Phenotype

The phenotype, a term used extensively in the field of genetics since its development in the early 1900s, comprises the characteristics, traits, values, or abnormalities that we observe, measure, test, or evaluate in an individual. As such, the phenotype may include behavioral, biochemical, clinical, molecular, morphological, physical, and physiological characteristics, as well as the presence or absence of disease. In genetics, we think of the phenotype as the outcomes and results that are determined by the interplay between the genotype and environmental factors. It is important to consider that the environment can also include the so-called genetic environment—that is, the genes at other genetic loci whose products might interact with a specified gene or its product during development or during processes later in life.

With respect to genetic disease, the phenotype includes the clinical signs and symptoms of the disease, clinical features that are observed or measured on an individual as the disease progresses, and various disease outcomes such as impairments, disabilities, and quality of life measures. Clinical diagnosis of a genetic disease usually occurs following the initial recognition of the phenotypic manifestations of the disease, which then spurs the physician to request genetic testing for confirmation and specification of the genetic mutation. For example, the muscular dystrophies comprise a group of hereditary diseases characterized by the progressive wasting of skeletal and sometimes cardiac and smooth muscles. The Muscular Dystrophy Association recognizes 9 different muscular dystrophies among 34 other various types of diseases affecting neuromuscular function. The presence of progressive muscle wasting and weakness often suggests the diagnosis of a form of muscular dystrophy. The presence of these symptoms in early childhood further narrows the diagnostic consideration to (1) Duchenne muscular dystrophy (DMD), (2) Becker muscular dystrophy (BMD), (3) one of the various limb-girdle muscular dystrophy (LGMD), or (4) several other less common dystrophies. The presence of progressive weakness with a predominantly limb and trunk distribution with weakness occurring more in the lower versus upper limbs suggests the possibility of either DMD, BMD, or one of the LGMD, at which point genetic testing for mutations in the appropriate genes underlying these disorders may be ordered based on the phenotypic manifestations.

In DMD, genetic mutations in the dystrophin gene lead to incorrect coding for the protein dystrophin with varying degrees of severity. The decreased expression of the fully functioning form of dystrophin leads to a loss of internal muscle structure, leading to slowly progressive muscle weakness and wasting, the clinical phenotype of DMD. The phenotypic expression of a disease may also correlate with the severity of the genetic mutation. This information may enhance or even redefine what we know about disease. DMD and BMD were originally considered to be two separate genetic diseases because of the variation in clinical disease symptom severity and prognosis of death between them. It is now known that DMD and BMD represent a spectrum of the phenotypic expression of differing mutations in the dystrophin gene. DMD (clinically severe, leading to death in the third decade of life) and BMD (milder clinical disease than DMD with significantly improved survival) are now classic examples of how minor variations in genotype may cause major variations in phenotype.

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