Genetics Flashcards
Genes
hereditary units of DNA transmitted from one gen to another
code for proteins
locus
specific location of a gene on a chromosome
alleles
different versions of a gene
humans have 2 alleles for each autosomal gene
Chromosomes
structure composed of genes located in nucleus of cell
-chromosomes can be distinguished from ea. other by overall length and position of centromere (divides chromosome into 2 arms of varying length)
homologous chromosomes
have the same genes at the same loci
one maternal + one paternal
genome
genetic info contained in the cells, ont he chromosomesfor a particular species
Number of chromosomes in a human
46 (23 pairs)
Number of chromosomes in a garden pea
14
Number of chromosomes in a fruit fly
8
Mutation
a change in some part of the DNA code
- can be spontaneous or induced by exposure to mutagenic chemicals or radiation
- varying effects depending on where in the gene code mutation occured
- net result= may change physical appearance or alter some other train
autosome
any chromosome that isnt a sex chromosome (humans have 22 paris)
allosome pair=sex chrom pair
chromosome number
Somatic cells contain one set of chromosomes from female parent and one homologous set from male parent
- Homologous chromosomes are similar in size, structure, and gene composition
- Humans have 22 pairs of autosomes, and 1 pair of sex chromosomes (allosomes) for 23 total pairs in each cell
haploid number
n= 23
number of chromosomes in sex cells/gametes
diploid nunber
2n=46
total number of chromosomes in somatic cells
which is the short arm of the chromosome?
p= short arm
which is the long arm of the chromosome?
q
how are chromosomes numbered?
numbered consecutively according to length beginning with longest chromosome first
exception= sex chromosome
Automsomes
somatic chromosomes
all except sex chromosomes
allosomes
sex chromosomes
what determines maleness?
genetic factors on the Y
males have one morphologically dissimilar pair of chromosomes
Karyotype
picture of persons chromosomes
mitosis
one exact cope of ea chromosome made and distributed through the division of original cell–> 2 daughter cells
Meiosis
- The process by which gamete cells are produced (egg and sperm)
- Resulting gametes have 23 new chromosomes (one member of each of the pairs), with new combos of the original maternal and paternal copies
- Occurs only in specialized germ cells of gonads
-2 consecutive cell divisions producing cells with half the original chromosome number
diploid 2n—>haploid n
oogenesis
diploid primordial cells in ovaries become oogonia
=1 haploid ovum (n) and polar bodies, which degenerate
spermatogenesis
diploid primordial cells in testes become spermatogenia
=4 sperm cells (spermatozoa)–> ea haploid (n)
genotype
all of the alleles of an organism
phenotype
measurable trait an organism has
-result of gene products that interact in a given enviro
Patterns of inheritance
Describe how disease is transmitted in families
-The patterns help predict the risk for relatives
Patterns of inheritance- what are single gene disorders
-Single gene disorders (Mendelian disorders)
Classified by whether they are
Autosomal or x-linked
Dominant or recessive pattern
punnett square
illustrates monofactorial cross- mating where single gene is analyzed
-demonstrates mendels principle of segregation: one parent has 2 copies of a gene for ea trait, but transmits only one via a gamete
codominance
when 2 alleles for a trait are equally expressed (ex: AB blood type)
-When alleles lack complete dominant and recessive relationships and are both observed phenotypically (expressed at same time)
ex: roan cow, checkerd chickens
what type of inheritance is AB blood type?
