Chapter 12: Molecular Detection of Inherited Diseases

Factor V Leiden is a _______ mutation (1691A--->G, R506Q) in the F5 gene and not a disorder.

point

MERRF (myoclonic epilepsy with ragged red fibers)

tRNA point mutations (mtDNA) m.8344A>G common myoclonus epilepsy, seizures, ataxia, myopathy Ragged red fibers Other: dementia, optic atrophy, deafness, neuropathy, spasticity, lipomas

Penetrance

the frequency of expression of a disease phenotype in individuals with a gene lesion.

Fertilization where one gamete contains an extra copy of one chromosome will result in what chromosomal abnormality? monosomy disomy tetraploidy trisomy

trisomy

Chimerism

two or more genetically distinct cell populations from different zygotes in an individual

Mosaicism

two or more genetically distinct populations of cells from one zygote in an individual

Fragile X syndrome results from expansion of GCC repeats 5' to the _______ gene.

FMR1

Nuclear mutation disorders

Mitochondrial DNA depletion syndrome Mitochondrial neurogastrointestinal encephalomyopathy Progressive external ophthalmoplegia

Lisch nodules - diagnosis?

Neurofibromatosis (von Recklinghausen's disease)

In ___-____ , the 3' end of one primer hybridizes to the target nucleotide.

SSP-PCR

This type of gene disorder affects structural proteins, cell surface receptor protein

Single-Gene disorder

__________ _________ can reveal cases of mosaicism where both premutations and full fragile X chromosomes are present in separate cell populations from the same patient

Southern Blot

Storage Diseases

Sphingolipids----Tay-Sachs Disease Glycogen----Von Gierke Sulfatides----Niemann-Pick Disease Glucocerebroside---Gaucher Disease

A gene was mapped to region 3, band 1, subband 1, of the long arm of chromosome 2. How would you express this location from an idiogram?

The designation of this locus is 2q31.1

Mutation in this gene (Xp21) is associated with Duchenne Muscular Dystrophy: a)Dystrophin b)P53 c)Musculin d)C-myc

a

Which method would best be used to detect the Leiden mutation? a) PCR-RFLP b) bDNA amplification c) PFGE d) Ribotyping

a

Mutation of Homogentisic Acid Oxidase can result in which of the following diseases? a. Phenylketonuria b. Severe combined immunodeficiency c. Vitamin D-resistant rickets d. Alkaptonuria

d

Duchenne muscular dystrophy

A human genetic disease caused by a sex-linked recessive allele; characterized by progressive weakening and a loss of muscle tissue.

The most frequently occurring mutation in the HFE gene results in the replacement of cysteine (C) with tyrosine (Y) at position 282. How is this expressed according to the recommended nomenclature?

C282Y

Hereditary hemachromatosis is associated with mutation of which gene? : FERR HFE HLA-H F5

HFE

Variable expressivity

a range of phenotypes in individuals with the same gene lesion. ---also reflects the interaction of other gene products and the environment on the disease phenotype

Huntington's disease

A human genetic disease caused by a dominant allele; characterized by uncontrollable body movements and degeneration of the nervous system; usually fatal 10 to 20 years after the onset of symptoms.

______ is associated with a polyalanine (GCN) repeat expansion in the PHOX2B gene.

CCHS

Triplet-repeat (__ __ __ ) expansions in sequences 5' to the FMR-1 gene are observed in fragile X carriers (up to 200 repeats) and fully affected individuals (more than 200 repeats)

CGG

a several-hundred-base-pair segment just upstream of the FMR1 transcriptional start site that contains a high frequency of 5′-CG-3′ dinucleotides compared with the rest of the genome

CpG island

Examples of Chromosomal Mutations

DiGeorge syndrome and velcardiofacial syndrome Cri du chat syndrome Contiguous gene syndrome; Wilms' tumor, aniridia, genitourinary anomalies, mental retardation syndrome

___________ and sex-linked mutations( which can be hemizygous in males) may result in disease states that negatively affect the reproductive health of a population and survival; thus, they are selected against over time

Dominant

Examples of Genome mutations

Down syndrome Edward syndrome Patau syndrome Klinefelter syndrome XYY syndrome Turner syndrome Multi X females

