Which hematologic disorder is transferred genetically from parents to offspring?

Autosomal Dominant Disorders

AD disorders are those in which a patient manifests clinical symptoms when only a single copy of the mutant gene is present (i.e., the patient is heterozygous for the mutation). Inheritance of AD disorders follows several general principles (Figure 1-7, A):

Each affected person has an affected parent.

Affected persons, on average, have equal numbers of affected and unaffected children.

Normal children of affected parents have only unaffected children.

Males and females are affected in equal proportions.

Each sex is equally likely to transmit the disorder to male and female children.

Vertical transmission of the disorder occurs through successive generations.

These general rules of AD inheritance are based on the assumption, not always valid, that no new mutations occur. In fact, in some disorders the incidence of new mutations is quite high. For example, up to 50% of the cases of neurofibromatosis result from new mutations.

Dominant mutations occur in two settings: (1) a 50% reduction in the level of functional protein leads to a clinical phenotype—a phenomenon known as haploinsufficiency, or (2) a mutation leads to a gain of function that causes disease. Three classes of proteins are frequently involved: (1) proteins that regulate complex metabolic pathways, such as membrane receptors and rate-limiting enzymes in pathways under feedback control; (2) structural proteins; and (3) proteins with alterations that cause a dominant negative function—that is, in which the mutant protein interferes with the function of the protein expressed from the normal allele. Examples of AD disorders are familial hypercholesterolemia, which is caused by mutations in the low-density lipoprotein receptor; osteogenesis imperfecta, caused by mutations in some members of the collagen gene family; and Huntington disease, caused by a triplet repeat expansion in the Huntington gene.

A characteristic of many AD disorders is incomplete penetrance, whereby not all persons carrying the relevant gene(s) exhibit a specific trait. A particular gene defect can therefore manifest with widely variable severity. For example, tuberous sclerosis, one of the neurocutaneous disorders, can be clinically silent. Some persons are diagnosed with this disorder only when they have multiple affected children. At that point, careful examination may reveal subtle evidence of tuberous sclerosis, such as a minor abnormality on a computed tomography scan of the head. Similar observations have been made for many different dominant diseases. Incomplete penetrance is a manifestation of the interaction of other gene products with the product of the disease gene. Increasingly, this phenomenon is being recognized as a step in the continuum between simple completely penetrant monogenic disorders and so-called complex disorders in which no single-gene mutation is sufficient to cause disease.

The phenomenon of germline mosaicism is a complicating factor in incomplete penetrance. Germline mosaicism occurs when a mutation is present in some of the germ cells but not in most other cells. The affected person is completely healthy but is at risk for having multiple affected children. Germline mosaicism is fairly common in Duchenne muscular dystrophy and occurs in other disorders as well.

Autosomal Dominant Inheritance

Autosomal dominant disorders occur when only one defective copy of an autosomal gene is required to cause disease. As a result, affected individuals have one normal and one mutated allele. Autosomal dominant disorders can therefore be inherited from one affected parent who also has one defective copy of the gene, or can occur sporadically as a result of a new mutation in a patient with no family history (Figure 3.1C). At least three different molecular mechanisms that can result in either full or partial disease penetrance have been proposed in autosomal dominant disorders:

Haploinsufficiency may occur if mutation of a single copy of a gene results in expression of only half the normal amount of functional protein and this is insufficient to allow normal physiologic function of the cell (see Figure 3.2A, and below, for further details).

Gain-of-function may occur as a result of mutations in particular proteins that either increase their activity or lengthen their functional lifespan, thus increasing their effect in the cell (see Figure 3.2A, and below, for further details).

A dominant negative effect may occur as a result of mutations that abrogate the activity of proteins that multimerize either with themselves or with other binding partners. In this case, the mutant protein affects the activity of every protein complex that it is integrated into, thus causing more than a 50% decrease in that protein’s activity. For example, if a protein dimerizes, only one-fourth of the dimers would be expected to contain two normal protein subunits; thus the percentage of functional protein complexes would be only 25% (see Figure 3.2A, B and below for further details).

Autosomal Dominant Disorders.

In autosomal dominant disorders, only one allele of a mutated gene is necessary for disease. This allele may come from the sire or from the dam; thus, if one parent carries even one mutated allele (heterozygous), each offspring has a 50% chance of inheriting the mutation. Examples of autosomal dominant disorders in animals include polycystic kidney disease (see Fig. 11-26, F), osteogenesis imperfecta (see Chapter 16), and chondrodysplasia (see Fig. 16-39). In autosomal dominant disorders, most mutations lead to reduced production of a protein or give rise to an inactive protein. The clinical effect of these loss-of-function mutations depends on the activity of the protein affected. If such mutations involve an enzyme, heterozygotes may be clinically normal because the normal allele can compensate for up to a 50% loss of enzymatic activity. In contrast, autosomal dominant disorders have serious effects on structural proteins, such as collagen or spectrin, even in heterozygotes with one normal allele. A 50% reduction in the amount of such proteins results in abnormal structure and assembly of collagen, and a spectrin deficiency causes osmotic fragility of erythrocytes and hereditary spherocytosis in golden retriever dogs.

Less common than loss-of-function mutations are gain-of-function mutations. In this type of mutation, the gene product acquires new biologic activities not usually associated with the normal-type protein.

