Genotype and Phenotype
المؤلف:
Cohn, R. D., Scherer, S. W., & Hamosh, A.
المصدر:
Thompson & Thompson Genetics and Genomics in Medicine
الجزء والصفحة:
9th E, P109-110
2025-12-11
65
For autosomal loci (and X-linked loci in females), the genotype of a person at a locus is determined by the alleles occupying that locus on the two homologous chromosomes (Fig. 1). Genotype should not be con fused with haplotype, which refers to the set of alleles at two or more neighboring loci on one of the two homologous chromosomes. More broadly, the term genotype can refer to all the allele pairs that collectively make up an individual’s genetic constitution across the entire genome. Phenotype, as described initially in Chapter 3, is the expression of genotype as a morphologic, clinical, cellular, or biochemical trait, which may be clinically observable or may only be detected by blood or tissue testing. The phenotype can be qualitative – such as the presence or absence of a disease – or can be quantitative, such as measured body mass index or a range of blood glucose levels. A phenotype may, of course, be either nor mal or pathologic in a given individual, but in this book, which emphasizes disorders of medical significance, the focus is on disease phenotypes (i.e., genetic disorders).
Fig1. The concepts of genotype and phenotype. (Left) The genotype refers to information encoded in the genome. Diagram of one pair of homologous chromosomes and two loci on that chromosome, Locus 1 and Locus 2, in an individual who is heterozygous at both loci. They have alleles A and a at locus 1 and alleles B and b at locus 2. The locus 1 genotype is Aa, while the locus 2 genotype is Bb. The two haplotypes on these homologous chromosomes are A-B and a-b. (Right) The phenotype is the physical, clinical, cellular, or biochemical manifestation of the genotype, as illustrated here by morphometric aspects of an individual’s face.
When a person has a pair of identical alleles at a locus encoded in nuclear DNA, they are said to be homozygous, or a homozygote. When the combination of alleles matches to the human reference genome it is referred to as homozygous wild-type. It is important to understand that the reference sequence is merely one possible com bination of alleles and that many allelic variants are not associated with disease.
When two different sets of alleles are present at a locus, a person is heterozygous, or a heterozygote. The term compound heterozygote is used to describe a genotype in which two different variants from a reference sequence are present, rather than one wild-type and one variant allele. These terms (homozygous, heterozygous, and compound heterozygous) can be applied either to a person or to a genotype. In the special case in which an XY male has a variant allele for a gene located on the X chromosome, they are referred to as hemizygous. Mitochondrial DNA is still another special case. In contrast to the two copies of each gene per cell, mitochondrial DNA molecules are typically present in hundreds or thousands of copies per cell. For this reason, the terms homozygous, heterozygous, and hemizygous are not used to describe genotypes at mitochondrial loci.
A single-gene disorder is one that is determined primarily by the alleles at a single locus. The known single-gene diseases are maintained in Online Mendelian Inheritance in Man (OMIM; https://omim.org), an indispensable resource for medical geneticists created by the late Victor A. McKusick. Most of these diseases follow one of the classic inheritance patterns in families (autosomal recessive, autosomal dominant, X linked) and are therefore referred to as mendelian because, like the characteristics of the garden peas Gregor Mendel studied, they occur on average in fixed and predictable proportions among the offspring of specific types of matings. OMIM additionally catalogues mitochondrial disorders, defects due to imprinting, and disorders where the genetic basis is not yet known, as well as genes of known function.
Pathogenic sequence variants in a single gene may produce diverse phenotypic effects in multiple organ systems, with a variety of signs and symptoms occur ring at different points during the life span. To cite just one example, individuals with a pathogenic variant in the VHL gene can have hemangioblastomas of the brain, spinal cord, and retina; renal cysts; pancreatic cysts; renal cell carcinoma; pheochromocytoma; endo lymphatic tumors of the inner ear; as well as tumors of the epididymis in males or of the broad ligament of the uterus in females. All of these disease manifestations stem from the same single variant. Under these circumstances, the disorder is said to exhibit pleiotropy (from Greek pleion and tropos, “more turns”), and the expression of the gene defect is said to be pleiotropic. Many pleiotropic effects are due to differences in the role of a gene in distinct cell types. With the example of VHL, the impact of pathogenic variants in VHL is cell type specific because the loss of cell cycle regulation gives rise to characteristic problems in specific cell types.
Single-gene disorders affect children disproportion ately but not exclusively. Serious single-gene disorders affect 1 in 300 neonates and are responsible for an estimated 16% of pediatric hospitalizations. Although less than 10% of single-gene disorders manifest after puberty, and only 1% occur after the end of the reproductive period, mendelian disorders are nonetheless important to consider in adult medicine. There are hundreds of mendelian disorders whose phenotypes include common adult illnesses such as heart disease, stroke, cancer, and diabetes. Although mendelian disorders are by no means the major contributory factor in causing these common diseases in the population at large, they are important in individual patients because of their significance for the health of other family members and because of the availability of genetic testing and detailed management options for many of them.
Penetrance and Expressivity
For some genetic conditions, a disease-causing genotype is always fully expressed at birth as an abnormal phenotype. Clinical experience, however, teaches that other disorders are not expressed at all or may vary substantially in their signs and symptoms, clinical severity, or age of onset, even among members of a family who all share the same disease-causing genotype. Geneticists use distinct terms to describe such differences in clinical expression.
Penetrance is the probability that an allele or alleles will have any phenotypic expression at all. When the frequency of expression of a phenotype is less than 100% – that is, when some of those who have the relevant genotype completely fail to express it – the disorder is said to show reduced or incomplete penetrance. Penetrance is all or nothing. It is the percentage of people at any given age with a predisposing genotype who are affected, regard less of the severity.
Penetrance of some disorders is age dependent – that is, it may occur any time, from early in intrauterine development all the way to the postreproductive years. Some disorders are lethal prenatally, whereas others can be recognized prenatally (e.g., by ultrasonography) but are consistent with a live born infant; still others may be recognized only at birth (congenital). Other disorders have their onset typically or exclusively in childhood or in adulthood. It is even possible that two individuals in the same family with the same disease causing genotype may develop the disease at very different ages.
In contrast to penetrance, expressivity refers not to the presence or absence of a phenotype but to the severity of expression of that phenotype among individuals with the same disease-causing genotype. When the severity of disease differs in people who have the same genotype, the phenotype is said to show variable expressivity. Even in the same family, two individuals carrying the same pathogenic variants may have some signs and symptoms in common, whereas their other disease manifestations may be quite different, depending on which tissues or organs happen to be affected. The challenge to the clinician caring for these families is to not miss very subtle signs of a disorder in a family member and, as a result, either mis take mild expressivity for lack of penetrance or infer that the individual does not have the disease-causing genotype.
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