Obligate carrier

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An obligate carrier is an individual who may be clinically unaffected but who must carry a gene mutation based on analysis of the family history; usually applies to disorders inherited in an autosomal recessive and X-linked recessive manner. [1] [2]

Contents

X-linked Recessive

Inheritance

In X-linked recessive disorders, only females can be the carriers of the recessive mutation, making them obligate carriers of this type of disease. Females acquire one X-chromosome from their father and one from their mother, and this means they can either be heterozygous for the mutated allele or homozygous. If heterozygous, she is a carrier of the mutated allele because the disease is recessive. If homozygous, she has the disease. An affected father with an X-linked recessive trait will always pass the trait on to the daughter. Therefore, all daughters of an affected male are obligate carriers. On the other hand, a carrier mother has a 50% chance of passing her mutated X-chromosome to the daughter. [3] This makes all daughters of carrier mothers possible carriers but not necessarily obligate carriers. Males cannot be obligate or possible carriers of X-linked recessive traits because they only have one X-chromosome, and so are always phenotypically affected when receiving the mutated X-chromosome from their mother. [4]

Females that are heterozygous for X-linked recessive disorders are obligate carriers, but can never be phenotypically affected, and this is because of X-inactivation. Heterozygous females have an X-chromosome from each parent; one with a mutated gene and one with a functional copy of the same gene. When the mutated chromosome is randomly inactivated in order to maintain the copy number, presence of the functional copy results in a normal phenotype. [5] Males only have one copy of any gene on the X-chromosome, and because they do not undergo X-inactivation, they only have the mutated gene. As a result, these types of diseases most commonly phenotypically affect males and rarely females.

Hemophilia

Hemophilia, or haemophilia, is an X-linked recessive disorder that impairs the body's control over blood clotting. Haemophilia A and Haemophilia B arise from mutations in the genes for factor VIII and factor IX, respectively. [6] Females with this disease are almost exclusively unaffected, obligate carriers. The mutations can be passed on to offspring by mothers and fathers, but the phenotype is only expressed in males that inherit the mutation. [7] All daughters of a hemophiliac father are obligate carriers of the disease.

Autosomal Recessive

In an autosomal recessive disease, if an individual is heterozygous for the mutant allele, they are a carrier because the disease is recessive. If homozygous, they have the disease. All offspring of an affected individual are either heterozygous or homozygous for the mutated allele. Consequently, all unaffected (heterozygous) offspring of an affected individual are obligate carriers of the disease because they will necessarily carry the mutated allele. [8]

Detection

Due to the predictable patterns of heritable disorders, techniques can be used to detect past, present, and future disease prevalence in individuals among a family. Specifically, pedigrees and laboratory methods are used to search for and predict obligate carriers for a specific disease such as hemophilia. After analysis of family history, one way to be completely sure that an individual is an obligate carrier is through genetic tests, such as mutational analysis. This allows professionals to see if the specific mutation exists in the chromosome of the individual. [9] [10] In potential hemophiliacs, factor assays are used to measure the amount of blood clotting in an individual. However, some carriers might have completely normal clotting levels and so this method is not always useful. [9] Genetic counselling informs patients that may have a family history of a certain disease about their risk of disease and potential risk in their children.

Related Research Articles

An allele is one of two, or more, forms of a given gene variant. For example, the ABO blood grouping is controlled by the ABO gene, which has six common alleles. Nearly every living human's phenotype for the ABO gene is some combination of just these six alleles. An allele is one of two, or more, versions of the same gene at the same place on a chromosome. It can also refer to one of multiple different sequence variations of several-hundred base-pairs long or longer regions of the genome that code for proteins. Alleles can come in different extremes of size. At the lowest extreme, an allele can be a single nucleotide polymorphism (SNP). At higher extremes, it can be up to several thousand base-pairs long. Most alleles result in little or no observable change in the function of the protein the gene codes for.

Genetic disorder Health problem caused by one or more abnormalities in the genome

A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development, or it can be inherited from two parents who are carriers of a faulty gene or from a parent with the disorder. When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA.

The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a specific gene depends on the number of copies of each chromosome found in that species, also referred to as ploidy. In diploid species like humans, two full sets of chromosomes are present, meaning each individual has two alleles for any given gene. If both alleles are the same, the genotype is referred to as homozygous. If the alleles are different, the genotype is referred to as heterozygous.

