000
|-
|[[Phenylketonuria]]
|1 in 12,000
|-
|[[Autosomal recessive polycystic kidney disease]]
|1 in 20,000<ref name="Swanson 2021 p. ">{{cite journal | vauthors = Swanson K | title = Autosomal recessive polycystic kidney disease | journal = American Journal of Obstetrics and Gynecology | volume = 225 | issue = 5 | pages = B7-B8 | date = November 2021 | pmid = 34507795 | doi = 10.1016/j.ajog.2021.06.038 | publisher = Elsevier BV | s2cid = 237480065 | doi-access = free }}</ref>
|-
|[[Mucopolysaccharidosis|Mucopolysaccharidoses]]
|1 in 25,000
|-
|[[Lysosomal acid lipase deficiency]]
|1 in 40,000
|-
|[[Glycogen storage disease]]s
|1 in 50,000
|-
|[[Galactosemia]]
|1 in 57,000
|-
! colspan="2" |X-linked
|-
|[[Duchenne muscular dystrophy]]
|1 in 5,000
|-
|[[Hemophilia]]
|1 in 10,000
|-
| colspan="2" |<span style="font-size:87%;"> Values are for liveborn infants</span>
|}
{{See also|Oligogenic inheritance|Polygenic inheritance}}
A '''single-gene disorder''' (or '''monogenic disorder''') is the result of a single [[Mutation|mutated]] gene. Single-gene disorders can be passed on to subsequent generations in several ways. [[Genomic imprinting]] and [[uniparental disomy]], however, may affect inheritance patterns. The divisions between [[Dominance (genetics)|recessive and dominant]] types are not "hard and fast", although the divisions between [[Autosome|autosomal]] and [[Sex linkage|X-linked]] types are (since the latter types are distinguished purely based on the chromosomal location of the gene). For example, the common form of [[dwarfism]], [[achondroplasia]], is typically considered a dominant disorder, but children with two genes for achondroplasia have a severe and usually lethal skeletal disorder, one that achondroplasics(ones affected with achondroplasia) could be considered carriers for. [[Sickle cell disease|Sickle cell anemia]] is also considered a recessive condition, but [[Zygosity#Heterozygous|heterozygous]] carriers have increased resistance to [[malaria]] in early childhood, which could be described as a related dominant condition.<ref name="Williams">{{cite journal | vauthors = Williams TN, Obaro SK | title = Sickle cell disease and malaria morbidity: a tale with two tails | journal = Trends in Parasitology | volume = 27 | issue = 7 | pages = 315–320 | date = July 2011 | pmid = 21429801 | doi = 10.1016/j.pt.2011.02.004 }}</ref> When a couple where one partner or both are affected or carriers of a single-gene disorder wish to have a child, they can do so through ''in vitro'' fertilization, which enables preimplantation genetic diagnosis to occur to check whether the embryo has the genetic disorder.<ref name="pmid15758612">{{cite journal | vauthors = Kuliev A, Verlinsky Y | title = Preimplantation diagnosis: a realistic option for assisted reproduction and genetic practice | journal = Current Opinion in Obstetrics & Gynecology | volume = 17 | issue = 2 | pages = 179–183 | date = April 2005 | pmid = 15758612 | doi = 10.1097/01.gco.0000162189.76349.c5 | s2cid = 9382420 }}</ref>

Most congenital [[Metabolism|metabolic]] disorders known as [[inborn errors of metabolism]] result from single-gene defects. Many such single-gene defects can decrease the fitness of affected people and are therefore present in the population in lower frequencies compared to what would be expected based on simple probabilistic calculations.<ref>{{cite journal | vauthors = Šimčíková D, Heneberg P | title = Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 18577 | date = December 2019 | pmid = 31819097 | pmc = 6901466 | doi = 10.1038/s41598-019-54976-4 | bibcode = 2019NatSR...918577S }}</ref>