codominance
incomplete dominance
heterozygotes have phenotypes that have both alleles visible as a blend (one allele isn’t expressed over the other)
Makes a third phenotype that’s a blending of the two
Human examples: wavy hair – it’s a blend that’s seen when a person with straight hair has a child with a person with curly hair;
-another ex: skin color
penetrance
the probability that individuals in a population who have a particular gene combination will show the condition
Example: if a mutation causing diabetes has 95% penetrance, 95% of people with the mutation combo will develop diabetes
genetic marker
Sequence of DNA with a known location on a chromosome
expression
the components of the phenotype that are exhibited in an individual
Example: myotonic muscular dystrophy
Phenotype may include myotonia, cataracts, narcolepsy, balding, infertility
–>2 people carrying this gene may express it differently
anticipation
Genetic diseases that increase in severity or have earlier onset with each successive generation
Examples: Fragile X, Huntington, myotonic muscular dystrophy
Chromosomal abnormalities: most common type
-can be numerical or structural
most common= aneuploidy (abnormal number)
Chromosomal abnormalities: balanced chromosomal abnormalities
no net loss or gain of chromosomal material
Balanced translocation or inversion
Chromosomal abnormalities: balanced chromosomal abnormalities–> Balanced translocation
rupture of a chromosome resulting in the pieces “re-sticking” in the wrong combinations
Chromosomal abnormalities: balanced chromosomal abnormalities–>inversion
a chromosome piece is lifted out, turned around, and reinserted
Chromosomal abnormalities: balanced chromosomal abnormalities–> Unbalanced chromosomal abormalities
additional or missing info
deletion or insertion
Unbalanced chromosomal abnormalities- unbalanced translocation
Tends to arise as an offspring of a balanced carrier
ex: Robertsonian translocation
Robertsonian translocation
ex of unbalanced translocation
- involve 2 chromosomes
- They are all acrocentric (centromeres are close to the end)
- Results in formation of a “new” chromosome
- The bigger chromosome can produce an unbalanced gamete
- Those involving chromosome 21 can produce gametes with 2 copies; upon fertilization, can produce Trisomy 21
Why use 3 generation pedigree
- Provides a concise visual tool
- Multifactorial genetic conditions now require that treatment and prevention measures be highly individualized
- PCP is at front line playing integral role in prevention and treatment of genetically based diseases
- genetic testing is more available to patients
- Many diseases with genetic links have been discovered and clarified
CONS of software pedigree programs
Many software pedigree programs available are actually less user friendly than drawing it out – harder to record nuances such as multiple relationships, > 3 generations, and tracking multiple diseases
Function of the 3 generation pedigree
- Making a diagnosis
- Deciding on testing strategies
- Establishing the pattern of inheritance
- Identifying people at risk
- Educating the patient
- Determining reproductive options
Purpose of 3 generation pedigree
- Genetic family history recorded in shorthand form
- How members are related to each other from generation to generation
- Graphic representation of medical family history using symbols
- Provides medical information and relationship information at a glance
Pedigree Standardization Task Force of the National Society of Genetics Counselors
Established in 1995, updated in 2008
standard pedigree language
Male -square
Female – circle
Diagonal line through symbol – deceased
Shaded symbol – affected with trait
Half-shaded symbol – carrier of trait
Relationship – line between individuals
Sibship – horizontal line showing siblings
Line of descent – line showing offspring
Individual line – attaches to sibship line
Two hash marks – divorced or separated (or no longer in a relationship)
siblings on a pedigree
draw siblings in birth order from left to right
includ either age or birth year
each gen goes on the same horizontal plane
Research pedigree
generations are given a roman numeral
-individuals given a number (1,2,3)
Clinical pedigree
Names recorded next to individual’s line
Surname recorded above sibship or relationship line
Initials often used
Autosomal dominant
65% of human monogenic disorders
- mutation in a single allele can cause dz
ex: Huntington’s Disease
affected= Hh or HH
Characteristics of Autosomal dominant
- Vertical pattern
- Multiple generations affected
- Variable expressivity
- Affected individuals in same family may show varying degrees of phenotypic expression (severity) - Reduced penetrance
Some with the genetic mutation may not show phenotype, making it appear that it “skipped” a generation - Males and females affected equally
- Male to male transmission can be seen
Autosomal recessive
25% of human monogenic disorders
Tends to involve enzymes or receptors
Rare
Males and females equally affected
Horizontal inheritance
-Multiple affected offspring
Often occurs in the context of consanguinity (blood related)
Heterozygous carriers of a defective allele are usually clinically normal
Example:
Cystic fibrosis
Characteristics of autosomal recessive
Horizontal pattern
Single generation affected
Males and females affected equally
Inheritance is from both parents, each being a heterozygote/carrier
Each offspring has a 25% chance of being affected, and a 50% chance of being a carrier
Higher association with consanguity (blood relative)
X-linked
5% of human monogenic disorders
Risk of developing disease due to a mutant x
chromosome differs between the sexes
Males are hemizygous (heterozygous) for mutant allele on the x
The terms “x-linked dominant” and “x-linked recessive” therefore only apply to females
Heterozygous females usually normal or mild
Who is more likely to develop a mutant phenotype in x-linked disorders?
Men
Males are hemizygous (heterozygous) for mutant allele on the x
More likely to develop a mutant phenotype regardless if the mutation is dominant or recessive
Who does “x-linked dominant” and “x-linked recessive” apply to?
Females only!
