Patterns of Mendelian Inheritance

The wild-type allele is denoted by uppercase R, a mutant allele by lowercase r.

As seen in the table, when both parents of an affected person are carriers, their children’s risk for receiving a recessive allele is 50% from each parent. The chance of inheriting two recessive alleles and therefore being affected is thus image × image or 1 in 4 with each pregnancy. The 25% chance for two heterozygotes to have a child with an autosomal recessive disorder is independent of how many previous children there are who are either affected or unaffected. The proband may be the only affected family member, but if any others are affected, they are usually in the same sibship and not elsewhere in the kindred (Fig. 7-4).


Figure 7-4 Typical pedigree showing autosomal recessive inheritance.

Sex-Influenced Autosomal Recessive Disorders

Gene Frequency and Carrier Frequency

The most common autosomal recessive disorder in white children is cystic fibrosis (CF) (Case 12), caused by mutations in the CFTR gene (see Chapter 12). Among white populations, approximately 1 child in 2000 has two mutant CFTR alleles and has the disease, from which we can infer that 1 in 23 individuals is a silent carrier who has no disease. (How one calculates heterozygote frequencies in autosomal recessive conditions will be addressed in Chapter 9.) Mutant alleles may be handed down from carrier to carrier for numerous generations without ever appearing in the homozygous state and causing overt disease. The presence of such hidden recessive genes is not revealed unless the carrier happens to mate with someone who also carries a mutant allele at the same locus and the two deleterious alleles are both inherited by a child.

Estimates of the number of deleterious alleles in each of our genomes range from 50 to 200 based on examining an individual’s complete exome or genome sequence for clearly deleterious mutations in the coding regions of the genome (see Chapter 4). This estimate is imprecise, however. It may be an underestimate, because it does not include mutant alleles whose deleterious effect is not obvious from a simple examination of the DNA sequence. It may also, however, be an overestimate, because it includes mutations in many genes that are not known to cause disease.



Figure 7-5 Pedigree in which parental consanguinity suggests autosomal recessive inheritance. Arrow indicates the proband.

Consanguinity is more frequently found in the background of patients with very rare conditions than in those with more common recessive conditions. This is because it is less likely that two individuals mating at random in the population will both be carriers of a very rare disorder by chance alone than it is that they would both be carriers because they inherited the same mutant allele from a single common ancestor. For example, in xeroderma pigmentosum (Case 48), a very rare autosomal recessive condition of DNA repair (see Chapter 15), more than 20% of cases occur among the offspring of marriages between first cousins. In contrast, in more common recessive conditions, most cases of the disorder result from matings between unrelated persons, each of whom happens by chance to be a carrier. Thus most affected persons with a relatively common disorder, such as CF, are not the result of consanguinity, because the mutant allele is so common in the general population. How consanguinity is measured for different matings is described in Chapter 9.

The genetic risk to the offspring of marriages between related people is not as great as is sometimes imagined. For marriages between first cousins, the absolute risks of abnormal offspring, including not only known autosomal recessive diseases but also stillbirth, neonatal death, and congenital malformation, is 3% to 5%, approximately double the overall background risk of 2% to 3% for offspring born to any unrelated couple (see Chapter 16). Consanguinity at the level of third cousins or more remote relationships is not considered to be genetically significant, and the increased risk for abnormal offspring is negligible in such cases.

The incidence of first-cousin marriage is low (≈1 to 10 per 1000 marriages) in many populations in Western societies today. However, it remains relatively common in some ethnic groups, for example, in families from rural areas of the Indian subcontinent, in other parts of Asia, and in the Middle East, where between 20% and 60% of all marriages are between cousins.


Characteristics of Autosomal Recessive Inheritance

An autosomal recessive phenotype, if not isolated, is typically seen only in the sibship of the proband, and not in parents, offspring, or other relatives.

For most autosomal recessive diseases, males and females are equally likely to be affected.

Parents of an affected child are asymptomatic carriers of mutant alleles.

The parents of the affected person may in some cases be consanguineous. This is especially likely if the gene responsible for the condition is rare in the population.

The recurrence risk for each sib of the proband is 1 in 4 (25%).

Autosomal Dominant Inheritance

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 a pure dominant or is incompletely dominant. There are a number of different ways that one mutant allele can cause a dominantly inherited trait to occur in a heterozygote despite the presence of a normal allele. Disease mechanisms in various dominant conditions are discussed in Chapter 12.

Denoting D as the mutant allele and d as the wild-type 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).

Autosomal Dominant Inheritance


The mutant allele causing dominantly inherited disease is denoted by uppercase D; the normal or wild-type allele is denoted by lowercase d.

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Nov 27, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Patterns of Mendelian Inheritance

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