Unsom Block 1: Genetics Part 1

Front 1

Gene

Back 1

Segment of DNA that encodes for a specific protein and certain RNAs

Front 2

Locus

Back 2

Region on a chromosome that contains a specific gene

Front 3

Alleles

Back 3

Alternative forms of a gene that differ in DNA sequens or in phenotypic consequences.

Front 4

Chromosome

Back 4

Structure that carries genes

Front 5

Homologous chromosomes

Back 5

Chromosomes that pair during meiosis, inherited from each parent. 2 copies of nearly identical chromosomes from each parent.

Front 6

Sister chromatids

Back 6

2 identical duplicated chromosomes (from one parent) joined by a single centromere.

Front 7

Polidy

Back 7

Amount of homologous chromosomes.

Front 8

Haploid

Back 8

1 copy of each chromosome (23 in humans)

Front 9

Diploid

Back 9

2 copies of each chromosome (46 in humans)

Front 10

Aneuploid

Back 10

Any number of chromosomes that is not an exact multiple of the haploid number

Front 11

Monosomy/Trisomy

Back 11

Result of non-disjunction during meiosis/mitosis resulting in absence or addition of an extra chromosome.

Usually only small chromosomes, larger ones result in death.

Front 12

Somatic cell

Back 12

Cells that do not pass on genetic info.

Front 13

Germ line cells

Back 13

Cells that pass on genetic info

Front 14

Mitosis vs Meiosis

Back 14

Meiosis - haploid gamete cells, pairing of homologous chromosomes.

Mitosis - normal cell division, no pairing of homologous chromosomes

Front 15

Synapsis

Back 15

Proteins bind homologous pairs of sister chromatids together, occurs in prophase 1.

Front 16

Crossing Over

Back 16

Recombinase expressed, genetic recombination during meiosis. 0 - 2 times on a chromosome.

Front 17

Spermatogeneis

Back 17

Symetrical division - all 4 turn into gametes.

Mitosis occurs throughout life and induced at puberty.

⬆Paternal Age = ⬆Point mutations

Front 18

Oogenesis

Back 18

Asymetrical division - only 1 turns into gamete.

Mitosis occurs in fetus, all precursors are arrested in prophase I, mitosis initiated during puberty.

⬆Maternal age = ⬆Chromosomal disorders

Front 19

Promotor Sequences

Back 19

Control levels of expression of mRNA which controls expression of protein. If mutated?

Front 20

Coding Sequences

Back 20

Exons, specify the sequence of amino acid in proteins, codons can code for more than 1 aa.

Front 21

Intervening Sequences

Back 21

Interons, interrupt coding sequences and are spliced out of mature mRNA

Front 22

Structural Regions

Back 22

Untranscribed regions 5' and 3' untranslated regions in mRNA

Front 23

Splicing

Back 23

Must have consensus sequence at splice junctions (border between interons/exons).

Front 24

Nonsense Mut.

Back 24

Insert stop codon, resulting in shorter protein (no fxn) or not expressed.

Front 25

Missense Mut.

Back 25

Changes codon specificity to new aa, expressed but may be a different fxn.

Front 26

Frameshift Mut.

Back 26

Small deletion or insertion that changes all subsequent codons.

Results in active and inactive proteins, just because it's active does not mean it is not detrimental.

Front 27

Gain of Function Mut.

Back 27

Novel protein product of or over-expression/miss-expression of a normal protein, usually dominant disorders

Front 28

Dominant Negative Mut.

Back 28

Mutant protein inhibits activity of normal protein.

Front 29

Lethal Mut.

Back 29

Occurs in domains of proteins that inhibits activity of normal protein.

If dominant mutation is lethal or reproductively lethal, it can't be passed on.

These mutations are random new mutations.

Front 30

Silent Mut.

Back 30

Occur in non-essential regions (interons, 5'/3' regions, non-transcribed/non-promotor) or it occurs in redundant base in codon.

Makes a conservative subsititution (similar aa or non-essential region of protein.).

Most mutations are not disease causing.

Front 31

Karyotyping

Back 31

Lymphocytes grown in culture and arrested in metaphase, lysed and chromosomes collected, chromosomes via banding pattern on long (q) and short (p) arms and centromeric position.

