Genetic Testing- TNR Expansion Flashcards Preview

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Flashcards in Genetic Testing- TNR Expansion Deck (136)
1

What is trinucleotide repeat expansion (TNR)?

a unique mutations mechanisms where mutant alleles are unstable and actually change in size from one generation to the next

2

What is trinucleotide repeat expansion (TNR)?

a unique mutations mechanisms where mutant alleles are unstable and actually change in size from one generation to the next

3

T or F. allele size shows a direct correlation with disease severity

T

4

Name four important TNR disorders

-Fragile X syndrome
-Huntington disease
-Friedrich ataxia
-Myotonic dystrophy

5

What is the disease gene for Fragile X syndrome?

CGG repeat on the 5' untranslated end of FMR1 gene on the X chromosome

6

What are the symptoms of Fragile X syndrome?

developmental delay and cognitive impairment

7

What is the number of CGG repeats for a normal FMR1 gene?

5-54 alleles

8

What is the number of CGG repeats for an intermediate FMR1 gene? What are the results of having this number of repeats?

In fragile X syndrome, there are intermediate alleles (gray, 55-200 repeats) that are not large enough to cause disease in a person who carries such an allele, but are large enough to be unstable during meiosis (aka the 'premutation' range). Thus, a full mutation and disease may arise in the next generation.

9

What is the number of CGG repeats for a fully mutated FMR1 gene?

>200 alleles. symptomatic

10

What is the disease gene for Huntington disease?

CAG repeat within an exon of the HTT gene on chromosome 4

11

What are the symptoms of Huntington disease?

progressive neuropsychiatric disorder

12

What is the number of CAG repeats for a normal HTT gene?

10-35

13

What is the number of CAG repeats for a fully mutated HTT gene?

>40.

Note that there is a small intermediate range, ranging from 36-40

14

What is the disease gene for Friedrich ataxia?

GAA repeat within an intron of the FXN gene on chromosome 9

15

What are the symptoms of Friedrich ataxia?

progressive ataxia

16

What is the number of CAG repeats for a normal FXN gene?

17

What is the number of CAG repeats for a fully mutated FXN gene?

>~70-200

18

What is the disease gene for Myotonic dystrophy?

CTG repeat in the 3' untranslated region of the DMPK gene on chromosome 19

19

What are the symptoms of Myotonic dystrophy?

progressive muscle wasting

20

What is the number of CAG repeats for a normal DMPK gene?

21

What is the number of CAG repeats for an intermediate DMPK gene?

35-49 (premutation)

22

What is the number of CAG repeats for a fully mutated DMPK gene?

mild phenotype: ~50-150
classic phenotype: ~100-1000
congenital: >1000

23

TNR expansion disorders are typically associated with what kinds of symptoms?

neurologic and muscular

24

T or F. Within the normal size range, the repeats are perfectly stable, and there is no risk of disease

T. In general, if we examined multiple generations from a normal family, we would expect allele sizes to be perfectly maintained. However, at the same time, there is variation in allele sizes across the normal population. Using the HD gene in normal families as an example, if we looked at one family, we could track an allele with 6 repeats through multiple generations, and there would be no change in its size. A different normal family can have allele sizes anywhere within the normal range (up to ~35 repeats for HD), and these will segregate through that family in a stable manner.


25

What is the molecular mechanism for allele expansion?

In spite of much research, unanswered questions remain about the molecular mechanism for allele expansion. There is evidence of "looping" out of one strand of the repeat segment during DNA repair or replication that is thought to account for increased copy number.


In alleles that are large enough to be unstable, expansion occurs in germ cells, and an expanded mutant allele may be passed to the next generation.


26

Diseases caused by TNR expansion can be put in what two categories?

Those where the triplet repeat is in coding sequence, and those where the triplet repeat is in a noncoding portion of the gene.


27

In TNR related diseases where the triplet repeat is in coding sequence (exon), the trinucleotide repeating sequence is always?

CAG, coding for glutamine

28

What happens when runs of glutamine get too high?

When runs of glutamine get too big, the protein has a toxic effect on neurons. In affected individuals, fragments of the abnormal protein are visible as aggregates within neurons

29

The associated toxicity of too much glutamine on neuron is called?

a gain of function abnormality, since presence of the abnormal protein exerts a dominant deleterious effect. Although loss of function (absence) of huntington protein (for example) may have serious developmental consequences, it does NOT cause huntington disease. It’s the TNR expansion that accounts for the observed pathogenicity.