Nonpolyglutamine Disorders

Fragile XE Friedrich ataxia Myotonic dystrophy Amyotrophic lateral sclerosis

amytrophic lateral sclerosis

Gene C9 open reading frame 72 (9p21.1) Repeat GGGGCC Expansion, (Normal)--(Symptomatic) (2-20)----(over 100)

____ is caused by expansion of the trinucleotide CAG (polyglutamine-encoding) repeat sequence in exon 1 of the huntingtin gene (HTT) to greater than 35 repeats. The age of disease onset in HD is inversely correlated with the size of the CAG repeat expansion

HD

Expansion of a CAG repeat within the HTT gene causes __________ __________

Huntington Disease

The frequency of this disorder is 3 to 7 per 100,000 people of European ancestry and less for Asian and African ancestries. In ___________ _______ , the CAG repeat expands from 9 to 37 repeats to 38 to 86 repeats.

Huntington's Disease

_________ _________ of metabolism are usually autosomal recessive

Inborn errors

___________ technology relies on a probe designed to hybridize to the normal or mutant sequence

Invader

Mitochondrial Gene mutation Diseases

Kearns-Sayre syndrome Pearson syndrome Myoclonic epilepsy with ragged red fibers Deafness Neuropathy, ataxia, retinitis pigmentosa (NARP)

Mutation of which of the following genes can lead to the excretion of homocysteine in urine? : FRDA DMD MTHFR CYT6

MTHFR

Premutations in fragile X carriers are easily detected by?

PCR

_____-____ relies on a restriction enzyme recognition site containing the target nucleotide

PCR-RFLP

CCHS

PHOX2b gene (4p12)13 triplet-repeat expansion inside of PHOX2b gene, resulting in the insertion of multiple alanine residues into the protein. detected by PCR

An individual born with Down syndrome has a trisomy (three copies of chromosome 21) with a total of 47 chromosomes. This type of genetic disorder is referred to as a(n): A: Aneuploidy B: Deletion C: Histone modification D: Translocation

a

Bead array technology is most appropriate for which of the following? a. Cystic fibrosis mutation detection b. Chromosomal translocation detection c. STR linkage analysis d. Restriction fragment length polymorphisms

a

Genetic analysis of a large multi-generational family indicates that the presence of a genetic mutation in many family members, yet only one individual in the family has the disease. What is the term/phase for this situation? a) Incomplete penetrance b) Chimerism c) Sex linkage d) Autosomal- recessive inheritance

a

Severe combined immunodeficiency is associated with point mutations in the gene for which of the following? a) Adenosine deaminase b)Dystrophin c)Phenylalanine hydroxylase d)Fibrillin

a

Which of the following are TRUE statements? More than one answer is correct. Please select all correct answers: a) Trisomy is an aneuploidy in which there are three copies of a particular chromosome rather than the normal two copies. b) Down syndrome is also known as trisomy 21 occurs when an individual has an extra copy of chromosome 21. c) Edwards syndrome is a more common chromosomal abnormality than Down syndrome. d) Patau syndrome is trisomy 18.

a, b

A female individual inherits both X chromosomes from her mother and develops a specific disease syndrome. A second female receives one X chromosome from her father and the other from her mother and develops a much milder form of the disease. This epigenetic phenomenon is known as: A: Genometastasis B: Genomic imprinting C: Histone deacetylation D: Mitochondrial mutation

b

A patient is tested for the presence of the factor V Leiden mutation by PCR-RFLP. The mutation forms a recognition site for the MnlI restriction enzyme. After amplification, digestion with MnlI and electrophoresis, the following bands are seen in the patient's sample: 220bp, 153 bp and 67 bp. One band (220 bp) is seen in the normal control. Which of the following is the correct interpretation of these results? a)Patient is normal. b)Heterozygous factor V mutation. c)Homozygous factor V mutation. d)Cannot determine with this information.

b

A patient with impaired judgment, personality changes, signs of abnormal body movements and depression comes to the physician's office for a follow-up visit. The physician suspects a single-gene disorder may be the cause of those clinical manifestations. A blood specimen was then sent to your clinical laboratory for mutation screening in the Huntingtin gene. Testing with standard PCR indicates that patient has Huntington Disease, HD. Which of the following would be consistent with this diagnosis? a) 25 CAG repeats in the Huntingtin gene b) 85 CAG repeats in the Huntingtin gene c) 25 CGA repeats in the Huntingtin gene d) 85 CGA repeats in the Huntingtin gene

b

CYP1A2 is an abbreviation that stands for cytochrome P-450: . a) subfamily I, polypeptide A2. b) subfamily IA, polypeptide 2. c) subfamily A2, polypeptide 1. d) subfamily 2, polypeptide 1A.