Detects: Changes in chromosomes number (trisomy, monosomy), as well as large deletions, inversions, duplications and translocation.

Very slow.

7p22.2 (chromosome 7, short p, band 22.2)

Front 32

Mosaicism

Back 32

Presence of cells that have different genotype caused by high amount of chromosomal rearrangement.

Ex: Milder form of kleinfelter's syndrome 46/47 XY/XXY where some pt. cell have XY and some have XXY.

Front 33

FISH

Back 33

Fluorescence in situ hybridization.

Specific fluorescent labeled nucleotide probes mark where chromosomes are.

Quicker than regular karyotyping.

Two preps are used (metaphase nuclei - determines chromosome structure and interphase nuclei - determines number).

Able to look for mosaicism

Front 34

Locus Specific Probe

Back 34

Probe in FISH.

Labels specific gene or region. Used to detect microdeletions.

Front 35

Centromeric Probe

Back 35

Probe in FISH.

Labels specific pair of chromosomes at their centromere.

Front 36

Chromosome Painting Probe

Back 36

Probe in FISH.

Labels a specific chromosome across entire length.

Used to detect trisomies, translocations and large duplications.

Front 37

Spectral Karyotyping

Back 37

Every chromosome is probed, usually ordered when lots of chromosomal recombination is suspected (cancer = ⬆recombinase).

Front 38

Microarray SNP Testing

Back 38

Chop up chromosomes, put DNA in wells w/probes. Indicated after normal karyotype.

Detects: # of chromosomes, deletion/duplication, and unbalanced translocation unable to detect balanced translocations (chopped up chromosomes) and low-level mosaicism.

Quick, can determine imbalances across the entire genome and high resolution.

Front 39

Chromosomal Non-Disjunction

Back 39

Occurs during gametogenesis, affects hundreds of genes and is random.

Can occur during:
1st meiotic division - gametes with copies of 2 diff. maternal chromosomes

2nd meiotic division - gametes with 2 sister chromatids.

Front 40

Duplications

Back 40

Part of chromosome copied and inserted into same/different chromosome.

Unbalanced.

Front 41

Inversions

Back 41

Section of chromosome is flipped. Can cause problems w/ segregation at gametogenesis.

Balanced.

Front 42

Insertions

Back 42

Section of chromosome is inserted into another chromosome. Can cause problems w/ segregation at gametogenesis.

Balanced.

Front 43

Isochromosomes

Back 43

Abnormal centromeric division, 2 long arms, 2 short arms. Problems w/ segregation at gametogenesis.

Balanced.

Front 44

Reciprocal Translocations

Back 44

Parts of chromosomes are exchanged.

Problems w/ segregation at gametogenesis.

Balanced - Indvid. are often normal/carriers (two copies of each gene).

Leads to increased incidence of non-disj. in next generation.

Front 45

Robertsonian Translocations

Back 45

Centric fusion of two chromosomes, likely to happen w/ acrocentric chromosomes.

No lost coding sequences, carrier unaffected, problems w/ segregation at gametogenesis.

Leads to increased incidence of non-disj. in next generation.

Front 46

Balanced vs Unbalanced Rearrangements

Back 46

Balanced - same amt. of genetic units brought over.

Unbalanced - not same amt. of genetic units brought over. Reproductively lethal, and caused by:

spontaneous mutations (recurrence risk elevated but low)

unbalanced inheritance from balanced rearrangements (recurrence risk is signif. elevated)

Front 47

Principle of Segregation

Back 47

Genes (homologous chromo) occur in paris of individ. only 1 of each chromo is transmitted to offspring from the parent

Front 48

Principle of Indep Assort

Back 48

Genes at different loci are transmitted independently (True for chromosomes and for distant genes on the same chromosome, but not for close genes (linkage).

Front 49

Co-dominance

Back 49

Heterozygotes have different phenotype than homozygotes.

Front 50

What makes Dom. vs Reces.

Back 50

Consequences of mutations on protein expression. Dosage sensitivity of trait - dependence of the trait on protein expression levels/activity.

Front 51

Consequences of Mutation

Back 51

Loss of fxn - dom or reces. (1 mut = lose 1/2 activity, 2 mut = lose all act.).

Gain of fxn - dom because of new activity.

Dom. neg. - dom. because it eliminates almost all protein activity.