Haemophilia Human genetic disease that impairs the bodys ability to make blood clots, a process needed to stop bleeding

Haemophilia is a mostly inherited genetic disorder that impairs the body's ability to make blood clots, a process needed to stop bleeding. This results in people bleeding for a longer time after an injury, easy bruising, and an increased risk of bleeding inside joints or the brain. Those with a mild case of the disease may have symptoms only after an accident or during surgery. Bleeding into a joint can result in permanent damage while bleeding in the brain can result in long term headaches, seizures, or a decreased level of consciousness.

Mendelian inheritance Type of biological inheritance

Mendelian inheritance is a type of biological inheritance that follows the principles originally proposed by Gregor Mendel in 1865 and 1866, re-discovered in 1900 by Hugo de Vries and Carl Correns, and popularized by William Bateson. These principles were initially controversial. When Mendel's theories were integrated with the Boveri–Sutton chromosome theory of inheritance by Thomas Hunt Morgan in 1915, they became the core of classical genetics. Ronald Fisher combined these ideas with the theory of natural selection in his 1930 book The Genetical Theory of Natural Selection, putting evolution onto a mathematical footing and forming the basis for population genetics within the modern evolutionary synthesis.

Dominance (genetics) One gene variant masking the effect of another in the other copy of the gene

In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and the second recessive. This state of having two different variants of the same gene on each chromosome is originally caused by a mutation in one of the genes, either new or inherited. The terms autosomal dominant or autosomal recessive are used to describe gene variants on non-sex chromosomes (autosomes) and their associated traits, while those on sex chromosomes (allosomes) are termed X-linked dominant, X-linked recessive or Y-linked; these have an inheritance and presentation pattern that depends on the sex of both the parent and the child. Since there is only one copy of the Y chromosome, Y-linked traits cannot be dominant nor recessive. Additionally, there are other forms of dominance such as incomplete dominance, in which a gene variant has a partial effect compared to when it is present on both chromosomes, and co-dominance, in which different variants on each chromosome both show their associated traits.

Haemophilia A Medical condition

Haemophilia A is a genetic deficiency in clotting factor VIII, which causes increased bleeding and usually affects males. In the majority of cases it is inherited as an X-linked recessive trait, though there are cases which arise from spontaneous mutations.

A heterozygote advantage describes the case in which the heterozygous genotype has a higher relative fitness than either the homozygous dominant or homozygous recessive genotype. The specific case of heterozygote advantage due to a single locus is known as overdominance. Overdominance is a condition in genetics where the phenotype of the heterozygote lies outside of the phenotypical range of both homozygote parents, and heterozygous individuals have a higher fitness than homozygous individuals.

X-linked recessive inheritance Mode of inheritance

X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males and in females who are homozygous for the gene mutation, see zygosity. Females with one copy of the mutated gene are carriers.

Sex linkage Sex-specific patterns of inheritance and presentation when a gene mutation is present on a sex chromosome

Sex linked describes the sex-specific patterns of inheritance and presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome (autosome). In humans, these are termed X-linked recessive, X-linked dominant and Y-linked. The inheritance and presentation of all three differ depending on the sex of both the parent and the child. This makes them characteristically different from autosomal dominance and recessiveness.

Human genetics Study of inheritance as it occurs in human beings

Human genetics is the study of inheritance as it occurs in human beings. Human genetics encompasses a variety of overlapping fields including: classical genetics, cytogenetics, molecular genetics, biochemical genetics, genomics, population genetics, developmental genetics, clinical genetics, and genetic counseling.

X-linked ichthyosis Medical condition

X-linked ichthyosis is a skin condition caused by the hereditary deficiency of the steroid sulfatase (STS) enzyme that affects 1 in 2000 to 1 in 6000 males. XLI manifests with dry, scaly skin and is due to deletions or mutations in the STS gene. XLI can also occur in the context of larger deletions causing contiguous gene syndromes. Treatment is largely aimed at alleviating the skin symptoms. The term is from the Ancient Greek 'ichthys' meaning 'fish'.

Congenital afibrinogenemia is a rare, genetically inherited blood fibrinogen disorder in which the blood does not clot normally due to the lack of fibrinogen, a blood protein necessary for coagulation. This disorder is autosomal recessive, meaning that two unaffected parents can have a child with the disorder. The lack of fibrinogen expresses itself with excessive and, at times, uncontrollable bleeding.

