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2: Genetic Disease

Gregory Barsh, MD, PhD

Introduction

Mechanisms of cellular and tissue dysfunction in genetic diseases are as varied as the organs they affect. To some extent, these mechanisms are similar to those that occur in nonheritable disorders. For example, a fracture resulting from decreased bone density in osteoporosis heals in much the same way as one caused by a defective collagen gene in osteogenesis imperfecta, and the response to coronary atherosclerosis in most individuals does not depend on whether they have inherited a defective low-density lipoprotein (LDL) receptor. Thus, the pathophysiologic principles that distinguish genetic disease focus not so much on the affected organ system as on the mechanisms of mutation, inheritance, and molecular pathways from genotype to phenotype.

This chapter begins with a discussion of the terminology used to describe inherited conditions, the prevalence of genetic disease, and some major principles and considerations in medical genetics. Important terms and key words used throughout the chapter are defined in Table 2–1.

Table 2–1Glossary of terms and keywords.
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Table 2–1 Glossary of terms and keywords.
Term Definition
Acrocentric Refers to the terminal location of the centromere on chromosomes 13, 14, 15, 21, and 22.
Allelic heterogeneity The situation in which multiple alleles at a single locus can produce one or more disease phenotypes.
Amorphic Refers to mutations that cause a complete loss of function for the respective gene, and therefore yield the same phenotype as a complete gene deletion.
Aneuploidy A general term used to denote any unbalanced chromosome complement.
Antimorphic Refers to mutations that when present in heterozygous form opposite a nonmutant allele will result in a phenotype similar to homozygosity for loss-of-function alleles.
Ascertainment bias The situation in which individuals or families in a genetic study are not representative of the general population because of the way in which they are identified.
Autosomal Located on chromosomes 1–22 rather than X or Y.
CpG island A segment of DNA that contains a relatively high density of 5′- CG-3′ dinucleotides. Such segments are frequently unmethylated and located close to ubiquitously expressed genes.
Dictyotene The end of prophase during female meiosis I in which fetal oocytes are arrested prior to ovulation.
Dominant A pattern of inheritance or mechanism of gene action in which the effects of a variant allele can be observed in the presence of a nonmutant allele.
Dominant negative A type of pathophysiologic mechanism that occurs when a mutant allele interferes with the normal function of the nonmutant gene product.
Dosage compensation Mechanism by which a difference in gene dosage between two cells is equalized. For XX cells in mammals, decreased expression from one of the two X chromosomes results in a concentration of gene product similar to an XY cell.
End-product deficiency A pathologic mechanism in which absence or reduction in the product of a particular enzymatic reaction leads to disease.
Epigenetic Refers to a phenotypic effect that is ...

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