What is not possible in x-linked disorders?
No male to male transmission is possible
Males and x-linked disorders
No male to male transmission is possible
Unaffected males do not transmit the phenotype
All daughters of an affected male are heterozygous carriers
Males usually more severely affected than females
Examples of x-linked dominant disorders
Alport’s Syndrome
Fragile X Syndrome
Examples of x-linked recessive disorders
Wiskott-Aldrich Syndrome
Duchenne muscular dystrophy
Multifactorial/Complex disease
Caused by interactions of variations in multiple genes and environmental factors
Genetic susceptibility genes
–>These genes make a person susceptible to a disorder, and certain environmental factors trigger the susceptibility
Examples of Multifactorial/Complex disease
Cancer Diabetes Asthma Heart disease Mental illness Cleft lip/cleft palate
Multifactorial/Complex disease- cancer
Sporadic inheritance of a cancer vs. inherited cancer syndrome for which a genetic test may be available (ex: BRCA)
- Sporadic cancer is more likely
- Most cancer is NOT inherited, but the predisposition to cancer IS inherited (ie BRCA)
The pedigree can help the clinician make more cost-effective, appropriate choices in genetic testing
-Determine who needs to be tested first, and who else needs to be tested
Down syndrome
Trisomy 21- gamete has 2 copies of chromosome 21 (leads to trisomy when fertilized)
Most common chromosomal abnormality in live births
Most common non-lethal trisomy
Prenatal testing for Down Syndrome
- Quad screen (maternal serum AFP, estriol, hCG, inhibin-alpha)
- Nuchal translucency
What causes Down Syndrome?
Trisomy 21 is cause of 95% of cases of Down Syndrome
4% due to Roberstonian translocation
Down Syndrome- When are parental chromosome studies indicated
indicated if trisomy was due to an unbalanced translocation
What is the prevalence of Down Sydrome
1:500 pregnancies
Increase incidence with advancing maternal age
Age 35 1:400
Age 45 1:35
Symptoms of Down Syndrome
Intellectual disability
Characteristic facial appearance
40% have cardiac defects
75% hearing loss
> 50% visual problems
7% have GI defects
Increased social skills in childhood as long as Syndrome isn’t severe
Half of adults with Down syndrome develop Alzheimer disease
Trisomy 18
AKA Edwards Syndrome
Second most common autosomal trisomy after trisomy 21 that goes to full term
Many die before birth or in first month
What is Trisomy 18 from
Usually from 3 copies of 18, but translocation can occur
Characteristics of Trisomy 18
Kidney and heart defects
Developmental delay
Club foot (Rocker bottom feet)–> hallmark sign
Low set ears, small jaw
clenched hand with overlapping fingers
Incidence of Trisomy 18
1:5000 live born infants
Increased risk with advanced maternal age
IUGR
Survival rate of Trisomy 18
Highly lethal in-utero – 85% lost between 10 weeks’ gestation and term
50% die in first week of life
2% 1 year survival rate
Heart, GI, kidney defects
Trisomy 13
- Patau syndrome
- Severe intellectual disability
- Many physical abnormalities
- Cleft lip or palate
- Seizures
- Small jaw
- Polydactyly
- Heart defects, brain/spinal
What is the incidence of Trisomy 13
1: 16,000 live births
Increased risk with advanced maternal age
Survival rate of Trisomy 13
cord abnormalities
-Many children die within first days or weeks of life
Etiology of Trisomy 13
- Most cases of Trisomy 13 from 3 copies of chromosome 13
- Some caused by Robertsonian translocation involving chromosomes 13 and 14
Cri-du-Chat Syndrome
Chromosomal abnormality: deletion of part of short arm of chromosome 5
Partial monosomy – when only a portion of a chromosome has one copy instead of two
Most cases are from a spontaneous mutation
1:50,000 births
Can be detected in utero with CVS (chorionic villi sampling)
What is the characteristic sign of Cri-du-Chat Syndrome?
Cat-like cry of affected children due to abnormal larynx development
Physical appearance of person with Cri-du-Chat syndrome?