30

In TNR related diseases where the triplet repeat is in non-coding sequence (be it at either end of the gene transcript or in an intron), the trinucleotide repeating sequence is always?

variable, could be CGG, GAA, CTG, and locations vary within the genes

31

In TNR related diseases where the triplet repeat is in non-coding sequence (be it at either end of the gene transcript or in an intron), what is the result of TNR expansion?

no protein produced and RNA toxicity

32

In fragile X, an expanded CGG repeat in the 5’ UTR (in exon 1, upstream of the initiating AUG) leads to what?

methylation of the promoter region and silencing of the gene

33

In myotonic dystrophy, an expanded repeat in in the 3’ UTR causes what?

since it is downstream of the normal stop codon, it's deleterious effects of repeat expansion are exerted at the RNA level

34

In Huntington disease, the CAG repeat is within the encoded protein. What results from expansion?

expanded polyglutamine causes toxic aggregates to form

35

What is genetic anticipation?

a condition where disease severity worsens in successive generations. Anticipation is explained by the fact that repeat copy number tends to expand each time it passes through meiosis (gametogenesis), and disease severity does correlate with repeat copy number.

leads to earlier progressive onset (not always) and increased severity in subsequent generations

36

What is the general approach to testing for TNR expansion?

Considered a targeted approach to testing since assays look directly at the TNR and provide an estimate of repeat number. Tests use patient DNA, and the result is reported as the number of repeats in each allele that the patient has.
 Main approach is PCR

37

T or F. Although the repeat copy number may vary, the flanking sequences are highly conserved

T. The goal of TNR testing is to generate a PCR product that spans the repeat segment and has defined end points in conserved flanking sequences. Thus, the size of the PCR product reflects the number of repeats present. The forward and reverse PCR primers would be specific for the relevant gene sequences on either side of the TNR repeat. Thus, for example, a PCR product from a mutant allele with 40 repeats would be 90bp larger than the product from a normal allele that had 10 repeats. Since a person has two copies of the HTT gene, both alleles would be sized.
T

38

Notes on the accuracy of genetic allele testing

For all indications, testing has the capacity to provide an accurate estimate of allele size. While testing can determine allele size in a parent and, also in a fetus or child, it is not possible to make precise predictions about how much a parent's unstable allele will expand in the next generation

39

Is Huntington disease the only TNR expansion disease related to coding segments?

NO, others include:
-Spinocerebellar ataxia
-Kennedy disease
-Machado-Joseph disease

Note that all these disorders are autosomal dominant, except for Kennedy disease, which is caused by expansion within a gene on the X chromosome

40

What is the inheritance mode of HD?

autosomal dominant

41

What is the average age of onset of HD and average life expectancy?

40 y/o; 15 years; progressive disease

42

What is the prevalence of HD?

~5;100,000

43

What causes HD?

TNR expansion leading to toxic aggregates of neurons involved in protein-protein interactions. The polyglutamine tract resulting from the expansion is near the N-terminus

44

Notes on the ranges of TNR repeats of normal, unstable, and mutated genes for HD.

normal- 10-35 (most common is 18)
unstable- 36-40 (reduced penetrance and may expand during meiosis)
mutated- >40 (symptomatic and will continue to expand in further generations)

45

T or F. People who are heterozygous for a repeat number in the low 40s will have the typical onset of symptoms in middle age.

T. However, while we think of HD as an adult onset disorder, those with very large expansions (100+) can express symptoms in the first or second decade of life.


46

What is the mode of inheritance of Friedrich ataxia?

autosomal recessive

47

What is the mode of inheritance of myotonic dystrophy type 1 (MDT1)?

autosomal dominant

48

What are some common symptoms of MDT1?

progressive muscle weakness and wasting, cardiac conduction defects, cataracts, prolonged muscle contraction, variable expressivity correlated to allele size

A common description of people with this disorder is that when they engage in a handshake or grab a doorknob, they often have difficulty letting go.


49

Doe MDT1 show anticipation?

Yes, there is earlier onset and increased severity with successive generations

In comparison, in HD, the primary evidence of anticipation is age of onset. Anticipation may vary in the specifics, but it is a general feature of TNR disorders.


50

How does TNR expansion cause disease in MDT1?

