The X chromosome contains 867 identified genes; most of these genes are responsible for the development of tissues like bone, neural, blood, hepatic, renal, retina, ears, ear, cardiac, skin, and teeth. There are at least 533 disorders due to the involvement of the genes on the X chromosome.[1] A 'trait' or 'disorder' determined by a gene on the X chromosome demonstrates X-linked inheritance.
In 1961, Mary Lyon proposed that in the cells of mammalian females, one X chromosome out of the two would undergo random inactivation in early embryonic life, and therefore, both males and females have a single active X. Lyon's hypothesis provided an improved understanding of the basic mechanisms responsible for X-linked diseases.[2][3][4][5]
Classically, the descriptions of X-linked inheritance are either X linked recessive and X linked dominant.
X linked Recessive Inheritance
Generally, it manifests only in males. A male with an affected allele on his single X chromosome is hemizygous and can not transmit the disorder to their male offsprings, but all his daughters would be obligate carriers. Healthy heterozygous carrier females pass the disorder to affected sons. So from affected males, it can be transmitted to male grandchildren through carrier daughter ('diagonal' or 'Knight's move' transmission).
RISK CALCULATION: The X chromosome from a male is transmitted to daughters, and the Y chromosome is transferred to sons. If an affected male has kids with a healthy female, none of his male offsprings will be affected, but all of his female offspring will be carriers. If a carrier female has kids with a healthy male, each male offspring has a 50% chance of being affected, and female offspring have a 50% chance of being a carrier.
VARIABLE EXPRESSION: Heterozygous female are those who are having mutant allele on one X chromosome, and normal allele on another X. Heterozygous female may have a variable expression of X linked recessive disorder due to the random process of X inactivation involving inactivation of the X chromosome with a mutant allele in some cells while inactivation of the X chromosome with a normal allele in other cells (mosaic pattern).[1]
X-LINKED DISORDERS IN FEMALES: Sometimes, females might be affected by X linked recessive disorders. This fact is explainable by one of the following possibilities.
(a) Heterozygosity: X inactivation is a random phenomenon that can involve a mutant allele containing X and a normal allele X in equal proportion in the heterozygous female. It is a possibility that the active X chromosome in the majority of the cells of a heterozygous female is the one having a mutant allele (skewed X inactivation), leading to disorder expression; this has been the case in Duchenne muscular dystrophy and hemophilia A.[6][7]
(b) Homozygosity: When both X chromosomes of females have a mutant allele, as reported in hemophilia A and ichthyosis.[8][9]
(c) Translocations: If a female is having a translocation involving an autosome and one of the X chromosomes and the translocation disrupts a gene on an X chromosome, in that case, a female might be affected. This pattern has been observed in Duchenne muscular dystrophy.[10][11][10]
(d) A female having only a single X chromosome (Turner syndrome), which is bearing a mutant allele. Hemophilia has been reported in the girl infant with the turner syndrome.[12]
X linked Dominant Inheritance
Male and female both are affected, but females are affected in excess and less severely. Affected males can transmit the mutant allele to female offspring but not to male offspring. Affected females can transmit the mutant allele to 50% of his male offspring and 50% of his female offspring. examples are Vitamin D resistant (hypophosphatemic) rickets, Charcot-Marie-tooth disease.[13][14]
Some X-like dominant disorders, such as incontinentia pigmenti (Bloch-Sulzberger syndrome), showed a mosaic pattern of involvement for heterozygous females.[15]
X-LINKED DOMINANT LETHALS: These disorders are incompatible with early embryonic survival. They are seen only in females and not in males because, in the severe form, they will cause the death of a male embryo, but as females are less severely affected female embryo will survive.[16]
Current View
Many female carriers of X-linked 'recessive' disorders demonstrate abnormal phenotype. This is due to the variable expressivity of X-linked disorders and the involvement of several mechanisms (e.g. skewed X-inactivation, somatic mosaicism...etc). So, recently it has been proposed that the terms' dominant' and recessive' should be discontinued, and all disorders should categorize as X-linked.[17][18][19]
Common X-linked Disorders
Because of the availability of genetic testing, most of these disorders can now be diagnosed by chorionic villus sampling during early pregnancy. Unfortunately, spontaneous mutations do occur, and the disorder may occur without any family history in some patients.
X linked Recessive Inheritance
The following features are necessary to establish the clinical diagnosis.
X linked Dominant Inheritance
The following features are necessary to establish the clinical diagnosis.
