Clinical phenotypes

It is important to realize, that diseases such as myocardial infarction or type 2 diabetes represent a heterogeneous group of several distinct subphenotypes definable by clinical or biochemical characteristics. Thus, contradictory findings in pharmacogenomic studies may only not be the consequence of a lack of a major isolated gene effect (of the gene variant studied) and chance findings, but also be caused by the variability in the mix of distinct clinical phenotypes hidden beneath a common characterization such as type 2 diabetes and modulated by differences in the environment between studies. 

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Certain mutant hemoglobins are common in many populations, and a patient may inherit more than one type. Hemoglobin disorders thus present a complex pattern of clinical phenotypes. The use of DNA probes for their diagnosis is considered in Chapter 40. 

Lenders, JWM, Eisenhofer, G, Abeling, NGGM et al. (1996) Specific genetic deficiencies of the A and B isoenzimes of monoamine oxidase are characterized by distinct neurochemical and clinical phenotypes. J. Clin. Invest. 97 1010-1019. 

Low levels or absence of adenosine deaminase (ADA) is associated with one form of severe combined immunodeficiency disease (SCID) characterized by B-andT-lymphocyte dysfunction due to toxic effects of deoxyadenosine (HI9). Most patients present as infants with failure to thrive, repeated infections, severe lymphopenia, and defective cellular and humoral immunity. Disease severity is correlated with the degree of deoxyadenosine nucleotide pool expansion and inactivation of S-adenosylhomocysteine hydrolase in red blood cells. Up to now, more than 40 mutations have been identified (A4, H20, S5, S6). The majority of the basic molecular defects underlying ADA deficiency of all clinical phenotypes are missense mutations. Nonsense mutations, deletions ranging from very large to single nucleotides, and splicing mutations have also been reported. It is likely that severe... 

A4. Arredondo-Vega, F. X., Santisteban, I., Kelly, S., Schlossman, C., Umetsu, D and Hershfield, M. S., Correct splicing despite a G- A mutation at the invariant first nucleotide of a 5 splice site A possible basis for disparate clinical phenotypes in siblings with adenosine deaminase (ADA) deficiency. Am. J. Hum. Genet. 54,820-830 (1994). 

RFLPs are often a reflection of individual genetic diversity and are not related to a clinical phenotype, but occasionally they can be diagnostic of an inherited disease. This technique is relatively new yet, it has been applied to the prenatal detection of sickle cell anemia, thalassemia, phenylketonuria, a,-antitrypsin deficiency, Huntington s chorea, Duchenne muscular dystrophy, hemophilia A and B, cystic fibrosis, and several other, diseases. 

Rapid sequencing and single nucleotide polymorphisms (SNPs) will play a major role in associating sequence variations with heritable clinical phenotypes of drug or xenobiotic response. SNPs occur approximately once every 300-3,000 base pairs if one compares the genomes of two unrelated individuals [13, 14]. Any two individuals thus differ by approximately 1-10 million base pairs, i.e., in < 1% of the approximately 3.2 billion base pairs of the haploid genome (23 chromosomes). 

Advances in genomic technologies such as transcriptional profiling are facilitating the classification of disease at the molecular level. Clinical phenotypes previously... 

Defects of complex IV. These disorders, also termed COX deficiency, have clinical phenotypes that fall into two main groups one in which myopathy is the predominant or exclusive manifestation and another in which brain dysfunction predominates (Fig. 42-3). In the first group, the most common disorder is fatal infantile myopathy, causing generalized weakness, respiratory insufficiency and death before age 1 year. There is lactic acidosis and renal dysfunction, with glycosuria, phosphaturia and aminoaciduria, also termed DeToni-Fanconi-Debre syndrome. The association of myopathy and cardiopathy in the same patient and myopathy and liver disease in the same family has also been described [14]. 

Chen, R. Y., Sham, P., Chen, E. Y., et al. (2001) No association between T102C polymorphism of serotonin-2A receptor gene and clinical phenotypes of Chinese schizophrenic patients. Psychiatry Res. 105, 175-185. 

It is important to point out that deletion of individual genes is not providing animal models for certain behavioral pathologies that are caused by a manifold of minor changes in a series of so-called susceptibility genes. To make a clinical phenotype overt, a number of exogenous factors, e.g., stressful life events and a susceptible genetic endowment, need to interact in at least most of the cases... 

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