The pathogenic mechanism in DM1 is not well understood. The expanded TNR in the 3’ UTR of the mRNA causes the mRNA to accumulate in cells and to sequester certain RNA-binding proteins. This sequestration seems to exert a negative trans effect on the ability of other mRNAs to undergo normal translation (i.e. mutant alleles are transcribed but not translated). Thus, the mutation is thought to exert a dominant toxic effect on the DMPK gene and other genes

51

What is a normal DMPK gene typically used for?

the normal protein is a protein kinase involved in intercellular conduction and impulse transmission in heart and skeletal muscle

52

What is the prevalence of MDT1?

~1:20,000

53

What is friedrich ataxia? when is the typical onset?

slow progressive ataxia with onset at puberty. Cardiomyopathy is common

54

What does the normal FXN gene (that when mutated causes Friedrich ataxia) code for?

FXN encoded Frataxin, a nuclear-encoded gene involved in mitochondrial function

55

T or F. Friedreich ataxia is the only TNR disorder with autosomal recessive inheritance

T

56

What does Friedrich ataxia result from?

TNR is located in an intron of the FXN gene, where its expansion disrupts normal transcription (loss of function mutation)

57

What is the most common form of inherited intellectual disability?

Fragile X syndrome

58

What is the inheritance mode of Fragile X syndrome and its prevalence?

mode: X linked
prevalence: 1:5000 men

Females heterozygous for a mutation may be affected, but phenotypes are more variable than in males (1/2-2/3 of full mutation females are affected). This variability presumably stems from effects of X inactivation.. All full mutation males are affected


59

What are some of the symptoms of Fragile X syndrome?

characteristic appearance of long face, large ears, a prominent jaw, and macro-orchidist (enlarged testes)

typical IQ in the 30-50 range, delayed developmental milestones, abnormal temperament with tantrums, hyperactivity, autism (Autistic features are common, and for this reason, testing for fragile X syndrome is fairly routine in the work up of children with suspected autism)

60

How dis Fragile X syndrome get its name?

The syndrome’s name comes from early observations that during chromosome analysis of affected individuals, a physical break could be elicited at the end of the X chromosome long arm. This is the site of the FMR1 gene, and long trinucleotide expansions cause the chromosome fragility.

61

What is the role of the normal FMR1 gene?

abundant in neurons and plays a role in binding mRNA and shuttling it from the nucleus to the cytoplasm

62

What does TNR expansion of the FMR1 gene cause?

excessive DNA methylation in the 5' UTR of the gene which turns off the gene (loss of function)

63

Normal FMR1 gene have how many alleles?

6-54. These alleles are stable from one generation to the next, with no risk of fragile X syndrome.


64

What is the most common allele number of normal FMR1 genes?

~30 repeats, although it is variable like other TNRs

65

Are permutation carriers of FMR1 gene (55-200 alleles) mutation more common in males or females?

females. The larger the premutation, the more likely it is to expand in the next generation.

NOTE: Premutation carriers (male and female) do not have fragile X syndrome; their intellect is normal.


66

What are 'transmitting males' in relation to FMR1 gene mutation?

Male premutation carriers are called transmitting males because they will transmit their premutation to all their daughters, but it will not expand in size.

Thus, ***In fragile X, expansion from premutation to full mutation occurs only in female meiosis and never in male meiosis.***

67

What are the allele expansion risks in MDT1? More maternal or paternal meiosis?

Similarly, in myotonic dystrophy, expansion risk is concentrated in females. In particular, children affected with the severe, congenital form almost always have inherited a greatly expanded maternal allele.


68

What are the allele expansion risks in HD? More maternal or paternal meiosis?

In contrast, although Huntington alleles can expand in both males and females, the most dramatic expansions are transmitted from fathers.
 Juvenile onset also more likely to come from expansion of paternal allele

69

Notes on Fragile X syndrome

There are interesting phenotypic abnormalities associated with premutations, which I’ll take a minute to discuss. First, whereas full mutations are heavily methylated and not expressed (loss of function), premutations are overexpressed, and once again, we see evidence of ill-defined “RNA toxicity”.
 This is associated with minor phenotypic abnormalities. In both male and female premutation carriers, intellect is normal, but there is increased risk for adult onset cerebellar ataxia and intention tremor (FXTAS-fragile X-associated tremor/ataxia syndrome). As expected for X-linked inheritance, this problem is milder in females.
However, female premutation carriers have an additional risk; they are at risk for premature ovarian failure (menopause prior to age 40).
The broader significance of these observations is that they add another example to a growing list of examples where carriers, once thought to be phenotypically normal, are now known to have mild phenotypic risks.


