81 The Genetic Revolution
John H. Greinwald Jr.
Genetic analysis of human disease has moved from the laboratory to the outpatient clinic, yet it can be confounding to the clinician unfamiliar with this field. This chapter presents a genetic review, followed by the current state of genetic analysis of pediatric sensorineural hearing loss—one of the prime examples of clinical genetics in otolaryngology.
Genetic Overview
Human genes are molecular codes for inherited factors. Genes are arranged linearly on 23 pairs (ie, 46) of chromosomes. These chromosomes consist of 22 pairs of autosomes and one pair of sex chromosomes. Males have an X and a Y pair of sex chromosomes, whereas females have two X chromosomes. The location of a gene on a chromosome is termed a locus. Each chromosome pair carries a distinctive set of gene loci, and on any given gene, the genetic codes may differ (alleles). The genetic code for a specific trait (genotype) consists of either two identical alleles (homozygous) or two disparate alleles (heterozygous). The physical manifestation of a trait, referred to as the phenotype, is determined by which alleles are present and how they interact. An allele is considered dominant if its presence results in a specific phenotype. It is considered autosomal recessive if both alleles are required for the expression of its phenotype. An X-linked recessive gene is present in only one allele (hemizygous) in males because the Y chromosome generally does not carry an allele complementary to the X chromosome. There may be several different types of base pair changes. A truncating mutation causes premature cessation of protein formation and may be either a nonsense or a splice site mutation. A missense mutation allows the protein to be produced, though an altered amino acid code is present.
Dominant traits are transmitted from one generation to another. There is a 50% chance that an affected heterozygous individual will transmit an abnormal gene to offspring. Penetrance is the ability of a gene to manifest any of the phenotypic characteristics related to that gene. In a family with a dominant condition, not all persons carrying the affected gene display the disease phenotype. This occurrence is called incomplete penetrance. Dominant disorders can also have variable expressivity, whereby family members present with different manifestations of the affected gene. It is thus presumed that environmental influences or interaction with other genes can modify phenotypic expression.
In the absence of consanguinity, an autosomal recessive trait is usually seen in offspring in small nuclear families. The offspring of heterozygous (ie, carrier) parents have a 25% risk of being affected. Being heterozygous for two different genes (double heterozygous) may cause hearing loss. An X-linked recessive trait can lack phenotypic expression if it is carried by a heterozygous female, but male offspring of this female would have a 50% chance of inheriting the gene.
Also, heritable disorders that are caused by abnormalities at the chromosomal level and involve extra or absent chromosomal material are characterized by developmental delays and various congenital anomalies.
Disparate genotypes can produce a similar phenotype. This phenomenon, referred to as genetic heterogeneity, often makes it difficult to identify causative genes. In patients with nonsyndromic hearing loss, gene identification is difficult because there is a high degree of heterogeneity and an absence of obvious phenotypic traits. By contrast, patients with syndromic hearing loss have definable traits that assist in gene identification.
Gene Structure
Each gene generally consists of (1) exons, which are DNA that codes for the actual protein; (2) introns, which are areas interspersed between exons; (3) splice sites, which are DNA at the exon–intron junction; and (4) untranslated regulatory regions, which are DNA that is upstream and downstream of the first and last exons, respectively.
