Heterozygous carriers

A co-dominant is a heritable trait in which both alleles of a polymoiphism are expressed and are reflected in the phenotype. The phenotype of heterozygous carriers is in between the phenotypes of the two homozygous genotypes. 

Enfalt A-C, Lundstrom K, Hansson I, Johansen S and Nystrom P E (1997), Comparison of non-carriers and heterozygous carriers of the RN allele for carcass composition, muscle distribution and technological meat quality in Hampshire-sired pigs , Livest Prod Sci, 47, 221-22. 

Galactose tolerance tests have also been used in attempts to detect heterozygous carriers for galactosemia (D5, H6) this is dealt with in Section 5.3.1. Some heterozygotes are made ill by the galactose load (D3, H3, H16). Galactose tolerance tests have now been replaced, for this purpose, by the more specific and sensitive method of assay of enzyme activity. 

H15. Hansen, P. S., Meinertz, H., Jensen, H. K., Fruergaard, P., Launbjerg, J., Klausen, 1. C., Lemming. L., Gerdes, U., Gregersen, N., and Faergeman-, O., Characteristics of 46 heterozygous carriers and 57 unaffected relatives in five Danish families with familial defective apolipoprotein Bin,. Atheroscler. Thromb. 14, 207-213 (1994). 

Most commonly, a homozygote is produced by the union of two heterozygous (carrier) parents. The recurrence risk for offspring of such matings is 25% (Fig II-1-4). Occasionally, an affected homozygote mates with a heterozygote in this case the recurrence risk for the offrpring is 50%,... 

Figure 11-1-4. Recurrence Risk for the Mating of Two Heterozygous Carriers (Aa) of a Recessive Mutation...

Affected male-homozygous normal female all of the dai teis will be heterozygous carriers all of the sons will be homozygous normal... 

Affected male-heterozygous carrier female on average, half of the sons will be affected and half will be normal on average, half of the daughters will be affected and half will be heterozygous carriers... 

A 25-year-old woman has mild expression of hemophilia A. A genetic diagnosis reveals that she is a heterozygous carrier of a mutation in the X-linked fector VIII gene. What is the most likely explanation for mild expression of the disease in this individual ... 

A 30-year-old man is phenotypically normal, but two of his siblings died from infantile Tay-Sachs disease, an autosomal recessive condition that is lethal by the age of five. What is the risk that this man is a heterozygous carrier of the disease-causing mutation ... 

A man who is affected with hemophilia A (X-linked recessive) mates with a woman who is a heterozygous carrier of this disorder. What proportion of this couple s daughters will... 

X-hnked recessive inheritance (choice E) could explain this pattern because affected males typically produce only heterozygous carrier daughters and unaffected sons (unless they mate with a carrier female). However, affected homozygous females, who will produce affected sons, would produce an affected daughter only if they mated with an affected male. 

Assuming random mating, the Hardy-Weinberg principle specifies a predictable relationship between gene and genotype frequeicies in populations. It can be applied to estimate the frequency of heterozygous carriers of an autosomal recessive mutation. 

The Hardy-Weinberg principle can be applied to estimate the prevalence of heterozygous carriers in populations when we know only the prevalence of the recessive disease. 

For autosomal recessive diseases, such as PKU, the prevalence of heterozygous carriers is much higher than the prevalence of affected homozygotes. In effect, the vast majority of recessive genes are hidden in the heterozygotes. 

As with autosomal recessive traits, the majority of X-linked recessive genes are hidden in female heterozygous carriers (although a considerable number are seen in affected males). 

If the incidence of cystic fibrosis is 1/2,500 among a population of Europeans, what is the predicted incidence of heterozygous carriers of a cystic fibrosis mutation in this population ... 

A man is a known heterozygous carrier of a mutation that causes hemochromatosis (autosomal recessive disease). Suppose that 1% of the general population consists of homozygotes for this mutation. If the man mates with somebody from the general population, what is the probability that he and his mate will produce a child who is an affected homozygote ... 

Answer C. Because the couple shares conunon ancestors (i.e., one set of grandparents), they are more likely to be heterozygous carriers of the same autosomal recessive disease-causing mutations. Thus, their risk of producing a child with an autosomal recessive disease is elevated above that of the general population. 

Answer . The frequency of sickle cell disease is elevated in many African populations because heterozygous carriers of the sickle cell mutation are resistant to malarial infection but do not develop sickle cell disease, which is autosomal recessive. Thus, there is a selective advantage for the mutation in heterozygous carriers, elevating its frequency in the population. 

Individuals with a family history of an autosomal or X-linked recessive disease may wish to know whether they are a heterozygous carrier of the disease. This can be established by genetic diagnosis (e.g., for cystic fibrosis, hemochromatosis, PKU, or albinism). In some specific cases, a population at high risk for a specific disease may be screened for carrier status using genetic diagnosis (e.g., Tay-Sachs disease in the Jewish population [see Clinical Correlate]). 

The most comprehensive analysis of TPMT phenotype versus genotype published to date was conducted by Schaeffeler et al. (140). In their study, RBC TPMT activity and genotype TPMT 2 and 3 alleles) were analyzed in 1214 healthy Caucasian blood donors. Discordant cases between phenotype and genotype were systematically sequenced. The frequencies of the mutant alleles were 4.4% for TPMT 3A, 0.4% for TPMT 3C, and 0.2% for TPMT 2. All seven TPMT-deficient subjects identified by Schaeffeler and colleagues were homozygous or compound heterozygous carriers for these alleles. 

Homozygous mutant and compound heterozygous mutant patients have reduced or absent LPL activity, while heterozygous carriers usually have normal LPL activity. 

Inactivating LPL mutations lead to a > 60% reduction in LPL activity in postheparin plasma from homozygous individuals [49]. Mutations that result in only reduced LPL enzyme activity usually show less reduction in the activity assay, even in homozygous patients [64]. Heterozygous carriers of a mutation have no reduction in LPL activity and show no clinical signs. 

Inactivating HL mutations lead to basically absent HL activity in postheparin plasma from homozygous individuals [81, 82]. Heterozygous carriers of a HL mutation have intermediate HL activity, which is lower than in normal controls. However, this lower HL activity does not translate into changes in lipoprotein metabolism, leaving these patients with similar lipoprotein profiles to normal controls [81, 82]. 

In homozygous FH patients, specific LDL binding to fibroblasts is reduced by more than 90% compared to that for control fibroblasts from normolipidemic individuals. Heterozygous carriers of a FH mutation have significantly reduced LDL binding compared to normolipidemic individuals like unaffected family members. 

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