Autosomal Dominant

Autosomal dominant disorders are the most prevalent Mendelian cardiovascular genetic disorders (Figure 8-1A). Examples of autosomal dominant cardiovascular disorders include hypertrophic cardiomyopathy (HCM), Marfan's syndrome (MFS), hereditary long QT syndrome (LQTS), and familial hypercholesterolemia. Any child of an affected individual has a 50% chance of being affected by the inherited disease. Because the disease gene is autosomal (i.e., not on a sex chromosome), dominant disorders occur without gender preference and with male-to-male transmission. Because only one disease allele is required for the phenotype to manifest, the disease is seen in every generation. There are exceptions to both these rules often resulting from the impact of interactions with other modifying genes. For instance, disease genes that are responsive to hormone levels may result in differences in male versus female disease manifestations, which is one form of so-called variable expressivity. In some cases, skip generations occur, that is, individuals who do not exhibit any disease manifestations but still transmit the disease to offspring and thus must carry a disease allele. This phenomenon is termed incomplete or reduced penetrance. Unaffected individuals do not carry the defective allele and do not transmit the disease to their offspring. Common examples of cardiovascular diseases that are transmitted in an autosomal dominant manner are listed in Table 8-1.

Autosomal inheritance

A trait that is determined by a gene on an autosome may be dominant or recessive. Heterozygotes are individuals with different alleles at the corresponding locus on the pair of homologous chromosomes. Homozygotes have the same allele. As such, autosomal dominant refers to the situation where a monogenetic disorder manifests clinically in the heterozygous state, and inheritance is usually from one parent only. Autosomal recessive traits refer to disorders that, while they can affect both sexes, require both abnormal genes for the disease to be clinically expressed.

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250 What is familial hypercholesterolemia (FH)?

An autosomal dominant disorder due to a mutation in the LDL receptor (causing a deficient or defective receptor) that leads to altered LDL catabolism and increased cholesterol synthesis. Approximately 1/500 people are heterozygous carriers of a mutation and 1/1,000,000 are homozygous for the disorder. Such people have higher rates of premature atherosclerosis and can have myocardial infarctions at a very young age. Physical examination often reveals tendinous xanthomas (cholesterol deposition in the extensor tendons) and corneal arcus. Management is aimed at aggressive LDL-lowering to reduce cardiovascular risk.

d ABri/ADan-Type CAA

An autosomal-dominant disorder in a British family showing progressive spastic paralysis, dementia, and ataxia was neuropathologically characterized by severe CAA, nonneuritic and perivascular plaques, NFTs, and ischemic leukoencephalopathy95 and was designated familial British dementia (FBD). A novel 4 K protein subunit named ABri was identified from isolated amyloid fibrils.96 The ABri is a fragment of a putative type-II single-spanning transmembrane precursor that is encoded by a novel gene, BRI2, located on chromosome 13. A stop codon mutation of this gene generates a longer open reading frame, resulting in a larger, 277-residue precursor, and the release of the 34 C-terminal amino acids from the mutated precursor generates the ABri amyloid subunits.96

Familial Danish dementia (FDD) is an autosomal-dominant disorder characterized clinically by cataracts, deafness, progressive ataxia, and dementia, and pathologically by severe CAA, hippocampal plaques, and NFTs. FDD is associated with a decamer duplication in the 3′region of the BRI2, which abolishes the normal stop codon, resulting in an extended precursor protein and the release of an amyloidogenic fragment, ADan.97

Pyogenic Sterile Arthritis, Pyoderma Gangrenosum, Acne (PAPA) Syndrome

This autosomal dominant disorder is characterized by pyoderma-gangrenosum-like ulcerative lesions, usually in the second decade of life, severe cystic acne, and episodes of inflammatory arthritis that lead to significant joint destruction.210 The pyoderma gangrenosum lesions are usually seen on the leg, and sterile abscesses have been described at sites of parenteral injections. Affected family members may show some features of the disorder, but not others. Mutations occur in PSTPIP1/CD2BP1, which encodes a protein that interacts with pyrin.211 PAPA syndrome is treated with oral corticosteroids, and marked improvement has been noted with TNF inhibitors and anti-IL-1 treatment.171

Branchio-oto-renal Syndrome

The autosomal dominant disorder known as branchio-oto-renal (BOR) syndrome comprises conductive and sensorineural deafness, branchial fistulas, and renal anomalies that include duplication of the collecting system, hydronephrosis, cystic kidneys, and unilateral or bilateral renal agenesis. There is considerable variation in expression and penetrance in this disorder, so a detailed family history is important. Without a family history, the diagnosis would be difficult to make prenatally. Mutations in the gene EYA1, located at 8q13.3, have been shown to be responsible in some cases.102 A definitive prenatal diagnosis is unlikely in low-risk cases, because the associated findings can be very subtle.103

Anticipation

Several autosomal dominant disorders show anticipation where the age of onset is earlier and the phenotype more severe in successive generations. Myotonic dystrophy is an example where the first generation may only develop cataracts in late middle age, the second generation may develop muscular weakness and stiffness in early adult life, and the third generation may have severe congenital onset. Anticipation in myotonic dystrophy is caused by instability of the amplified CTG trinucleotide repeat mutation. The number of repeats tends to increase with each generation, particularly when transmitted by a female. Mildly affected adults in the first generation of an affected family may have only 50 repeats but a congenitally affected infant may have more than 2000.