†Althoughfull-blownsymptomsrequirebiallelicmutations,heterozygotesforthalassemiaandsicklecellanemiamaypresentwithmildclinicaldisease.Thus,thesedisorderssometimesarecategorizedas“autosomalcodominant”entities.
http://ebooksmedicine.net gene are influenced by other genetic loci, which are called modifier genes. As discussed later in the section on cystic fibrosis these modifier loci can affect the severity or extent of the disease.
• The use of proactive prenatal genetic screening in high-risk populations (e.g., persons of Ashkenazi Jewish descent) has significantly reduced the incidence ( 7.1 ) of certain genetic disorders such as Tay-Sachs disease.
Disorders of Autosomal Dominant Inheritance
Disorders of autosomal dominant inheritance are manifested in the heterozygous state, so at least one parent in an index case usually is affected. Both males and females can be affected, and both sexes can transmit the condition. When an affected person marries an unaffected one, each child has one chance in two of having the disease. The following features also pertain to autosomal dominant diseases:
With any autosomal dominant disorder, some patients do not have affected parents. Such patients owe their disorder to new mutations involving either the egg or the sperm from which they were derived. Their siblings are neither affected nor at increased risk for development of the disease.
Clinical features can be modified by reduced penetrance and variable expressivity. Some persons inherit the mutant gene but are phenotypically normal, a phenomenon referred to as reduced penetrance. The variables that affect penetrance are not clearly understood. In contrast with penetrance, if a trait is consistently associated with a mutant gene but is expressed differently among persons carrying the gene, the phenomenon is called variable expressivity. For example, manifestations of neurofibromatosis 1 range from brownish spots on the skin to multiple tumors and skeletal deformities.
In many conditions, the age at onset is delayed, and symptoms and signs do not appear until adulthood (as in Huntington disease).
In autosomal dominant disorders, a 50% reduction in the normal gene product is associated with clinical signs and symptoms. Because a 50% loss of enzyme activity can be compensated for, involved genes in autosomal dominant disorders usually do not encode enzyme proteins, but instead fall into two other categories of proteins:
Those involved in regulation of complex metabolic pathways, often subject to feedback control (e.g., membrane receptors, transport proteins). An example of this pathogenic mechanism is found in familial hypercholesterolemia, which results from mutation in the low-density lipoprotein (LDL) receptor gene (discussed later).
Key structural proteins, such as collagen and components of the red cell membrane skeleton (e.g., spectrin, abnormalities of which result in hereditary spherocytosis).
The biochemical mechanisms by which a 50% reduction in the levels of such proteins results in an abnormal phenotype are not fully understood. In some cases, especially when the gene encodes one subunit of a multimeric protein, the product of the mutant allele can interfere with the assembly of a functionally normal multimer. For example, the collagen molecule is a trimer in which the three collagen chains are arranged in a helical configuration. The presence of mutated collagen chains reduces the assembly of the remaining normal chains, producing a marked deficiency of collagen. In this instance the mutant allele is called dominant negative, because it impairs the function of a normal allele. This effect is illustrated in some forms of osteogenesis imperfecta (Chapter 21).
Disorders of Autosomal Recessive Inheritance