=== Autosomal dominant ===
{{Main|Autosomal dominant#Autosomal dominant gene}}
Only one mutated copy of the gene will be necessary for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent.<ref name="Griffiths">{{cite book|title=Introduction to Genetic Analysis| vauthors = Griffiths AJ, Wessler SR, Carroll SB, Doebley J |date=2012|publisher=W.H. Freeman and Company|isbn=978-1-4292-2943-2|edition=10th|location=New York|chapter=2: Single-Gene Inheritance}}</ref>{{rp|57}} The chance a child will inherit the mutated gene is 50%. Autosomal dominant conditions sometimes have reduced [[penetrance]], which means although only one mutated copy is needed, not all individuals who inherit that mutation go on to develop the disease. Examples of this type of disorder are [[Huntington's disease]],<ref name="Griffiths" />{{rp|58}} [[neurofibromatosis type 1]], [[neurofibromatosis type 2]], [[Marfan syndrome]], [[hereditary nonpolyposis colorectal cancer]], [[hereditary multiple exostoses]] (a highly penetrant autosomal dominant disorder), [[tuberous sclerosis]], [[Von Willebrand disease]], and [[acute intermittent porphyria]]. Birth defects are also called congenital anomalies.<ref>{{cite journal | vauthors = Malherbe HL, Modell B, Blencowe H, Strong KL, Aldous C | title = A review of key terminology and definitions used for birth defects globally | journal = Journal of Community Genetics | volume = 14 | issue = 3 | pages = 241–262 | date = June 2023 | pmid = 37093545 | pmc = 10272040 | doi = 10.1007/s12687-023-00642-2 }}</ref>

