Presymptomatic Testing

Introduction

However, there is limited evidence for Y-linked genes save for determinants that dictate male differentiation. The only characteristic that may be located on the Y chromosome is the attribute of hairy ears, which is not altogether devastating.

Because males have one X chromosome but females have two, there are only two possible genotypes in males and three in females with respect to a mutant allele at an X-linked locus.

A male with a mutant allele at an X-linked locus is “hemizygous” for that allele, whereas females may be “homozygous” for either the wild-type or mutant allele or may be heterozygous.

For example, if X_H is the wild-type allele for the gene for coagulation factor VIII and a mutant allele, X_h, causes hemophilia A, the genotypes expected in males and females would be as follows:

• 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 enzymes 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: (1) those involved in regulation of complex metabolic pathways, (2) key structural proteins, such as collagen and cytoskeletal components of the red cell membrane.

Disorders of autosomal dominant inheritance often involve mutations in genes that regulate complex metabolic pathways or produce structural proteins. Examples of autosomal dominant disorders include Huntington disease Opens in new window (triplet nucleotide repeats), osteogenesis imperfect (mutations in the collagen gene), and familial hypercholesterolemia (mutations in the receptor for very-low-density lipoproteins).

Whenever the gene Opens in new window is present, it is expressed in the phenotype Opens in new window and can be traced through a number of generations. Expression of these genes rarely skips a generation, and a person not affected will not transmit the gene.

Therefore the affected individual will have an affected parent, unless the condition is the result of fresh mutation, which is a common finding in most autosomal dominant conditions. An exception to this is Huntington disease Opens in new window, in which new mutations are extremely rare.

Incidence

The incidence of some autosomal dominant disorders is high, at least in specific geographical areas: for example, 1 in 500 for familial hypercholesterolemia Opens in new window in populations of European or Japanese descent; 1 in 550 for myotonic dystrophy in the Charlevoix and Saguenay-Lac Saint Jean regions in northeaster Quebec; and about 1 in 2500 to 3000 for several conditions, such as Huntington disease Opens in new window in populations of northern European origin, neurofibromatosis, and polycystic kidney disease.

Although many autosomal dominant disorders are individually much less common, they are so numerous in the aggregate that their hereditary nature; when they are transmitted through families, they become problems not only for individuals but also for whole kindreds, often through many generations. In some cases, the burden is compounded by social difficulties resulting from physical or mental disability.

The risk and severity of dominantly inherited disease in the offspring depend on whether one or both parents are affected and whether the trait is strictly dominant or incompletely dominant.

Denoting “D” as the mutant allele and “d” as the normal allele, matings that produce children with an autosomal dominant disease can be between two heterozygotes (“D/d”) for the mutation or, more frequently, between a heterozygote for the mutation (“D/d”) and a homozygote for a normal allele (“d/d”):

Each child of “D/d” by “d/d” mating has a 50% chance of receiving the affected parent’s abnormal allele “D” and a 50% chance of receiving the normal allele “d”.

In the population as a whole, the offspring of “D/d” by “d/d” parents are approximately 50% “D/d” and 50% “d/d”. Of course, each pregnancy is an independent event, not governed by the outcome of previous pregnancies. Thus, within a family, the distribution of affected and unaffected children may be quite different from the theoretical expected ratio of 1:1, especially if the sibship is small.

Typical autosomal dominant inheritance can be seen in the pedigree Opens in new window of a family with a dominantly inherited form of hereditary deafness. In medical practice, homozygotes for dominant phenotypes are not often seen because matings that could produce homozygous offspring are rare.

Again denoting the mutant allele as “D” and the normal allele as “d”, the matings that can produce a “D/D” homozygote might theoretically be “D/d” by “D/d”, “D/D” by “D/d”, or “D/D” by “D/D”, or the patient might, in exceedingly rare instances, have received a new mutation from a genetically unaffected parent.

Practically speaking, however, only the mating of two heterozygotes need be considered because “D/D” homozygotes are very rare and generally too severely affected to reproduce (fitness = 0).

In the case of two heterozygotes matings, 3/4 of the offspring of a “D/d” by “D/d” mating will be affected to some extent and 1/4 unaffected. In theory, the 3/4 affected could all have the same condition if it is a pure dominant, or 1/3 of the affected would be homozygotes and much more severely affected than the “D/d” heterozygotes if it is an incompletely dominant condition.

In fact, as earlier said, no dominant human disorders have been clearly proved to be pure dominants. Even Huntington disease Opens in new window, which is the disorder most frequently claimed to be a pure dominant because the disease is generally similar in the nature and severity of symptoms in heterozygotes and homozygotes, appears to have a somewhat accelerated time course from the onset of disease to death in homozygous individuals compared with heterogygotes.