70

T or F. allele size shows a direct correlation with disease severity

T

71

Name four important TNR disorders

-Fragile X syndrome
-Huntington disease
-Friedrich ataxia
-Myotonic dystrophy

72

What is the disease gene for Fragile X syndrome?

CGG repeat on the 5' untranslated end of FMR1 gene on the X chromosome

73

What are the symptoms of Fragile X syndrome?

developmental delay and cognitive impairment

74

What is the number of CGG repeats for a normal FMR1 gene?

5-54 alleles

75

What is the number of CGG repeats for an intermediate FMR1 gene? What are the results of having this number of repeats?

In fragile X syndrome, there are intermediate alleles (gray, 55-200 repeats) that are not large enough to cause disease in a person who carries such an allele, but are large enough to be unstable during meiosis (aka the 'premutation' range). Thus, a full mutation and disease may arise in the next generation.

76

What is the number of CGG repeats for a fully mutated FMR1 gene?

>200 alleles. symptomatic

77

What is the disease gene for Huntington disease?

CAG repeat within an exon of the HTT gene on chromosome 4

78

What are the symptoms of Huntington disease?

progressive neuropsychiatric disorder

79

What is the number of CAG repeats for a normal HTT gene?

10-35

80

What is the number of CAG repeats for a fully mutated HTT gene?

>40.

Note that there is a small intermediate range, ranging from 36-40

81

What is the disease gene for Friedrich ataxia?

GAA repeat within an intron of the FXN gene on chromosome 9

82

What are the symptoms of Friedrich ataxia?

progressive ataxia

83

What is the number of CAG repeats for a normal FXN gene?

less than 30

84

What is the number of CAG repeats for a fully mutated FXN gene?

>~70-200

85

What is the disease gene for Myotonic dystrophy?

CTG repeat in the 3' untranslated region of the DMPK gene on chromosome 19

86

What are the symptoms of Myotonic dystrophy?

progressive muscle wasting

87

What is the number of CAG repeats for a normal DMPK gene?

less than 35

88

What is the number of CAG repeats for an intermediate DMPK gene?

35-49 (premutation)

89

What is the number of CAG repeats for a fully mutated DMPK gene?

mild phenotype: ~50-150
classic phenotype: ~100-1000
congenital: >1000

90

TNR expansion disorders are typically associated with what kinds of symptoms?

neurologic and muscular

91

T or F. Within the normal size range, the repeats are perfectly stable, and there is no risk of disease

T. In general, if we examined multiple generations from a normal family, we would expect allele sizes to be perfectly maintained. However, at the same time, there is variation in allele sizes across the normal population. Using the HD gene in normal families as an example, if we looked at one family, we could track an allele with 6 repeats through multiple generations, and there would be no change in its size. A different normal family can have allele sizes anywhere within the normal range (up to ~35 repeats for HD), and these will segregate through that family in a stable manner.


92

What is the molecular mechanism for allele expansion?

In spite of much research, unanswered questions remain about the molecular mechanism for allele expansion. There is evidence of "looping" out of one strand of the repeat segment during DNA repair or replication that is thought to account for increased copy number.


In alleles that are large enough to be unstable, expansion occurs in germ cells, and an expanded mutant allele may be passed to the next generation.


93

Diseases caused by TNR expansion can be put in what two categories?

Those where the triplet repeat is in coding sequence, and those where the triplet repeat is in a noncoding portion of the gene.


94

In TNR related diseases where the triplet repeat is in coding sequence (exon), the trinucleotide repeating sequence is always?

CAG, coding for glutamine

95

What happens when runs of glutamine get too high?

When runs of glutamine get too big, the protein has a toxic effect on neurons. In affected individuals, fragments of the abnormal protein are visible as aggregates within neurons

96

The associated toxicity of too much glutamine on neuron is called?

a gain of function abnormality, since presence of the abnormal protein exerts a dominant deleterious effect. Although loss of function (absence) of huntington protein (for example) may have serious developmental consequences, it does NOT cause huntington disease. It’s the TNR expansion that accounts for the observed pathogenicity.