Chondrodystrophy refers to a skeletal disorder caused by one of myriad genetic mutations that can affect the development of cartilage. As a very general term, it is only used in the medical literature when a more precise description of the condition is unavailable.

Factor VII deficiency Medical condition

Factor VII deficiency is a bleeding disorder characterized by a lack in the production of Factor VII (FVII) (proconvertin), a protein that causes blood to clot in the coagulation cascade. After a trauma factor VII initiates the process of coagulation in conjunction with tissue factor in the extrinsic pathway.

Haemophilia in European royalty Preponderance of a genetic disorder throughout Western European royalty

Haemophilia figured prominently in the history of European royalty in the 19th and 20th centuries. Queen Victoria of the United Kingdom, through two of her five daughters – Princess Alice and Princess Beatrice – passed the mutation to various royal houses across the continent, including the royal families of Spain, Germany, and Russia. Victoria's youngest son, Prince Leopold, Duke of Albany, also suffered from the disease, though none of her three elder sons did. Tests on the remains of the Romanov imperial family show that the specific form of haemophilia passed down by Queen Victoria was probably the relatively rare haemophilia B. The presence of haemophilia B within the European royal families was well-known, with the condition once popularly known as "the royal disease".

X-linked dominant inheritance Mode of inheritance

X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome. As an inheritance pattern, it is less common than the X-linked recessive type. In medicine, X-linked dominant inheritance indicates that a gene responsible for a genetic disorder is located on the X chromosome, and only one copy of the allele is sufficient to cause the disorder when inherited from a parent who has the disorder. In this case, someone who expresses an X-linked dominant allele will exhibit the disorder and be considered affected.

Pseudodominance is the situation in which the inheritance of a recessive trait mimics a dominant pattern.

Hereditary carrier

A hereditary carrier, is a person or other organism that has inherited a recessive allele for a genetic trait or mutation but usually does not display that trait or show symptoms of the disease. Carriers are, however, able to pass the allele onto their offspring, who may then express the genetic trait.

Kufor–Rakeb syndrome Medical condition

Kufor–Rakeb syndrome (KRS) is an autosomal recessive disorder of juvenile onset also known as Parkinson disease-9 (PARK9). It is named after Kufr Rakeb in Irbid, Jordan. Kufor–Rakeb syndrome was first identified in this region in Jordan with a Jordanian couple's 5 children who had rigidity, mask-like face, and bradykinesia. The disease was first described in 1994 by Najim Al-Din et al. The OMIM number is 606693.

References

  1. ↑ "MedlinePlus: Genetics".
  2. ↑ Robin L. Bennett (1999). The practical guide to the genetic family history. Wiley–Liss Ltd. pp.  54. ISBN   0-471-25154-2.
  3. ↑ Jack, Gyda Hlin Skuladottir; Malm-Willadsen, Karolina; Frederiksen, Anja; Glintborg, Dorte; Andersen, Marianne (2013). "Clinical Manifest X-Linked Recessive Adrenoleukodystrophy in a Female". Case Reports in Neurological Medicine. 2013: 491790. doi: 10.1155/2013/491790 . PMC   3705873 . PMID   23864971.
  4. ↑ Bianci, Ilaria; Lleo, Ana; Gershwin, Eric, M.; Invernizzi, Pietro (2012). "The X chromosome and immune associated genes". J Autoimmun. 38 (2–3): J187–J192. doi:10.1016/j.jaut.2011.11.012. PMID   22178198.
  5. ↑ Riggs, A.D. (1975). "X inactivation, differentiation, and DNA methylation". Cytogenet Cell Genet. 14 (1): 9–25. doi:10.1159/000130315. PMID   1093816.
  6. ↑ White, Gilbert, C.; et al. (2001). "Definitions in Hemophilia". Thromb Haemost. 85 (3): 560. doi:10.1055/s-0037-1615621.
  7. ↑ "Heredity of hemophilia". Canadian Hemophilia Society. 11 April 2018. Retrieved 2 April 2021.
  8. ↑ Tissot, Robert. "Autosomal Recessive Inheritance". Human Genetics. UIC. Retrieved 7 December 2015.
  9. 1 2 "Carrier Diagnosis". World Federation of Hemophilia. Retrieved 2 April 2021.
  10. ↑ Peake, I.R.; et al. (1993). "Haemophilia: strategies for carrier detection and prenatal diagnosis". Bull World Health Organ. 71 (3–4): 429–458. PMC   2393505 . PMID   8324863.
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