Basic Principles of Genetics

Introduction

The completion of the human genome sequence, with an estimated size of 3.2 gigabases (Gb) and containing ~20 000–25 000 genes , represents a powerful tool in medicine that facilitates the identification of disease-associated genes. Detailed information on human sequence variation and advanced technologies for its detection have broadened our knowledge of the genetic basis of human disease. The pathogenesis of many disorders also involves epigenetics, which represent heritable changes in phenotype and/or gene expression that do not result from changes in the DNA sequence.

Rapid advances in the development of molecular biology techniques (see Ch. 3 ), together with information-based tools derived from the sequencing of the human genome, provides the physician with direct access to clinically relevant genetic information. Consequently, it is important for physicians in general, and dermatologists in particular, to understand basic concepts of genetics ( Table 54.1 ). Familiarity with new technology and approaches to identifying disease-causing genes is essential in order to appropriately utilize and interpret the results of genetic studies in the patient care setting. The wealth of new information emphasizes the need to bridge the gap between the bench and the bedside, bringing together efforts from both the clinical and research arms of dermatology.

Access to patients with genetic disorders and accurate clinical descriptions are essential for investigations aimed at the identification of disease-causing genes. Combined with functional studies and translational approaches, these findings can in turn provide benefits to affected individuals. Such insights have importance in genetic counseling and prenatal diagnosis, and they can also contribute to the identification of at-risk individuals/families, prediction of disease course and possible complications, determination of response to therapeutic interventions, and even the development of targeted treatments.

Since the early 1980s, the molecular bases of numerous cutaneous genetic disorders have been elucidated, including multiple forms of epidermolysis bullosa (EB; see Ch. 32 ), ectodermal dysplasia (ED; see Ch. 63 ), ichthyosis (see Ch. 57 ), and hypotrichosis (see Chs 68 & 69). The gene-identification strategies employed for these relatively uncommon Mendelian (single-gene) disorders have provided a foundation for the study of common complex disorders such as atopic dermatitis, psoriasis, and alopecia areata. Advances in mapping and detecting human sequence variation have led to more sophisticated approaches, including genome-wide association studies (GWAS) and whole-exome sequencing. Functional genomic studies, e.g. comparison of the transcriptome (expressed genes) in samples from patients and unaffected individuals, have also helped to identify candidate genes for further investigation. The clinician plays a key role in enabling such research, which requires a well-characterized collection of patient samples.

Mendelian Patterns of Inheritance

A key initial step in the assessment of the risk for a particular inherited disease is determination of its mode of inheritance. For this purpose, it is essential to collect accurate information on the clinical phenotype and to examine as many family members as possible to classify their status – affected or unaffected. The family is usually ascertained through one family member, the proband , around whom the pedigree is built with information on the phenotypes and relationships between different individuals.

Even when a single-gene defect is enough to cause a disease phenotype (monogenic disorders), the clinical expression can be affected by variable expression and even incomplete penetrance (see below). Genes are expressed on a particular genetic background, which is different in every individual, and genes and their products interact with other genes and proteins. One can therefore expect that monogenic disorders will show some degree of variability.

Allelic heterogeneity refers to mildly or even considerably different clinical entities due to different mutations in the same gene ( Table 54.2 ). In contrast, locus (genetic) heterogeneity refers to mutations in different genes that result in the same phenotype ( Table 54.3 ). Of note, there are some diseases, such as EB simplex, that display both allelic and locus heterogeneity. Thus, diagnosis based purely on either clinical signs/symptoms or the results of genetic testing can lead to misclassification, underscoring the importance of integrating clinical and molecular findings.

Once a phenotype and its range of clinical findings are defined, the trait can be followed within a pedigree. The transmission of the trait in the pedigree defines the pattern of inheritance of the disease. The genes responsible for monogenic traits can be located either on autosomes, resulting in an autosomal pattern of inheritance, or on the X chromosome in the case of an X-linked pattern of inheritance. Irrespective of the gene location, when a mutation in one of two alleles is sufficient to produce the phenotype, the trait is considered dominant . In contrast, when both alleles of a gene (or one allele in hemizygotes) must be altered in order to produce the phenotype, the condition is considered recessive . Hence, Mendelian inheritance patterns include autosomal dominant, autosomal recessive, X-linked dominant, and X-linked recessive ( Table 54.4 ). There are also Y-linked genes that primarily affect male fertility , although their relevance in more general diseases is possible.

This chapter focuses on genodermatoses, but the explanations of Mendelian and complex traits also apply to extracutaneous diseases.

Autosomal Dominant Inheritance

In a pedigree of an autosomal dominant disease, each affected person other than the first affected family member, who has a de novo mutation, has an affected parent. Both sexes are equally affected and can transmit the trait, and there is vertical transmission from generation to generation ( Fig. 54.1A ) . Since a single mutant allele is enough to produce the phenotype, each offspring of an affected individual has a 50% risk of inheriting the mutant allele and therefore the disorder. Examples of autosomal dominant genodermatoses include EB simplex, Darier and Hailey–Hailey diseases, and nail–patella syndrome.

A patient with an autosomal dominant disease is usually heterozygous for the disease-causing mutation. Homozygosity for autosomal dominant traits occasionally occurs, and this usually results in a more severe phenotype. For example, a mutation in the keratin 14 gene ( KRT14 ) may give rise to localized EB simplex when heterozygous but generalized EB simplex when homozygous . Exceptions to the expected autosomal dominant inheritance pattern may also be due to incomplete penetrance or variable expression (see below).

Dominant mutations can give rise to a phenotype by: (1) haploinsufficiency, in which the protein produced from one wild-type (non-mutant) allele is not sufficient to sustain normal function; or (2) a dominant negative effect , where the mutated proteins physically interfere with wild-type proteins and prevent them from functioning properly. The latter mechanism often occurs when the mutated protein forms dimers or polymers; examples include keratins (e.g. KRT14 in EB simplex) and tyrosine kinase receptors (e.g. KIT in piebaldism).