Front 52

Dosage Sensitivity of Trait

Back 52

Haploinsufficinency - 1/2 protein expression/activity is insufficient (one normal allele). Dominant.

Haplosufficiency - 1/2 protein expression/activity is sufficient (one normal allele). Recessive

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Haplosuffciency

Back 53

One allele is enough for compensation of the mutation, usually recessive disorders

Front 54

Haploinsuffcincy

Back 54

One normal allele is not enough for compensation of the mutation usually dominant disorders

Front 55

Risk of Occurrence

Back 55

Probability that a couple will have an affected child.

Depends on population frequencies of the disorder and the rate of spont. mut.

Front 56

Risk of Recurrence

Back 56

Probability that a genetic disorder in a family will recur in another member of in future generations.

Depends on mode of inheritence. Risk of recurrence is higher than the risk of occurrence

Front 57

Probability, Multip Rule, Add Rule

Back 57

Front 58

Hardy-Weinburg

Back 58

Dom. - disease freq. approx. equal to heterozygote freq (2q; homozygotes are rare).

Reces. - disease freq.=allele freq squared (q² ).

X-linked reces.- freq. of affected males = allele freq (q), and freq. of carrier females is twice the freq.of affected males (2q).

X-linked dom.- freq. of affected females is twice the freq. of affected males (2q vs q)

Front 59

Autosomal Dominant

Back 59

Vertical pattern of inheritance.

Father-to-son transmission of disease gene is possible.

Equal number of affected males and females.

Most common mating: affected heterozygote and normal homozygote.

Disease freq = 2q → (2)(Frequency)(Chance of getting either allele i.e. A or a)

Front 60

Autosomal Dominant Probability

Back 60

Problems: Punnett Square. (Mother risk)(Father risk)(Chance of getting allele)

Front 61

Autosomal Recessive

Back 61

Horizontal pattern of inheritance.

Co-sanguinity is sometimes seen.

Equal number of affected males and females.

Most common mating is between two heterozygotes.

Disease freq = q² Carrier freq. = 2q (solve q)

Front 62

Autosomal Dominant Probability

Back 62

Problems: Punnett Square. (Mother risk)(Father risk)(Chance of getting allele)

Front 63

2/3 Rule

Back 63

If no affected people in sibship and know that parents must be a carrier, probability of a child being a carrier is 1/2. If there are affected individuals in sibship or both parents are carriers, probability of a child being a carrier is 2/3. Only applies when you know there is a possibility of homozygous affected individual, but they are not affected.

Front 64

X-linked recessive

Back 64

Vertical pattern of inheritance. Skipped generations (brothers, cousins, uncles, but not parents)

Females are heterozygous carriers, males are hemizygous affected. 2 mutant alleles required to cause disease in females.

Common matings
Heterozygous female x normal males = 1/2 affected sons, 1/2 daughters carriers
Normal female x affected males = 0 sons affected, 100% daughters affected

Affected males = q
Affected females = q²
Carrier females = 2q

Front 65

X Chromosomes

Back 65

Share a psudoautosomal area (small area of homology that allows pairing up). Genes in this area are still active and will still result in disease

Front 66

X-linked recessive and spontaneous new mutations

Back 66

In a family w/no previous history of an X-linked recessive disorder, possibility that an affected individual is due to a spontaneous new mutation must be considered.

Reproductively lethal but spontaneous mutations allow it to still propagate. (Haldane principle - in pop w/ stable disease freq. rate of spontaneous new mutation = rate of loss of alleles)

1/3 of alleles lost (1 X chromo) is lost) and 1/3 of alleles new mutations. 2/3 (2 X chromor are retained) chance of carriers.

In spontaneous mutations, you should not see affected individuals more than once. If you do this suggest that their mothers are carriers.

Front 67

X-linked dominant

Back 67

Vertical pattern of inheritance. No skipped generations.

Twice as many affected females as males

Common Matings
Heterozygous females x normal male = 50% sons affected, 50% daughters affected
Normal females x affected males = 0% sons affected, 100% daughters affected

No male to male transmission. Disease in females is more severe

Front 68

Autosomal, male dominant (sex-influenced trait)

Back 68

Both sexes have same defect, but only manifested in suceptible sex.

Balding - males are bald, females have thin hair.