b

Reduced penetrance: A: Is the manifestation of an autosomal dominant disorder in a number of different systems of the body B: Is observed in an individual who has the genotype for a disease but does not exhibit the disease phenotype C: Occurs when the same mutations at distinct loci are present in more than one gene D: Is associated with mitochondrial disorders that exhibit trinucleotide repeats

b

The majority of disease-associated mutations in the human population are: a. autosomal dominant b. autosomal recessive c. X-linked d. found on the Y chromosome

b

Which of the following is a block of specific sequence variants that are inherited together? A: Allele B: Haplotype C: Locus D: Polymorphism

b

Which of the following molecular methodologies would be the best for detecting a trinucleotide repeat disorder such as Huntington's disease? a) Heteroduplex analysis b) Variable number tandem repeat analysis c) Single strand conformation polymorphism analysis d) Reverse-Transcriptase PCR

b

MELAS is a disease condition that results from an A to G mutation at position 3242 of the mitochondrial genome. This change creates a single ApaI restriction site in a PCR product, including the mutation site. What would you expect from a PCR-RFLP analysis for this mutation in a patient with MELAS? a. A single PCR product resistant to digestion with ApaI b. A single PCR product that cuts into two fragments upon digestion with ApaI c. A single PCR product only if the mutation is present d. Two PCR products

b Amplification of the regions containing the restriction site will yield one amplicon, which will cut into two ApaI fragments in the presence of mutation. In the absence of the mutation (and the disease), the PCR product would be resistant to digestion with ApaI

large mitochondrial deletions are detected with ________ hybridization techniques

blot

A girl experiences a genetic disease while her parents are not affected by that disease. Which of the following inheritance patterns best fits with this family? a) Autosomal-dominant b) X-linked recessive c) Autosomal-recessive d) Y-linked recessive

c

A patient was tested for Huntington's disease. PCR followed by PAGE revealed 25 CAG units. How should the A. this patient has Huntington's disease B. this patient has a 1/25 chance of contracting Huntington's disease C. this patient is normal at the Huntington locus D. the test is inconclusive

c

All of the following are trinucleotide repeat disorders, EXCEPT: a)Spinocerebellar Ataxia Type 8 b)Huntington Disease c)Asperger Disease

c

In which of the following inheritance patterns are homozygous alleles necessary to express the disease phenotype? A: Autosomal dominant B: X-linked dominant C: Autosomal recessive D: Trinucleotide repeats

c

Missense mutations in cell growth regulator proteins can result in which of the following diseases? a. Familial hypercholesteremia b. Muscular dystrophy c. Neurofibromatosis d. Phenylketonuria

c

Most people with the C282Y or H63D HFE gene mutations develop hemochromatosis symptoms. This is a result of: a. iron loss b. excessive drinking c. high penetrance d. healthy lifestyle e. glycogen accumulation

c

Mutation in what gene is associated with Fragile X syndrome? a)H63D b)CFTR c)FMR1 d)F5

c

Proto-oncogenes are associated with vital biological functions. These functions involve: A: Apoptosis B: DNA repair C: Signal transduction D: Tumor growth

c

Which of the following is a trinucleotide repeat expansion disorder? a) Angelman's syndrome b) Marfan syndrome c) Friedrich ataxia d) Pearson syndrome

c

Which of the following is not a mutation found in the HFE gene of hemochromatosis? a) C282Y b) H63D c) 5382insC d) S65C

c

Which of the following is not a triplet-repeat expansion disorder? a. Fragile X syndrome b. Huntington disease c. Factor V Leiden d. Congenital central hypoventilation syndrome

c

Exon 4 of the HFE gene from a patient suspected of having hereditary hemachromatosis was amplified by PCR. The G to A mutation, frequently found in hemachromatosis, creates an Rsa1 site in exon 4. When the PCR products are digested with Rsa1, which of the following results would you expect to see if the patient has the mutation? A. none of the PCR products will be cut by Rsa1 B. there will be no PCR product amplified from the patient DNA C. the patient's PCR product will yield extra bands upon Rsa1 digestion D. the normal control PCR products will yield extra Rsa1 bands compared with the patient sample Rsa1 will not distinguish normal from mutant

c The patient's DNA should be amplifiable, and the amplicon will yield extra bands upon Rsa1 digestion. Normal DNA should not be digested at the mutated site.

