Exam 2; Genetic Disease Flashcards by Courtney Kast

How many protein encoding genes are there in the human genome

roughly 19,000

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This refers to a permanent change in the DNA

mutation

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What can become of a mutation that effects germ cells

it can be inherited/transmitted to progeny

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What can become of a mutation that effects somatic cells

can result in tumor or developmental abnormalities

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What is a point mutation

a single nucleotide base substituted (missence)

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What is a frameshift mutation

insertion or deletion of one or two base pairs, altering the reading frame of the DNA

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What is a trinucleotide repeat mutation

amplification of sequence of 3 nucleotides (Fragile X syndrome)

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What is a single nucleotide polymorphism

variation in just one nucleotide at a single site on the DNA molecule, over 6 million have been identified

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What is a copy number variation

different numbers of large contiguous stretches of DNA; may account for much phenotypic variation

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What are epigenetic changes

modulation of gene expression without altered DNA sequence; important in development as well as normal homeostasis

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This of a promoter region makes them inaccessible to RNA polymerase thus reducing protein synthesis

methylation

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What can occur is there are alterations in non-coding RNAs

microRNAs inhibit translation of their target messenger RNAs into their corresponding proteins

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This type of disorder implies that the altered gene locus is on an autosome and the disease will be evident clinically when only one of the chromosomes in the pair exhibits a mutation at the affected gene locus

autosomal dominant disorder (ADD)

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True or False

autosomal dominant disorders are evident at birth since they create outward physical changes

False; many exhibit delayed age onset (Huntington’s disease)

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What is it when the person has a mutant gene (ADD) but does not express it phenotypically

reduce or incomplete penetrance

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What is it when the trait is seen phenotypically in the individuals having the mutant gene but is expressed differently among the individuals (ADD)

variable expressivity

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What is it when the affected individuals (ADD) may not have affected parents because their disease arose from a new mutation

de novo mutation

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What are the chances of a person have (ADD) if only one parent is affected

50%

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This disorder implies that the trait is expressed only in both gene at a given locus are affected (homozygous individuals)

autosomal recessive disorders (ARD)

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True or False

The parents of an ARD child usually do not show the disease

True

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Offspring of an heterozygous ARD carrier have what changes of having or being a carrier of the disease

1 in 4 chance of having it

2 in 4 (1 in 2) chance of carrying it

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If the mutant gene is rare (ARD) there is a strong possibility that the affected child is the product of what

a consanguineous (from the same ancestor) relationship

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What are three characteristics of ARD

two germline mutations (one from each parent) to develop the disease
equally transmitted by men and women
25% offspring; horizontal pattern in family

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Many ARD disorders present how

with enzyme defects that produce inborn errors of metabolism; in heterozygous individuals, this may not be evident clinically but would have reduced numbers

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What is the age of onset of ARD compared to ADD

more frequently early in life

The expression of the defect of ARD is what compared to ADD

expression is more uniform and complete penetrance is common

Which is more common, ARD or ADD

ARD

How many Y-linked disorders have been discovered

None (except the trait "hairy ears"), all sex-linked diseases are X-linked

Almost all X-linked disorders are this

recessive, therefore females are usually heterozygous

Who is typically affected by X-linked disorders

homozygous females and males (only have 1X; homozygous) i.e. hemophilia

What is lyonization

16 days after conception, all but one X-chromosome is the nucleus of each cell is inactivated; either the maternal or paternal X, all progeny will have the same inactivated X chromosome

What are the cell types of a lyonization female

a mixture; those with active paternal X and those with active maternal X; typically proportionally equal

This refers to inactivation of an abnormally high percentage of normal X chromosomes leading to clinical evidence of the disease in a heterozygote

unfavorable lyonization

This ADD has nearly 100% penetrance, even though the gene has quite variable expressivity among the affected individuals

neurofibromatosis

These disorders are inherited in a variety of patterns; mutation of genes that encode proteins necessary for formation of normal bone and connective tissue

diseases caused by mutations in structural proteins

This is an ADD due to the mutation of FBN1 gene resulting in abnormal fibrillin; a glycoprotein necessary for normal elastic fiber production