97

In TNR related diseases where the triplet repeat is in non-coding sequence (be it at either end of the gene transcript or in an intron), the trinucleotide repeating sequence is always?

variable, could be CGG, GAA, CTG, and locations vary within the genes

98

In TNR related diseases where the triplet repeat is in non-coding sequence (be it at either end of the gene transcript or in an intron), what is the result of TNR expansion?

no protein produced and RNA toxicity

99

In fragile X, an expanded CGG repeat in the 5’ UTR (in exon 1, upstream of the initiating AUG) leads to what?

methylation of the promoter region and silencing of the gene

100

In myotonic dystrophy, an expanded repeat in in the 3’ UTR causes what?

since it is downstream of the normal stop codon, it's deleterious effects of repeat expansion are exerted at the RNA level

101

In Huntington disease, the CAG repeat is within the encoded protein. What results from expansion?

expanded polyglutamine causes toxic aggregates to form

102

What is genetic anticipation?

a condition where disease severity worsens in successive generations. Anticipation is explained by the fact that repeat copy number tends to expand each time it passes through meiosis (gametogenesis), and disease severity does correlate with repeat copy number.

leads to earlier progressive onset (not always) and increased severity in subsequent generations

103

What is the general approach to testing for TNR expansion?

Considered a targeted approach to testing since assays look directly at the TNR and provide an estimate of repeat number. Tests use patient DNA, and the result is reported as the number of repeats in each allele that the patient has.
 Main approach is PCR

104

T or F. Although the repeat copy number may vary, the flanking sequences are highly conserved

T. The goal of TNR testing is to generate a PCR product that spans the repeat segment and has defined end points in conserved flanking sequences. Thus, the size of the PCR product reflects the number of repeats present. The forward and reverse PCR primers would be specific for the relevant gene sequences on either side of the TNR repeat. Thus, for example, a PCR product from a mutant allele with 40 repeats would be 90bp larger than the product from a normal allele that had 10 repeats. Since a person has two copies of the HTT gene, both alleles would be sized.
T

105

Notes on the accuracy of genetic allele testing

For all indications, testing has the capacity to provide an accurate estimate of allele size. While testing can determine allele size in a parent and, also in a fetus or child, it is not possible to make precise predictions about how much a parent's unstable allele will expand in the next generation

106

Is Huntington disease the only TNR expansion disease related to coding segments?

NO, others include:
-Spinocerebellar ataxia
-Kennedy disease
-Machado-Joseph disease

Note that all these disorders are autosomal dominant, except for Kennedy disease, which is caused by expansion within a gene on the X chromosome

107

What is the inheritance mode of HD?

autosomal dominant

108

What is the average age of onset of HD and average life expectancy?

40 y/o; 15 years; progressive disease

109

What is the prevalence of HD?

~5;100,000

110

What causes HD?

TNR expansion leading to toxic aggregates of neurons involved in protein-protein interactions. The polyglutamine tract resulting from the expansion is near the N-terminus

111

Notes on the ranges of TNR repeats of normal, unstable, and mutated genes for HD.

normal- 10-35 (most common is 18)
unstable- 36-40 (reduced penetrance and may expand during meiosis)
mutated- >40 (symptomatic and will continue to expand in further generations)

112

T or F. People who are heterozygous for a repeat number in the low 40s will have the typical onset of symptoms in middle age.

T. However, while we think of HD as an adult onset disorder, those with very large expansions (100+) can express symptoms in the first or second decade of life.


113

What is the mode of inheritance of Friedrich ataxia?

autosomal recessive

114

What is the mode of inheritance of myotonic dystrophy type 1 (MDT1)?

autosomal dominant

115

What are some common symptoms of MDT1?

progressive muscle weakness and wasting, cardiac conduction defects, cataracts, prolonged muscle contraction, variable expressivity correlated to allele size

A common description of people with this disorder is that when they engage in a handshake or grab a doorknob, they often have difficulty letting go.


116

Doe MDT1 show anticipation?

Yes, there is earlier onset and increased severity with successive generations

In comparison, in HD, the primary evidence of anticipation is age of onset. Anticipation may vary in the specifics, but it is a general feature of TNR disorders.


117

How does TNR expansion cause disease in MDT1?