Front 69

X-chromosome inactivation (lyonization)

Back 69

Methylation is being copied as well. Daughter cells will have same inactivated X.

Pesudoautosomal reagion genes are still active and will still result in disease

Front 70

Non-Random X-inactivation

Back 70

Structural abnormality on one X - inactivated, cells w/structural abnormality on one X are not viable → No mosacism

Balanced translocation between one X chromosome and autosome - normal X is inactivated (if translocated X is inactivated, autosome also inactivated → not viable → no mosacism

Front 71

Phenotype

Back 71

Interaction of two alleles at a given loci

Front 72

Dominant v. Recessive

Back 72

Refers to interaction of alleles not traits or genes.
Dominant/Recessive disorders refers to the clinical manifestation of disease

Dominant = 1 mutant allele causes disease
Recessive = 2 mutant alleles cause disease

Front 73

Allelic Heterogeneity (AH)

Back 73

Differing mutations in same alleles on same gene/loci, lead to same phenotype. Can have both dominant and recessive forms.

Causes
different modes of inheritance
different severity of disease

CF - different mutations have different effects on protein expression/activity, but same phenotype

Front 74

AH problems

Back 74

70% of alleles are ∆F508, 20% alleles are one of 24 common mutations, 10% of alleles are rare.

1.) Homozygous for ∆F508 = need 2 alleles = (0.7)(0.7) = 49%
2.)Heterozygous ∆F508 and other = (0.7)(0.2)(2) = 28% (For heterozygotes, must multiply by 2 since you can get from one from mother and one from father and vice versa
3.) Homozygous for other = (0.2)(0.2) = 4%
4.) Heterozygous carrier w/rare undetected alleles = (0.9)(0.1)(2) = 18%
5.) Homozygous unaffected = (0.1)(0.1) = 2%

Front 75

Dominant Negative

Back 75

Occurs in Allelic heterogeneity

Dimerization between mutant form and normal form - leads to inactivation of normal form.
Affected person having child = 50% of having affected child

Front 76

Locus Heterogeneity (LH)

Back 76

Mutations in different alleles, different loci, cause the same disease (occurs in multi-protein complexes or when proteins/enzymes affect same pathway)

Hemophilia - mutations in diff. genes cause same phenotype
- A = mutation in factor VIIIa
- B = mutation in factor IXa
- Both are part of VIII complex and indistinguishable clinically. Important to know which type so you give correct clotting factor

Front 77

LH problems

Back 77

No affected daughter - carrier of 2 different mutations = no phenotype

(chance of getting affected from mother X, 1/2)(1/2 normal son)(1/2 affected son) = 1/8

Front 78

Penetrance (P)

Back 78

All or none phenomenon = frequency of expression of a dominant disorder in obligate heterozygote

Non-penetrant - unaffected heterozygote w/affected offspring

Retinoblastoma
- Mutation in tumor suppressor is not enough to cause tumor (1st hit). Must have random mutation too (2nd hit).
- Homozygous for tumor suppressor mutation = death
- Sporadic - need two hits in same cell
- Familial - only need 1 hit, already have mutation in tumor suppressor

Front 79

P Problems

Back 79

1.) (1/2)(0.9) = 45%, 0.9 = penetrance
2.) (1/2)(0.1) = 5%, 0.1 = non-penetrant
3.) (1/2)(0.1)(1/2)(0.1) = 1/400, (from dad)(non-penetrant)(chance of having allele)(non-penetrant)
4.) no greater risk = spont. mutation

Front 80

Variable Expressivity (VE)

Back 80

Pentrance is complete, but severity is variable (mildly affected parent → severely affected child)

Front 81

Pleiotropy

Back 81

Diverse affects of a single gene on several organ systems and functions

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Dominant Disorders w/no Previous Family History

Back 82

New mutations - passed from one generation to the next

Germline mosaicism - parent is mosaic for mutation. mutation found in germline cells, but in a few of the somatic cells

Delayed Age of Onset - can have children and die of an unrelated cause before manifestation of the disorder

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New mutation Problem

Back 83

Low
1/2
3/4 affected, 2/3 affected live, 1/3 normal

Front 84

Germline Mosaicism Problem

Back 84

Risk for carrier parent - equal to proportion of germ cells in parent that carries the mutation
Recurrence risk for affected child - 50% chance the affected individual will pass on affected allele