marfan syndrome

What is the prevalence of Marfan syndrome

1 in 5,000

What are the clinical manifestations of Marfan syndrome

``` tall, thin body abnormally long legs arachnodactyly (long fingers) dislocation of lens of the eye aortic aneurysm and dissection, leading to heart failure and aortic rupture ```

This syndrome is highly variable (at least 6 clinical variants) and deals will a problem in collagen synthesis (30 types of collagen)

Ehlers-Danlos Syndrome

What are the clinical manifestations of Ehlers-Dalos syndrome

hyper extensible skin and hyperbole joints skin fragility and delayed wound healing rupture of the colon and large arteries hernia

This is one of the more common inherited disorders (ADD) resulting from a mutation of the gene that encodes the LDL receptor

familial hypercholesterolemia

What is the frequency of familial hypercholesterolemia

1 in 500

What results from familial hypercholesterolemia

impaired metabolism and increased LDL cholesterol in the plasma

What are two clinical manifestations of familial hypercholesterolemia

xanthomas of the skin | premature atherosclerosis

Heterozygotes have what in regards to familial hypercholesterolemia

2-3x increase LDL

Homozygotes have what in regards to familial hypercholesterolemia

over 5x normal LDL levels, typically die of MI by age 15/20

This drug can be used to treat familial hypercholesterolemia

lomitapide

This is an ARD that affects 1 in 10,000 caucasian infants and is caused by a lack of phenylalanine hydroxylase leading to hyperphenylalaninemia and PKU

phenylketouria

What is the clinical manifestation of phenylketouria

affected infants are normal at birth but elevated phenylalanine levels impair brain development leading to mental retardation by 6 months

What steps are taken to prevent phenylketouria

screening of newborns in mandatory in the US | restricting dietary sources of phenylalanine will prevent the development of mental retardation

This AR transmission commonly affects infants and young children and is characterized by accumulation of insoluble large molecules (sphingolipids, mucopolysaccharides) in macrophages leading to hepatosplenomegaly

Lysosomal storage diseases

What is also frequently involved with lysosomal storage diseases

CNS involvement, mental retardation and/or early death i.e. Tay-Sachs, Niemann-Pick, Gaucher, Mucopolysaccharidoses

Most of these are AR traits and is due to the lack of any one of several enzymes necessary to degrade mucopolysaccharides; 7 variants

mucopolysaccharide storage disease

What are the clinical manifestations of mucopolysaccharide storage diseases

coarse facial hair clouding of the cornea joint stiffness mental retardation

This is caused by a deficiency of alpha-L-iduronidase (laronidase); life expectancy is only 6-10 years if untreated

Hurler syndrome

What are some treatment options for Hurler syndrome

bone marrow transplant enzyme therapy that may improve the outlook, but not completely correct it, costs >$300,000/annually treatment can extend the life expectancy to +/- 30 years

This is caused by a deficiency of L-iduronate sulfatase and is in a X-linked inheritance pattern

Hunter syndrome

What are the clinical manifestations of Hunter syndrome

coarse facial hair joint stiffness mental retardation milder than Hurler syndrome

Disorders with multifactorial inheritance has what two characteristics

many physiologic trains (height, weight, BP, etc.) | may underlie common diseases such as diabetes, hypertension, gout, etc.

What characterizes a disorder with multifactorial inheritance

two or more genes responsible, plus environmental, non-genetic influences

What is the frequency of inheriting a disorder with multifactorial inheritance

2-7%

It is estimated that what percentage of newborns have a chromosome abnormality

1 in 200

In as many as what percentage of 1st trimester spontaneous abortions, the fetus has a chromosome abnormality

50%

What is a euploid

a normal chromosome count (2 x 23 = 46)

What is a polyploid

an increase chromosome count that is a multiple of that normally seen (3 x 23 = 46) it generally results in a spontaneous abortion

What is an aneuploidy

any number that is not an exact multiple of the normal chromosome, like a trisomy or monosomy

What is a structural abnormality of a chromosome

chromosome breakage followed by loss or rearrangement of material

This is a translation of a part of one chromosome to another non homologous chromosome

translocation

What is reciprocal translocation

fragments exchanged between two chromosomes

This is when a chromosome breaks in two points, then the released fragments are reunited after a complete turnaround

inversion

This is the most common chromosomal disorder; due to meiotic non-disjunction of chromosome 21 during formation of the ovum - associated with advanced maternal age

trisomy 21; Down Syndrome

What are the chances of having a child with down syndrome at 45

45 1:25

What are the clinical manifestations of down syndrome

``` mental retardation epicanthic folds flat facial profile cardiac malformation increases susceptibility to infection (periodontal disease) large tongue increase prevalence of acute leukemia ```

This is defined as male hypogonadism that develops when there are at least two X chromosomes and one or more Y chromosomes

Klinefelter

This is due to partial or complete absence of one of the X chromosomes

Turner syndrome

What is the phenotype of some one with Klinefelters

male

What are the clinical manifestations of Klinefelters

``` increased length of lower limbs reduced body hair gynecomastia hypogonadism male sterility (most common cause) ```

What occurs dentally involving Klinefelters

taurodontism (weird molars and elongated pulp chambers)

What are the clinical manifestations of Turners syndrome

markedly short stature webbing of the neck; low posterior hairline "shield-like" chest high arched palate variety of congenital cardiovascular malformations failure to develop secondary sex characteristics; primary amenorrhea (no menstruation)

What are three ways to diagnose a genetic disease

FISH comparative genetic hybridization molecular diagnosis; PCR, restriction enzymes, comparison of the order, fluorescently labeled nucleotides

What are four PRE-NATAL indications for genetic analysis

mother age >34 parent who is a carrier of a chromosomal translocation Hx of previous child with chromosomal abnormality parent who is a carrier of an X-linked disorder

What are the six POST-NATAL indications for genetic analysis

``` multiple congenital anomalies unexplained mental retardation and/or developmental delay suspected aneuploidy suspected sex chromosomal abnormality infertility multiple spontaneous abortions ```