The pathogenic mechanism in DM1 is not well understood. The expanded TNR in the 3’ UTR of the mRNA causes the mRNA to accumulate in cells and to sequester certain RNA-binding proteins. This sequestration seems to exert a negative trans effect on the ability of other mRNAs to undergo normal translation (i.e. mutant alleles are transcribed but not translated). Thus, the mutation is thought to exert a dominant toxic effect on the DMPK gene and other genes

118

What is a normal DMPK gene typically used for?

the normal protein is a protein kinase involved in intercellular conduction and impulse transmission in heart and skeletal muscle

119

What is the prevalence of MDT1?

~1:20,000

120

What is friedrich ataxia? when is the typical onset?

slow progressive ataxia with onset at puberty. Cardiomyopathy is common

121

What does the normal FXN gene (that when mutated causes Friedrich ataxia) code for?

FXN encoded Frataxin, a nuclear-encoded gene involved in mitochondrial function

122

T or F. Friedreich ataxia is the only TNR disorder with autosomal recessive inheritance

T

123

What does Friedrich ataxia result from?

TNR is located in an intron of the FXN gene, where its expansion disrupts normal transcription (loss of function mutation)

124

What is the most common form of inherited intellectual disability?

Fragile X syndrome

125

What is the inheritance mode of Fragile X syndrome and its prevalence?

mode: X linked
prevalence: 1:5000 men

Females heterozygous for a mutation may be affected, but phenotypes are more variable than in males (1/2-2/3 of full mutation females are affected). This variability presumably stems from effects of X inactivation.. All full mutation males are affected


126

What are some of the symptoms of Fragile X syndrome?

characteristic appearance of long face, large ears, a prominent jaw, and macro-orchidist (enlarged testes)

typical IQ in the 30-50 range, delayed developmental milestones, abnormal temperament with tantrums, hyperactivity, autism (Autistic features are common, and for this reason, testing for fragile X syndrome is fairly routine in the work up of children with suspected autism)

127

How dis Fragile X syndrome get its name?

The syndrome’s name comes from early observations that during chromosome analysis of affected individuals, a physical break could be elicited at the end of the X chromosome long arm. This is the site of the FMR1 gene, and long trinucleotide expansions cause the chromosome fragility.

128

What is the role of the normal FMR1 gene?

abundant in neurons and plays a role in binding mRNA and shuttling it from the nucleus to the cytoplasm

129

What does TNR expansion of the FMR1 gene cause?

excessive DNA methylation in the 5' UTR of the gene which turns off the gene (loss of function)

130

Normal FMR1 gene have how many alleles?

6-54. These alleles are stable from one generation to the next, with no risk of fragile X syndrome.


131

What is the most common allele number of normal FMR1 genes?

~30 repeats, although it is variable like other TNRs

132

Are permutation carriers of FMR1 gene (55-200 alleles) mutation more common in males or females?

females. The larger the premutation, the more likely it is to expand in the next generation.

NOTE: Premutation carriers (male and female) do not have fragile X syndrome; their intellect is normal.


133

What are 'transmitting males' in relation to FMR1 gene mutation?

Male premutation carriers are called transmitting males because they will transmit their premutation to all their daughters, but it will not expand in size.

Thus, ***In fragile X, expansion from premutation to full mutation occurs only in female meiosis and never in male meiosis.***

134

What are the allele expansion risks in MDT1? More maternal or paternal meiosis?

Similarly, in myotonic dystrophy, expansion risk is concentrated in females. In particular, children affected with the severe, congenital form almost always have inherited a greatly expanded maternal allele.


135

What are the allele expansion risks in HD? More maternal or paternal meiosis?

In contrast, although Huntington alleles can expand in both males and females, the most dramatic expansions are transmitted from fathers.
 Juvenile onset also more likely to come from expansion of paternal allele

136

Notes on Fragile X syndrome

There are interesting phenotypic abnormalities associated with premutations, which I’ll take a minute to discuss. First, whereas full mutations are heavily methylated and not expressed (loss of function), premutations are overexpressed, and once again, we see evidence of ill-defined “RNA toxicity”.
 This is associated with minor phenotypic abnormalities. In both male and female premutation carriers, intellect is normal, but there is increased risk for adult onset cerebellar ataxia and intention tremor (FXTAS-fragile X-associated tremor/ataxia syndrome). As expected for X-linked inheritance, this problem is milder in females.
However, female premutation carriers have an additional risk; they are at risk for premature ovarian failure (menopause prior to age 40).
The broader significance of these observations is that they add another example to a growing list of examples where carriers, once thought to be phenotypically normal, are now known to have mild phenotypic risks.