DMD = 1-5% recurrence risk in "de novo" due to possibility of germline mosaicism

Front 85

Delayed Age of Onset Problem

Back 85

II2 = dependent on carrier status
III 50%
IV1 = 1/4

Front 86

Sequence Analysis

Back 86

Nucleotide sequence is determined from segment of DNA, usually exons and interon-exon boundaries

Identifies only specific targeted mutations w/in a given segment of DNA

Don't sequence whole gene since there's not much variance in interons

Detected sequence alterations may be:
- Known to be pathogenic/benign (confirmed)
- Predicted to be benign/pathogenic/unknown but not reported (needs confirmation)
- Promotor mutation can be detected by looking at how much RNA is produced - Northern Blot

If not detected:
- Pt. has sequence alteration in region of gene not covered by lab's tests
- Pt. has sequence alteration that can't be detected (large deletions can't be detected since chromo w/o deletion will mask the one that has the deletion.
- Pt. does not have mutation in tested gene (sequence mutation may exist in another gene)

Front 87

Mutation Scanning

Back 87

Exons are physically tested to confirm presence of a mutation before sequencing is used to pinpoint.
Makes it faster to analyze when a disorder is caused by numerous possible mutations w/in a gene
- Uses conformation sensitive gel elect. CSGE, ss conformational-polymorph SSCP, denat gradient gel elect.DGGE

Reduces the amount of DNA that needs to be sequenced

Front 88

Targeted Mutation Analysis

Back 88

Tests for presence of a specific mutation, a specific type, or a set of mutations. Not used when there are a high proportion of rare alleles

If affected pt. is not detected, you must use sequence analy. or mutation scanning for mutation ID

Front 89

Deletion/Duplication Analysis

Back 89

Detect deletions/duplications of entire exon, multiple exons, or whole gene that are not ID by sequence analy.

Uses Q/RT-PCR, multi ligation dep. probe amplif MPLA, and SNP microarrays (CGH, CHIPs)

Front 90

QT-PCR

Back 90

aka RTQ-PCR, use of PCR to determine amt. of DNA/RNA in a sample, used to detect heterozygous deletions/duplications

Hemizygous deletion mutations can determined standard PCR, cannot determine status of females due to other X

Front 91

DNA/RNA Analysis

Back 91

Blotting (good for large amts):
Northern: RNA, size of intact mRNA, gene expression levels - promotor mutations
Southern: genomic DNA, size/presence of DNA fragments containing gene of interest

PCR (good for small amts):
Distinguish small differences in size

Front 92

Protein Electrophoresis

Back 92

Electrophoretic mobility of hemoglobin - neonatal screening


Every person w/sickle cell disease has the same point mutation β-globin: Glu6Val

Front 93

Direct DNA testing

Back 93

PCR → Dot blot → Hybridize w/ labeled allele sp. oligonucleotides (single bp diff)

1, 2, 7, 8, 10 = SCA
4, 5, 6, 9 = carrier
3 - Sickle C (shows up as normal - 1 copy normal, 1 copy sickle C = only probing SCA = sickle C won't show)

Front 94

Trisomy 18

Back 94

Chromosomal Abnormality:
Extra Copy of 18

Mode of Inheritance:
Mostly non-disjunction (rarely translocation)

Clinical Symptoms:
Severe growth and developmental retardation, multi-organ failure; rocker-bottom feet, clenched fist, microcephaly

Addt'l Info:
1/5000 live births
<10% survive past 1st yr
Recurrence low (unless one of parents have balanced translocation)

Diagnosis: Karyotype

Front 95

Trisomy 13

Back 95

Chromosomal Abnormality:
Extra Copy of 13

Mode of Inheritance:
Non-disjunction (5% translocation)

Clinical Symptoms:
Polydactyly, rocker bottom feet, microcephaly, omphalocele, multiple organ systems effected (CNS, renal, cardiac), cutis aplasia, congenital heart disease

Addt'l Info:
1/10,000
Survival: 7-10 days

Insensitive to triple/quad screen

Diagnosis: Karyotype, FISH

Front 96

Kleinfelter 47, XXY

Back 96

Chromosomal Abnormality:
Extra Copy of X

Mode of Inheritance:
Non-disjunction

Clinical Symptoms:
Gynecomastia, infertility, taller stature, poor muscle tone, microorchidism (small testicles), learning behavioral issues, decreased testosterone