=== Autosomal recessive ===
{{Main|Autosomal dominant#Autosomal recessive allele}}
Two copies of the gene must be mutated for a person to be affected by an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene and are referred to as [[genetic carrier]]s. Each parent with a defective gene normally do not have symptoms.<ref>{{Cite web|url=https://learn.genetics.utah.edu/content/disorders/inheritance/|title=Inheritance Patterns for Single Gene Disorders|website=learn.genetics.utah.edu|access-date=2019-07-01|archive-date=2019-07-01|archive-url=https://web.archive.org/web/20190701160447/https://learn.genetics.utah.edu/content/disorders/inheritance/|url-status=live}}</ref> Two unaffected people who each carry one copy of the mutated gene have a 25% risk with each pregnancy of having a child affected by the disorder. Examples of this type of disorder are [[albinism]], [[medium-chain acyl-CoA dehydrogenase deficiency]], [[cystic fibrosis]], [[sickle cell disease]], [[Tay–Sachs disease]], [[Niemann–Pick disease]], [[spinal muscular atrophy]], and [[Roberts syndrome]]. Certain other phenotypes, such as wet versus dry [[earwax]], are also determined in an autosomal recessive fashion.<ref name="Wade">{{cite news | vauthors = Wade N |title=Japanese Scientists Identify Ear Wax Gene |url=https://www.nytimes.com/2006/01/29/science/japanese-scientists-identify-ear-wax-gene.html |work=The New York Times |date=29 January 2006 |access-date=20 February 2023 |archive-date=21 March 2023 |archive-url=https://web.archive.org/web/20230321093938/https://www.nytimes.com/2006/01/29/science/japanese-scientists-identify-ear-wax-gene.html |url-status=live }}</ref><ref name="Yoshiura">{{cite journal | vauthors = Yoshiura K, Kinoshita A, Ishida T, Ninokata A, Ishikawa T, Kaname T, Bannai M, Tokunaga K, Sonoda S, Komaki R, Ihara M, Saenko VA, Alipov GK, Sekine I, Komatsu K, Takahashi H, Nakashima M, Sosonkina N, Mapendano CK, Ghadami M, Nomura M, Liang DS, Miwa N, Kim DK, Garidkhuu A, Natsume N, Ohta T, Tomita H, Kaneko A, Kikuchi M, Russomando G, Hirayama K, Ishibashi M, Takahashi A, Saitou N, Murray JC, Saito S, Nakamura Y, Niikawa N | title = A SNP in the ABCC11 gene is the determinant of human earwax type | journal = Nature Genetics | volume = 38 | issue = 3 | pages = 324–330 | date = March 2006 | pmid = 16444273 | doi = 10.1038/ng1733 | s2cid = 3201966 }}</ref> Some autosomal recessive disorders are common because, in the past, carrying one of the faulty genes led to a [[Heterozygote advantage|slight protection]] against an infectious disease or [[toxin]] such as [[tuberculosis]] or [[malaria]].<ref>{{cite book |doi=10.1038/npg.els.0001760 |chapter=Heterozygous Advantage |title=eLS |year=2002 | vauthors = Mitton JB |isbn=978-0-470-01617-6 }}</ref> Such disorders include cystic fibrosis,<ref>{{cite journal | vauthors = Poolman EM, Galvani AP | title = Evaluating candidate agents of selective pressure for cystic fibrosis | journal = Journal of the Royal Society, Interface | volume = 4 | issue = 12 | pages = 91–98 | date = February 2007 | pmid = 17015291 | pmc = 2358959 | doi = 10.1098/rsif.2006.0154 }}</ref> sickle cell disease,<ref name="pmid19442502">{{cite journal | vauthors = Allison AC | title = Genetic control of resistance to human malaria | journal = Current Opinion in Immunology | volume = 21 | issue = 5 | pages = 499–505 | date = October 2009 | pmid = 19442502 | doi = 10.1016/j.coi.2009.04.001 }}</ref> [[phenylketonuria]]<ref>{{cite journal | vauthors = Woolf LI | title = The heterozygote advantage in phenylketonuria | journal = American Journal of Human Genetics | volume = 38 | issue = 5 | pages = 773–775 | date = May 1986 | pmid = 3717163 | pmc = 1684820 | author-link = Louis Isaac Woolf }}</ref> and [[thalassaemia]].<ref>{{cite book|title=Williams Hematology| vauthors = Weatherall DJ |date=2015|publisher=McGraw Hill Professional|isbn=978-0-07-183301-1|edition=9e|page=725|chapter=The Thalassemias: Disorders of Globin Synthesis|chapter-url=https://accessmedicine.mhmedical.com/content.aspx?bookid=1581&sectionid=94305138|access-date=2023-02-20|archive-date=2023-02-20|archive-url=https://web.archive.org/web/20230220185654/https://accessmedicine.mhmedical.com/content.aspx?bookid=1581&sectionid=94305138|url-status=live}}</ref>
<gallery widths="220" heights="360">
File:Autosomal recessive inheritance for affected enzyme.png|Hereditary defects in [[enzymes]] are generally inherited in an autosomal fashion because there are more non-X chromosomes than X-chromosomes, and a recessive fashion because the enzymes from the unaffected genes are generally sufficient to prevent symptoms in carriers.
Autosomal dominant inheritance for structural protein.png|On the other hand, hereditary defects in structural proteins (such as [[osteogenesis imperfecta]], [[Marfan's syndrome]] and many [[Ehlers–Danlos syndrome]]s) are generally autosomal dominant, because it is enough that some components are defective to make the whole structure dysfunctional. This is a [[dominant-negative mutation|dominant-negative]] process, wherein a mutated gene product adversely affects the non-mutated gene product within the same cell.
</gallery>

