Non Mendelian Inheritance (Genetic Anticipation)

Non-Mendelian Inheritance - Lesson 1: Triplet Repeat Disorders

1.1   Triplet Repeat Expansion

Some genetic conditions are caused by an unusual genetic change – an expansion of a segment of DNA that contains a repeat of 3 nucleotides (triplet repeat), such as CAGCAGCAG . . . CAG.

In these disorders, healthy individuals have a variable number of triplet repeats, but there is a threshold beyond which a high number of repeats causes disease. This threshold varies in different disorders.

The triplet repeat expansion is sometimes called a dynamic or unstable mutation because, as the gene is passed from parent to offspring, the number of triplet repeats may increase. In this way, the condition may worsen (be more severe) or have an earlier onset from generation to generation (genetic anticipation).

Myotonic dystrophy pedigree with increasing severity and decreasing age of onset.

1.2   Expansion of Triplet Repeats

When an individual has a number of repeats in the normal range, it is not expected to expand when passed to the next generation.

However, when the number of repeats falls in the premutation range (a normal, but unstable number of repeats), then the repeats may or may not expand upon transmission to the next generation. Therefore, normal individuals who carry a premutation do not have the condition, but are at risk of having a child who has inherited a triplet repeat in the full mutation range and who will be affected.

Sometimes the premutation range and the affected range overlap. In this gray area, someone may or may not express symptoms of the disorder.

Triplet repeats in the affected range often expand when passed to the next generation. Rarely, it will contract to a smaller number of repeats.

In disorders caused by triplet repeats, the likelihood an expansion will occur is based on the size of the premutation and whether the triplet repeat is inherited from the mother or the father. For example, the myotonic dystrophy triplet repeat is most likely to expand when inherited from the mother. The Huntington disease triplet repeat is most likely to expand when inherited from the father.

Repeat Ranges for Huntington  Disease

1.3   Triplet Repeat Disorders

Triplet repeat disorders have been shown to exhibit autosomal dominant, autosomal recessive, and X-linked inheritance patterns. However, the more common triplet repeat disorders are autosomal dominant.

Some examples of conditions caused by triplet repeat expansions are fragile X syndrome, myotonic muscular dystrophy, and Huntington disease.

Clinical Information on Diseases:

o Fragile X syndrome

o Myotonic muscular dystrophy

o Huntington disease

Individuals with fragile X syndrome (left) and a family with myotonic dystrophy

(L: Reprinted from J Pediatr, 96(5), Turner G, Daniel A, Frost M, "X-linked mental retardation, macro-

orchidism, and the Xq27 fragile site", 837, ©1980, with permission from Elsevier Science; R: Reprinted

from Medical Genetics, 2nd ed., Jorde LB, et al, ©2000, with permission from Elsevier Science.)

1.3.1   Fragile X Syndrome

Characterized by moderate mental retardation in affected males and mild mental retardation in affected females.

Fragile X is the most common form of inherited mental retardation.

Fragile X syndrome is associated with increased CGG repeats in the FMR1 gene, which is on the X chromosome.

o The intermediate range refers to a range of repeats that is normally stable, but 10%-30% may change in repeat size when transmitted from a female; an allele in the premutation range, when transmitted from a female, always changes in size (usually an expansion).

It is inherited in a X-linked dominant manner.

Males with fragile X syndrome often have abnormal facies, including a long face, large ears, prominent jaw and macroorchidism (abnormally large testes).

Affected females tend to have milder features than the males.

Approximately 16 to 25 per 10,000 males are affected with fragile X syndrome.

DescriptionCGG repeat size

Normal range 6 to 40

Intermediate range

41 to 60

Premutation range

61 to 200

Affected range Greater than 200

Boys with fragile X syndrome

(Reprinted from Medical Genetics, 2nd ed., Jorde LB,

et al, ©2000, with permission from Elsevier

Science.)

1.3.2   Myotonic Dystrophy(or dystrophia myotonica or DM)

One of the most common inherited forms of muscle disease: 1 in 20,000 affected.

Characterized by muscle weakness and myotonia (slow relaxation of the muscles after contraction) which progresses slowly over time.

Can also affect other organs such as the eyes, heart, and brain.

Exhibits variable presentation, even within families.

DM is described as mild, classical, or congenital based on the severity of the symptoms and the age of onset.

The age of onset is earlier and the symptoms more severe the larger the repeat size becomes.

Description CTG repeat size

Normal range 5 to 37

Premutation range(No symptoms, but children at risk)

38 to 49

Mild 50 to about 150

Classical About 100 to 1000-1500

Congenital About 1000 and greater

1.3.3   Huntington Disease

This is a progressive disorder of motor, cognitive, and psychiatric changes. The prevalence is around 3 to 7 per 100,000 individuals of western European descent.

The mean age of onset is 35 to 44 years; median survival time is 15 to 18 years after the onset of symptoms.

Notice the variable severity and presentation in the

facies of  this three generation family with

myotonic dystrophy. The infant has more than 1000

repeats, whereas the mother and grandmother each have

about 100 repeats(Reprinted from Medical

Genetics, 2nd ed., Jorde LB, et al, ©2000, with

permission from Elsevier Science.)

In the early stage, manifestations include subtle changes in coordination, minor chorea (involuntary movements), difficulty in mental planning, and often a depressed or irritable mood.

In the next stage, chorea becomes more prominent with increasing difficulty with voluntary activity and worsening dysarthria and dysphagia.

In late stages of HD, behavior problems are gradually lessened; motor disability becomes severe and the individual is often totally dependent, mute, and incontinent.

Huntington disease is associated with increased CAG repeats in the HD gene on chromosome 4.

It exhibits an autosomal dominant inheritance pattern.

Predictive molecular testing is available. However, presymptomatic individuals must follow a well defined genetic counseling process before testing or receiving results.

Description CAG repeat size

Normal range 10 to 26

Premutation range

27 to 41

Affected range 36 to 121