[1] | Migeon BR, X-linked diseases: susceptible females. Genetics in medicine : official journal of the American College of Medical Genetics. 2020 Apr 14; [PubMed PMID: 32284538] |
[2] | LYON MF, Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature. 1961 Apr 22; [PubMed PMID: 13764598] |
[3] | Gendrel AV,Heard E, Fifty years of X-inactivation research. Development (Cambridge, England). 2011 Dec; [PubMed PMID: 22069183] |
[4] | Harper PS, Mary Lyon and the hypothesis of random X chromosome inactivation. Human genetics. 2011 Aug; [PubMed PMID: 21643983] |
[5] | Sagie S,Monovich E, [MARY LYON (1925-2014) AND THE RANDOM INACTIVATION OF CHROMOSOME X]. Harefuah. 2016 Mar; [PubMed PMID: 27305745] |
[6] | Brioschi S,Gualandi F,Scotton C,Armaroli A,Bovolenta M,Falzarano MS,Sabatelli P,Selvatici R,D'Amico A,Pane M,Ricci G,Siciliano G,Tedeschi S,Pini A,Vercelli L,De Grandis D,Mercuri E,Bertini E,Merlini L,Mongini T,Ferlini A, Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype. BMC medical genetics. 2012 Aug 16; [PubMed PMID: 22894145] |
[7] | Yang C,Yu Z,Zhang W,Cao L,Ouyang W,Hu F,Zhang P,Bai X,Ruan C, A novel missense mutation, p.Phe360Cys, in FIX gene results in haemophilia B in a female patient with skewed X-inactivation. Haemophilia : the official journal of the World Federation of Hemophilia. 2018 Mar; [PubMed PMID: 29405493] |
[8] | Nair PS,Shetty S,Ghosh K, A homozygous female hemophilia A. Indian journal of human genetics. 2012 Jan; [PubMed PMID: 22754241] |
[9] | Nagtzaam IF,Stegmann AP,Steijlen PM,Herbergs J,Van Lent-Albrechts JA,Van Geel M,Van Steensel MA, Clinically manifest X-linked recessive ichthyosis in a female due to a homozygous interstitial 1·6-Mb deletion of Xp22.31. The British journal of dermatology. 2012 Apr; [PubMed PMID: 21985695] |
[10] | Jacobs PA,Hunt PA,Mayer M,Bart RD, Duchenne muscular dystrophy (DMD) in a female with an X/autosome translocation: further evidence that the DMD locus is at Xp21. American journal of human genetics. 1981 Jul; [PubMed PMID: 7258185] |
[11] | Uchida T,Ogata H,Shirai Z,Mitsudome A, [Duchenne muscular dystrophy (DMD) in a female with an X-autosome translocation]. No to hattatsu = Brain and development. 1988 Jan; [PubMed PMID: 3279979] |
[12] | Shahriari M,Bazrafshan A,Moghadam M,Karimi M, Severe hemophilia in a girl infant with mosaic Turner syndrome and persistent hyperplastic primary vitreous. Blood coagulation [PubMed PMID: 26484646] |
[13] | Morena J,Gupta A,Hoyle JC, Charcot-Marie-Tooth: From Molecules to Therapy. International journal of molecular sciences. 2019 Jul 12; [PubMed PMID: 31336816] |
[14] | Pavone V,Testa G,Gioitta Iachino S,Evola FR,Avondo S,Sessa G, Hypophosphatemic rickets: etiology, clinical features and treatment. European journal of orthopaedic surgery [PubMed PMID: 24957364] |
[15] | Cammarata-Scalisi F,Fusco F,Ursini MV, Incontinentia Pigmenti. Actas dermo-sifiliograficas. 2019 May; [PubMed PMID: 30660327] |
[16] | Franco B,Ballabio A, X-inactivation and human disease: X-linked dominant male-lethal disorders. Current opinion in genetics [PubMed PMID: 16650755] |
[17] | Dobyns WB, The pattern of inheritance of X-linked traits is not dominant or recessive, just X-linked. Acta paediatrica (Oslo, Norway : 1992). Supplement. 2006 Apr; [PubMed PMID: 16720459] |
[18] | Germain DP, General aspects of X-linked diseases 2006; [PubMed PMID: 21290690] |
[19] | Dobyns WB,Filauro A,Tomson BN,Chan AS,Ho AW,Ting NT,Oosterwijk JC,Ober C, Inheritance of most X-linked traits is not dominant or recessive, just X-linked. American journal of medical genetics. Part A. 2004 Aug 30; [PubMed PMID: 15316978] |