=== X-linked dominant ===
[[File:Human karyotype with bands and sub-bands.png|thumb|Schematic [[karyotype|karyogram]] showing an overview of the [[human genome]]. It shows annotated [[Locus (genetics)|bands and sub-bands]] as used in the [[International System for Human Cytogenomic Nomenclature|nomenclature of genetic disorders]]. It shows 22 [[homologous chromosome]]s, both the female (XX) and male (XY) versions of the [[sex chromosome]] (bottom right), as well as the [[human mitochondrial genetics|mitochondrial genome]] (to scale at bottom left).{{cn|date=March 2023}}{{further|Karyotype}}]]
{{Main|X-linked dominant}}
X-linked dominant disorders are caused by mutations in genes on the [[X chromosome]]. Only a few disorders have this inheritance pattern, with a prime example being [[X-linked hypophosphatemic rickets]]. Males and females are both affected in these disorders, with males typically being more severely affected than females. Some X-linked dominant conditions, such as [[Rett syndrome]], [[incontinentia pigmenti]] type 2, and [[Aicardi syndrome]], are usually fatal in males either ''in utero'' or shortly after birth, and are therefore predominantly seen in females. Exceptions to this finding are extremely rare cases in which boys with [[Klinefelter syndrome]] (44+xxy) also inherit an X-linked dominant condition and exhibit symptoms more similar to those of a female in terms of disease severity. The chance of passing on an X-linked dominant disorder differs between men and women. The sons of a man with an X-linked dominant disorder will all be unaffected (since they receive their father's Y chromosome), but his daughters will all inherit the condition. A woman with an X-linked dominant disorder has a 50% chance of having an affected foetus with each pregnancy, although in cases such as incontinentia pigmenti, only female offspring are generally viable.

=== X-linked recessive ===
{{Main|X-linked recessive inheritance}}
X-linked recessive conditions are also caused by mutations in genes on the X chromosome. Males are much more frequently affected than females, because they only have the one X chromosome necessary for the condition to present. The chance of passing on the disorder differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected (since they receive their father's Y chromosome), but his daughters will be carriers of one copy of the mutated gene. A woman who is a carrier of an X-linked recessive disorder (X<sup>R</sup>X<sup>r</sup>) has a 50% chance of having sons who are affected and a 50% chance of having daughters who are carriers of one copy of the mutated gene. X-linked recessive conditions include the serious diseases [[hemophilia A]], [[Duchenne muscular dystrophy]], and [[Lesch–Nyhan syndrome]], as well as common and less serious conditions such as [[male pattern baldness]] and red–green [[color blindness]]. X-linked recessive conditions can sometimes manifest in females due to [[skewed X-inactivation]] or monosomy X ([[Turner syndrome]]).{{cn|date=March 2023}}

=== Y-linked ===
{{Main|Y linkage}}
Y-linked disorders are caused by mutations on the Y chromosome. These conditions may only be transmitted from the heterogametic sex (e.g. male humans) to offspring of the same sex. More simply, this means that Y-linked disorders in humans can only be passed from men to their sons; females can never be affected because they do not possess Y-allosomes.{{cn|date=March 2023}}

Y-linked disorders are exceedingly rare but the most well-known examples typically cause infertility. Reproduction in such conditions is only possible through the circumvention of infertility by medical intervention.

=== Mitochondrial ===
{{Main|Mitochondrial disease|Mitochondrial DNA}}
This type of inheritance, also known as maternal inheritance, is the rarest and applies to the 13 genes encoded by [[mitochondrial DNA]]. Because only egg cells contribute mitochondria to the developing embryo, only mothers (who are affected) can pass on mitochondrial DNA conditions to their children. An example of this type of disorder is [[Leber's hereditary optic neuropathy]].<ref>{{cite book | vauthors = Shemesh A, Sood G, Margolin E | chapter = Leber Hereditary Optic Neuropathy (LHON) | title = StatPearls [Internet] | location = Treasure Island (FL) | publisher = StatPearls Publishing | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK482499/ }}</ref>

It is important to stress that the vast majority of [[mitochondrial diseases]] (particularly when symptoms develop in early life) are actually caused by a [[nuclear gene]] defect, as the mitochondria are mostly developed by non-mitochondrial DNA. These diseases most often follow autosomal recessive inheritance.<ref>{{Cite book|title=Thompson & Thompson Genetics in Medicine| vauthors = Nussbaum R, McInnes R, Willard H |publisher=Saunders|year=2007|isbn=978-1-4160-3080-5|location=Philadelphia PA|pages=144, 145, 146}}</ref>