Addt'l Info:
Diagnosis: Karyotype

Front 97

Turner Syndrome 45, X

Back 97

Chromosomal Abnormality:
Missing Copy of X

Mode of Inheritance:
Non-disjunction

Clinical Symptoms:
Infertility, small breast, short stature, brown spots (nevi), low hairline, malformation of ears, congenital heart defects, elevated LH, FSH

Addt'l Info:
1/2000 female live births
Recurrence = very low

Diagnosis: Karyotype

Front 98

Gaucher

Back 98

Chromosomal Abnormality:
Mutation on chromosome 1q21: defect in enzyme glucocerebrosidase (breaks down fatty acid glucosylceramide)

3 types: severity depends on mutation

Mode of Inheritance:
Autosomal recessive

Clinical Symptoms:
Glucosylceramide accumulates in white blood cells, impairs organ function, cognitive impairment, bone fractures, hepatosplenomegaly, erlenmeyer flask deformity, anemia, edema, leukoctyopenia

Addt'l Info:
1/500-1/1000 Ashkenazi Jewish and Eastern European populations

Diagnosis: measure beta-glucocerebrosidase activity in leukocytes

Genetic testing: DNA analysis (RT-PCR)
Treatment: Enzyme Replacement Therapy, or Bone Marrow Transplant

Front 99

Familial Hypercholesteroleima

Back 99

Chromosomal Abnormality:
Mutations in LDL receptor

Mode of Inheritance:
Autosomal dominant

Clinical Symptoms:
Elevated plasma cholesterol (LDL and total) levels, accelerated arthero-scleoris, distinctive cholesterol skin deposits (xanthomas), corneal arcus

Addt'l Info:
1/500

Diagnosis: Serum cholesterol levels & family history

Front 100

Duchenne/Becker Muscular Dystrophy

Back 100

Chromosomal Abnormality:
Mutations (insertions and deletions) of the dystrophin gene (dystrophin-glycoprotein complex which links cytoskeleton of muscle fibers to the ECM)

Mode of Inheritance:
X-linked recessive
(Almost exclusively in males, female are carriers)
Allelic heterogeneity

Clinical Symptoms:
Absence or dysfunction of dystrophin: Progressive degeneration of skeletal muscle fibers, severe pain, impaired movement, death (respiratory/cardiac failure), elevated creatine phosphokinase in blood due to degradation of muscle cells, contraction of calves

Addt'l Info:
DMD: 1/3500 male births; more severe (lack of functional dystrophin)
1/3 arise from spontaneous mutations

BMD: 1/20,000 male births; less severe (insufficient functional dystrophin protein)

Diagnosis: Serum CPK test
Genetic testing: analysis of X chromosome for deletions/insertions (Xp21)

Front 101

Hemophilia

Back 101

Chromosomal Abnormality:
Point mutation

Mode of Inheritance:
X-linked recessive
Locus Heterogeneity

Clinical Symptoms:
Type A: deficiency of clotting factor VIII (most common)
Type B: deficiency of clotting factor IX
Both affect the intrinsic pathway at the same stage, results in same phenotype (poor clotting)

Addt'l Info:
30% of cases are spontaneous mutations
Type A: 1/10,000 males
Type B: 1/20,000 males

Diagnosis: Gene mutation analysis to confirm which factor is affected

Treatment: replacement therapy

Front 102

22q Microdeletion Syndrome (DiGeorge Velocardiofacial Syndrome)

Back 102

Chromosomal Abnormality:
De novo mutation (microdeletion on chromosome 22q) TBX1 located in this region, required for neural crest cell migration

Mode of Inheritance:
Autosomal Dominant – deletion in one allele, will cause disease
7% will inherit microdeletion

Clinical Symptoms:
CATCH-22, Cardiac abnormality, Abnormal facies (flat philtrum), Thymic aplasia, Cleft palate, Hypocalcemia, hypoparathyroidism, 22-abnormality on chromosome 22, mental retardation

Addt'l Info:
1/3800 among Hispanics
1/6000 among white, black Asians

Diagnosis: FISH
Recurrence risk depends on if de novo mutation or inherited.