Which of the following can be detected by PCR? a. Large mitochondrial deletions b. Full fragile X disorder c. Mitochondrial point mutations

c and b

Diseases with genetic components are often referred to as ________ ("born with") diseases

congenital

A family with a disease history was examined over several generations. It was observed that both males and females were affected. Children of affected fathers were never affected. Children of affected mothers were always affected. Which of the following describes this inheritance pattern? a) Sex-linked b) Incomplete penetrance c) Autosomal-dominant d) Mitochondrial-related

d

A male experiences breast enlargement and hypogonadism with a low testosterone level. Which of the following genetic abnormalities might explain this condition? a. 47, XY,+13 b. 47, XYY c. 47,XY,+21 d. 47, XXY

d

Both parents are carriers of an autosomal recessive disorder. What percent chance do these parents combined have to pass down this affected gene to their child? a)0% b)25% c)50% d)75% e)100%

d

Congenital disease: a) is always transmitted to offspring through germ line cells. b) is associated only with developmental disorders. c) symptoms generally appear, or are diagnosed during adolescence. d) None of the above.

d

Deletion in the paternal chromosome 15: del(15)(q11q13) results in Prader-willi syndrome. However, deletion in the same region in the maternal chromosome results in a completely different condition known as Angelman syndrome. This phenomenon is an example of: a)Mosaicism b)Loss of heterozygosity c)Hemizygosity d)Genomic imprinting

d

The inheritance of two copies of an altered gene from a single parent without receiving the normal allele from the other parent is known as: A: Germline mosaicism B: Pleiotropy C: Reduced penetrance D: Uniparental disomy

d

This type of polymorphism consists of a series of repeated DNA sequences that can be between 40 and 500 base pairs in length and is sometimes referred to as a minisatellite sequence. A: Haplotype B: Restriction endonuclease C: Short tandem repeat D: Variable number of tandem repeats

d

Which of the following genetic diseases is which glucocerebrosides accumulate in macrophages? a. Pseudo-Hurler polydystrophy b. Niemann-Pick c. Tay-Sachs d. Gaucher

d

Which of the following methods can detect the factor V Leiden mutation? a. PCR-RFLP b. SSP-PCR c. Invader technology d. All the others

d

Aneuploidy

gain or loss of any autosome caused by erroneous separation of chromosomes during egg or sperm production (chromosomal non-disjunction)

which describes the situation that occurs when expression of a particular gene depends on the sex of the parent who transmitted it.

gametic imprinting

Gonadal mosaicism

generation of new mutations in germ line cells; seen as AD phenotype in child from unaffected parents

Males are _____________ for X-linked genes, having only one copy on the X chromosome

hemizygous

Genetically, if a disease phenotype is frequently present with the DNA variant, then the variant is said to have _____ ________.

high penetrance

The mutation del(15)(q11q13) results in a different syndrome if it occurs on the paternal chromosome verses the maternal chromosome. This difference results from which of the following? incomplete penetrance imprinting autosomal dominance sex linkage

imprinting

Polyploidy

more than two of any autosome

Bead arrays are used to detect _________ _________ mutations such as those found in cystic fibrosis.

multiple point

uniparental disomy

occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent. UPD can occur as a random event during the formation of egg or sperm cells or may happen in early fetal development.

the diagnosis of FXTAS or FXPOI is associated with a ___________-sized repeat (55-200 CGG repeats)

premutation

Autosomal recessive

-largest category of Mendelian disorders -recurrence risk is 25% if siblings are affected

While at the doctor's office with your father, you overheard his physician tell another physician that test results came in, confirming the presence of the Factor V Leiden mutation, a mutation associated with deep venous thrombosis. Which of the following is the mutation your father has: A1691G G1619A 1691G>A C282Y

1691G>A