Myopia (nearsightedness) and Phenylketonuria (pronouced fee-nill-key-toe-NURR-ee
ID: 97489 • Letter: M
Question
Myopia (nearsightedness) and Phenylketonuria (pronouced fee-nill-key-toe-NURR-ee-uh) or PKU is an inherited disorder of metabolism that can cause intellectual and developmental disabilities (IDDS) if not treated. Both are inherited as recessive traits occuring on separate chromosome pairs. A man who is normal phenotypically, but a carrier for both traits marries a woman with an identical genotype with respect to these traits. What is the chance that their first child will be myopic? what is the chance that a child will have PKU? what is the chance that a child will inherit both myopia and PKU simultaneously? What is the likelihood that a child will have neither PKU nor myopia?
Explanation / Answer
In single gene disorders (as opposed to multifactorial-complex disorders), the mutation's population frequency is low, its penetrance is high, and the contribution of environment is lower with notable exceptions of PKU and few others. Genetic counseling is important for personal-decision making involving reproductive issues. In assigning the inheritance pattern of a genetic disease, important features of pedigrees to consider are: sex ratio in affected individuals, male-to-male transmission, mother-to-son transmission (XLR) - mother-to-son/daughter transmission (mtDNA); proportion of offspring (proportion of siblings) affected and consanguinity. Situations that can confound the interpretation include: quasi-dominant inheritance (a homozygote and heterozygote (carrier) mating for a recessive disease); autosomal dominant sex-limited inheritance, de novo mutations (including new mutation on the second X-chromosome in a woman carrier for a X-chromosome mutation), phenocopy, skewed X-chromosome inactivation (atypical Lyonisation.
Every patient has an affected parent; the risk of transmission of the disease to the offspring is 50%; no sex preference; two affected parents may have a healthy child (25% chance); homozygotes may have a more severe disease or may not exist (due to early, including embryonic, lethality, as in acute intermittent porphyria); normally there is no generation skipping resulting in a vertical pattern in the pedigree. If both parents appear to be normal for an AD disease but the offspring has it, the possibilities are as follows: biologic parents are different; incomplete penetrance in (affected) parent; phenocopy (the disorder is not genetically determined but mimicking one) or genocopy (having a phenotype caused by an AD disease but caused by a different genetic mechanism); de novo mutation; gonadal mosaicism for the disease mutation in one parent. Uniparental disomy (UPD) is the presence of a pair of chromosomes originated from the same parent. The first step is usually the formation of a trisomy and then the loss of a chromosome (due to postzygotic nondisjunction) but gametic complementation (fusion of a gamete with two copies of the same chromosome with a gamete with none of the same chromosome) is also possible.
The end result may be a homozygote child from a carrier parent. One particular UPD results in an interesting situation: Maternal UPD for chromosome 15 (15q11-q13) will result in Prader-Willi syndrome, while paternal UPD for the same chromosome will cause Angelman syndrome. UPD does not have to occur for the whole chromosome. Due to chromosomal rearrangements, UPD can occur for a portion of the chromosome. This pattern applies to complex diseases (like diabetes, hypertension, schizophrenia, cancer) where multiple genes and environmental factors play a role in the development of the disease. It has been best worked out in pyloric stenosis and orofacial cleft syndrome. These disorders are presumed to result from additive effects of multiple susceptibility genes with low penetrance. Individual mutations may not have any particular phenotype, but when act in concert and in the presence of the necessary environmental conditions, they may produce a disease phenotype. Under a model of multiple interacting loci, no single locus could account for more than a 5-fold increase in the risk of first-degree relatives. The disease shows increased incidence in families but with no recognizable inheritance pattern. The features of multifactorial inheritance are:
- The more severe the condition, the greater the risk to sibs,
- Carter effect: the sibs or offspring of a patient in less commonly affected sex have higher susceptibility to the disease,
- If it is a rare disease, the frequency of the disease among relatives is higher,
- If more than one individual in a family is affected, recurrence risk is higher,
- The risk falls rapidly as one passes from 1st to 2nd degree relatives.
There are two models proposed to explain multifactorial inheritance: multifactorial threshold model (a combined effect of multiple genes interacting with environmental factors; i.e. several or many genes, each of small effect, combine additively with the effects of non-inherited factors) and mixed model (a multifactorial liability with the involvement of a major gene). Multifactorial threshold model is based on a discontinued binary distribution for a quantitative trait meaning that the diseases are present or not in an individual but their inheritance is as if they were quantitative characters. This is due to a threshold effect that makes them appear as discontinued. For many diseases, there are at least two thresholds -differing by sex or causing different severity.
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