Treatment: Calcium & Vitamin D

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Neurofribromatosis

Back 103

Chromosomal Abnormality:
Type 1: Mutation at chromosome 17q11.2 (gene deletion affecting production of neurofibromin 1, a tumor suppressor)
Type 2: Mutation at chromosome 22q12 affecting production of merlin (neurofibromin 2), also a tumor suppressor

Mode of Inheritance:
Autosomal Dominant (gene deletion in neurofibromin)
Variable expressivity
Germ line cell mosaicism (rare)

Clinical Symptoms:
Neurofibromas (abnormal growth of neural tissue throughout body), Café au lait spots, freckles on growth and axilla (armpit), optic glioma and Lisch nodules

Addt'l Info:
1/3500
50% of cases arise from spontaneous mutation

Neurofibromatosis affects all neural crest cells and their derivatives

Whole gene deletion → more clinically significant manifestation

Diagnosis: FISH

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Marfan Syndrome

Back 104

Chromosomal Abnormality:
Mutation (most single aa changes) in connective tissue FBN1 gene chromosome 15 (q) long arm
(FBN1 codes for fibrillin-1)

Also insertions, deletions, or splicing errors can occur (more severe disease)

Mode of Inheritance:
Autosomal Dominant
High penetrance, haplo-insufficiency
Variable expressivity

Clinical Symptoms:
Defects in ocular system (dislocated lens), skeletal system (excessive linear growth/joint laxity – abnormal curvature of the spine, sunken or protruding chest), cardiovascular system (aortic dissection)

Additional Information:
2-3/10,000 individuals
25% of cases due to de novo mutations

System disorder of connective tissue (high degree of clinical variability)

Specific test: reveals great flexibility (Steinberg sign, Walker-Murdoch sign), arm span greater than height, pectus carinatum (pigeon test)

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Sickle Cell Anemia

Back 105

Chromosomal Abnormality:
Point mutation, single amino acid change Glu6Val resulting in mutated β-globin gene (mutated HbS)

SNP – single nucleotide polymorphism

Mode of Inheritance:
Autosomal Recessive

Clinical Symptoms:
Hemolytic anemia, sickled RBCs, hypoxemia, dehydration, multiple organ damage (autosplenectomy – immune system), marrow hyperplasia, skeletal system, hyper-bilirubinemia, renal failure, leg ulcers, dactylitis (hematopoiesis in hands and feet)

Additional Information:
Sickle Cell Disease 1/400 African Americans
Sickle Cell Trait (heterozygous) 1/12 AA

Also high incidence in Mediterranean, in regions with endemic malaria

Rare, but another single amino acid Glu6Lys, change can result in mutated β-globin gene (HbC) – Sickle C

Front 106

PKU

Back 106

Chromosomal Abnormality:
Deficiency in PAH gene (mutation on chromosome 12) causes hyperphenylalaninemia

Mode of Inheritance:
Autosomal Recessive
Allelic heterogeneity

Clinical Symptoms:
Mental retardation
Musty odor (due to excretion of excess phenylalanine thru sweat), rashes,
elevated phenylalanine,

Additional Information:
1/10,000 live births
PAH (phenylalanine hydroxylase) converts phenylalanine to tyrosine
Similar to FAS, to have phenylalanine in their system

Children born to women with PKU at high risk for developing PKU (teratogenic exposure to phenylalanine)
Dietary restrictions to limit intake of phenylalanine (restriction to proteins)

Front 107

Cystic Fibrosis

Back 107

Chromosomal Abnormality:
Mutation in gene for cystic fibrosis transmembrane conductance regulator (CFTR), 7q31.2

Mode of Inheritance:
Autosomal Recessive

Clinical Symptoms:
Abnormal transport of chloride/sodium across epithelium = thick, viscous secretions.
Sinus infections, poor growth, coughing, shortness of breath, malabsorption of nutrients, pancreatitis, lack of normal bowel movements, clubbing of fingers/toes, infertility, amenorrhea

Additional Information:
Caucasian of European descent = 1/25 carrier chance
1/2000-3000 live births

Diagnosis: FISH, Sweat test

Treatment: Most delay the decline in organ function. Pancreatic enzyme supplements, antibiotics (IV, Inhaled, p.o.), mechanical/chemical treatments to break up secretions in lungs, Lung transplant (late-progression)