Editing Haemophilia (section)

==Genetics==
[[File:X-linked recessive (2).svg|thumb|upright=1.85|[[X-linked recessive inheritance]]]]

Typically, females possess two [[X-chromosome]]s, and males have one X and one [[Y chromosome|Y-chromosome]]. Since the mutations causing the disease are [[X-linked recessive inheritance|X-linked recessive]], a female carrying the defect on one of her X-chromosomes may not be affected by it, as the equivalent dominant [[allele]] on her other chromosome should express itself to produce the necessary clotting factors, due to X inactivation. Therefore, [[heterozygous]] females are just [[Genetic carrier|carriers]] of this genetic disposition. However, the Y-chromosome in the male has no gene for factors VIII or IX. If the genes responsible for production of factor VIII or factor IX present on a male's X-chromosome are deficient there is no equivalent on the Y-chromosome to cancel it out, so the deficient gene is not masked and the disorder will develop.<ref>{{Cite web|title=Hemophilia|url=https://www.genome.gov/genetics-glossary/hemophilia|access-date=21 January 2022|website=Genome.gov|language=en}}</ref>

Since a male receives his single X-chromosome from his mother, the son of a healthy female silently carrying the deficient gene will have a 50% chance of inheriting that gene from her and with it the disease; and if his mother is affected with haemophilia, he will have a 100% chance of being a haemophiliac. In contrast, for a female to inherit the disease, she must receive two deficient X-chromosomes, one from her mother and the other from her father (who must therefore be a haemophiliac himself). Hence, haemophilia is expressed far more commonly among males than females, while females, who must have two deficient X-chromosomes in order to have haemophilia, are far more likely to be silent carriers, survive childhood and to submit each of her genetic children to an at least 50% risk of receiving the deficient gene. However, it is possible for female carriers to become mild haemophiliacs due to [[lyonisation]] (inactivation) of the X-chromosomes. Haemophiliac daughters are more common than they once were, as improved treatments for the disease have allowed more haemophiliac males to survive to adulthood and become parents. Adult females may experience [[menorrhagia]] (heavy periods) due to the bleeding tendency. The pattern of inheritance is X-linked recessive.<ref>{{Cite web |title=Hemophilia: MedlinePlus Genetics |url=https://medlineplus.gov/genetics/condition/hemophilia/#inheritance |access-date=21 January 2025 |website=medlineplus.gov |language=en}}</ref> This type of pattern is also seen in [[colour blindness]].{{citation needed|date=September 2021}}

A mother who is a [[Genetic carrier|carrier]] has a 50% chance of passing the faulty X-chromosome to her daughter, while an affected father will always pass on the affected gene to his daughters. A son cannot inherit the defective gene from his father. [[Genetic testing]] and [[genetic counselling]] is recommended for families with haemophilia. [[Prenatal testing]], such as [[amniocentesis]] and [[chorionic villus sampling]]<ref>{{Cite journal |last=Ljung |first=R. C. |date=June 1996 |title=Prenatal diagnosis of haemophilia |url=https://pubmed.ncbi.nlm.nih.gov/8800503/ |journal=Bailliere's Clinical Haematology |volume=9 |issue=2 |pages=243–257 |doi=10.1016/s0950-3536(96)80061-8 |issn=0950-3536 |pmid=8800503}}</ref> [[Chorionic villus sampling|are available to pregnant women who may be carriers of the condition.]]<ref>{{Cite web|last=Naqvi|first=Erum|title=Hemophilia and Pregnancy – Hemophilia News Today|url=https://hemophilianewstoday.com/women-with-hemophilia__trashed/pregnancy-and-hemophilia/|access-date=2 October 2021|language=en-US}}</ref>

As with all genetic disorders, it is also possible for a human to acquire it spontaneously through [[mutation]], rather than inheriting it, because of a new mutation in one of their parents' gametes. Spontaneous mutations account for about 33% of all cases of haemophilia A.<ref>{{cite book |last1=Kumar |first1=Parveen |last2=Clark |first2=Michael |title=Kumar & Clark's Clinical Medicine |year=2009 |publisher=Saunders Elsevier |isbn=978-0-7020-2993-6 |edition=7th}}</ref> The most common mutation that causes severe cases of haemophilia A is an inversion within intron 22 of the factor VIII gene (F8) which is located near the tip of the X chromosome, leading to an abnormal crossover during meiosis.<ref name="z939">{{cite book | last=Hart | first=Daniel P. | last2=Giangrande | first2=Paul L.F. | title=Molecular Hematology 4e | chapter=The molecular basis of hemophilia | publisher=Wiley | date=6 November 2019 | isbn=978-1-119-25286-3 | doi=10.1002/9781119252863.ch17 | pages=221–234}}</ref> About 30% of cases of haemophilia B are the result of a spontaneous gene mutation.

If a female gives birth to a haemophiliac son, either the female is a carrier for the blood disorder or the haemophilia was the result of a spontaneous mutation.<ref>{{Cite web |last=CDC |date=19 April 2019 |title=Information for Women {{!}} Hemophilia {{!}} NCBDDD {{!}} CDC |url=https://www.cdc.gov/ncbddd/hemophilia/women.html |access-date=16 May 2022 |website=Centers for Disease Control and Prevention |language=en-us}}</ref> Until modern direct [[Genetic fingerprinting|DNA testing]], however, it was impossible to determine if a female with only healthy children was a carrier or not.<ref>{{Cite journal |last1=Oldenburg |first1=Johannes |last2=Pezeshkpoor |first2=Behnaz |last3=Pavlova |first3=Anna |date=November 2014 |title=Historical review on genetic analysis in hemophilia A |url=https://pubmed.ncbi.nlm.nih.gov/25377322/ |journal=Seminars in Thrombosis and Hemostasis |volume=40 |issue=8 |pages=895–902 |doi=10.1055/s-0034-1395161 |issn=1098-9064 |pmid=25377322|s2cid=23864314 }}</ref>

If a male has the disease and has children with a female who is not a carrier, his daughters will be carriers of haemophilia. His sons, however, will not be affected with the disease. The disease is X-linked and the father cannot pass haemophilia through the Y-chromosome. Males with the disorder are then no more likely to pass on the gene to their children than carrier females, though all daughters they sire will be carriers and all sons they father will not have haemophilia (unless the mother is a carrier)<ref>{{Cite web |last=CDC |date=1 August 2022 |title=How Hemophilia is Inherited {{!}} Hemophilia {{!}} NCBDDD {{!}} CDC |url=https://www.cdc.gov/ncbddd/hemophilia/inheritance-pattern.html |access-date=19 December 2022 |website=Centers for Disease Control and Prevention |language=en-us}}</ref>

===Severity===
There are numerous different mutations which cause each type of haemophilia. Due to differences in changes to the genes involved, people with haemophilia often have some level of active clotting factor. Individuals with less than 1% active factor are classified as having severe haemophilia, those with 1–5% active factor have moderate haemophilia, and those with mild haemophilia have between 5% and 40% of normal levels of active clotting factor.<ref name=emed/>