Autosomal Recessive Inheritance
Autosomal recessive disorders are coded for by genes located on the nonsex chromosomes. In contrast to autosomal dominant inheritance, the heterozygote, who has one abnormal allele and one normal allele, does not differ clinically from a person homozygous for the normal gene. Rather, the person must be homozygous for the abnormal allele for the disease or trait to be expressed. In some cases, the person has two abnormal alleles of a certain gene, but each is abnormal in a different way. Such persons are referred to as compound heterozygotes. As described above for autosomal dominant disease, trinucleotide repeat expansions can also be the type of mutation causing autosomal recessive disease, such as Friedreich's ataxia.
For the disease to be present in the offspring, both parents must have one copy of an abnormal allele, and the risk of disease for each of their offspring, of either sex, is 25%. In autosomal recessive inheritance, the previous generations usually are not affected with the disease. Although the classic description of pedigrees for autosomal recessive inheritance includes two or more affected siblings, with today's small average family size of 2.4 children, it is not unusual for the disease to appear sporadically within the family. One cannot exclude autosomal recessive disease on the basis of a negative family history. In these cases it is sometimes necessary to rely on knowledge of the usual mode of inheritance of the disease. Although some diseases, such as CF, are always inherited in an autosomal recessive pattern, other clinically defined diseases may be inherited in one of several ways. For example, retinitis pigmentosa can be inherited as an autosomal dominant, autosomal recessive, or X-linked recessive disease.
Even the same gene can have different mutations that act in a dominant or recessive fashion. For example, both autosomal dominant and autosomal recessive retinitis pigmentosa can be caused by different mutations in the rhodopsin gene.7 Furthermore, different mutations in the same gene can cause different clinical disorders. For example, mutations in the peripherin/RDS gene can cause autosomal dominant retinitis pigmentosa, as well as several types of macular dystrophy.5
For autosomal recessive diseases, the risk for an affected person to have an affected child is low, unless the disease is very common or the affected person marries a blood relative or a person also afflicted with the same autosomal recessive disease. However, even among couples who meet neither of these criteria, the risk is greater than the general population risk. For example, if one assumes that the carrier frequency of the gene for phenylketonuria (PKU) is 1 in 50 in the general population, the risk for healthy parents without a positive family history is 1/50 × 1/50 × 1/4 = 1/10,000. However, if a man has PKU, the risk for his children is 1 × 1/50 × 1/2 = 1/100. The risk for the affected man's healthy sister to have a child with PKU is 2/3 × 1/50 × 1/4 = 1/300.
There are some unusual mechanisms by which autosomal disease may occur, in which only one parent is a carrier for the gene defect. New mutations may occur, as has been documented at the molecular level. For example, a patient with spinal muscular atrophy type I was shown to be homozygous for the common deletion of exons 7 and 8 of the SMN1 gene. The mother was a carrier of the deletion, but the father was not. Nonpaternity was excluded, and it was concluded that the mutation had arisen by new mutation.52 In another type of situation, uniparental disomy for a chromosomal segment with an autosomal recessive gene defect was shown to cause “homoallelic” disease in a patient with a retinal dystrophy.40 Uniparental disomy refers to the inheritance of both of a pair of chromosomes or chromosomal segments from one parent rather than one from each parent. This can occur by various mechanisms, such as trisomic rescue, in which the zygote starts out with trisomy for a given chromosome, but the extra chromosome is lost early in subsequent cell divisions. Therefore, caution is always warranted in making presumptions about carrier status, particularly if prenatal diagnosis may be involved.