Intellectual disability, wide set eyes, low ears
Klinefelter’s Syndrome
Extra X chromosome, 47 XXY–> so MEN
Occurs during gametogenesis
Affects male physical and cognitive development
Accounts for many first trimester losses
Physical traits become more apparent after puberty (will have some female characteristics)
Most common sex chromosome aneuploidy in males
Hypogonadism, infertility (b/c testicles not developing properly)
Gynecomastia(abnormal breast tissue in men), reduced hair
Turner Syndrome
45 X, affects development in females (does not affect males)
Monosomy
Characteristics of Turner Syndrome
Gonadal dysgenesis–> non-functional ovaries
Short stature
Broad chest
Webbed neck
Amenorrhea
Infertility
Cardiovascular abnormalities
Huntingtons disease
A neurodegenerative disease – progressive brain disorder
What Huntingtons disease causes
Causes uncontrolled movements
emotional problems
loss of thinking ability,
changes in personality
Involuntary jerking movements- Chorea
Early signs of Huntington’s Disease
depression, irritability, poor coordination, trouble learning
When do you see Huntington’s Disease
-Latent for a long time
Adult onset: genetic defect is latent for 3-5 decades, then manifests as progressive neuronal dysfunction
Etiology of Huntington’s Disease
Genetic defect: HD gene on chromosome 4 that codes for a unique protein called huntingtin
- CAG trinucleotide repeat
- Normal: 10-35 repeats
- In HD: 36-120 repeats
- Abnormal protein causes microscopic deposits of protein in neurons
- Most cases are inherited, but some occur as new spontaneous mutations (so MUST offer genetic counseling to offspring)
What is the average time from symptom onset to death in Huntingtons disease
15 years
Mode of inheritance of Huntington’s disease
Autosomal dominant
If one parent has the disorder, each child has a 50% chance of manifesting it
Only human disorder of complete dominance
***Heterozygotes are just as affected clinically as homozygotes (HH, Hh)
Alzheimer’s Disease
A neurodegenerative disease
Most common form of dementia in older individuals
65% of dementia from Alzheimer’s Disease
35% of dementia are vascular in nature
Alzheimer’s Disease- age of onset, population
Usually begins after age 60; risk increases with age
Death usually occurs within 10 years
People with parent, sibling, or child with AD are at increased risk
Pathophysiology of Alzheimer’s disease
Loss of cholinergic neurons in brain (loss of acetylcholine)
Formation of plaques and tangles
Atrophy of brain
Resultant effect – blocked communication
Mode of inheritance of Alzheimers disease
Several gene mutations cause predisposition to AD
Clinical manifestations of Alzheimers disease
Progressive mental deterioration: memory loss, confusion, disorientation
The two forms of Alzheimers disease
familial (early onset) and sporadic (late onset)
Familial Alzheimer’s Disease
Also called early onset AD
Many members of multiple generations affected
Symptoms start before age 65
Mutations on chromosomes 1, 14, or 21
Induce formation of a “sticky” protein that forms clumps in the brain
Rare - <5% of cases of AD
Autosomal dominant
50% chance of developing early onset AD if one parent has it
Sporadic Alzheimer’s Disease
Also called late onset AD
- Usually develops after age 65
- Accounts for most cases of AD
One gene has been shown to increase risk
- Chromosome 19 apolipoprotein E (APOE) gene
- Not everyone carrying the gene develops disease
*Definitive diagnosis: autopsy-plaques and tangles
Risk factors of Hereditary breast and ovarian cancer syndrome
Gender
Age
Family history
Mode of inheritance of Hereditary breast and ovarian cancer syndrome
Up to 10% of breast and ovarian cancers are caused by known predisposing genetic factors
Clinical manifestations of Hereditary breast and ovarian cancer syndrome
Early age of breast cancer onset (< 50)
FH of both breast and ovarian cancer
Increased bilateral cancers
Increased development of both cancers in same person
Increased incidence of prostate cancer in family
Male breast cancer
Overview of BRCA1/2
tumor suppressor genes
Normally control cell growth and death, and DNA repair and stability
If a person has one mutated copy of either gene, their cancer risk goes up
Second gene associated with breast cancer
BRCA2 on chromosome 13
Mutations is inherited in autosomal dominant manner
Associated with male breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer
BRCA1
First gene associated with breast cancer
- ->BRCA1 on chromosome 17
- ->Mutation is inherited in autosomal dominant manner
- ->Not all families with this gene get hereditary breast cancer
BRCA2
Second gene associated with breast cancer
BRCA2 on chromosome 13
Mutations is inherited in autosomal dominant manner
–>Associated with male breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer
Hereditary Breast and Ovarian cancer syndrome- genetic testing
Preferable to first test an individual who is affected by cancer before testing unaffected family members
Helps to identify whether a detectable BRCA1 or BRCA2 mutation could be responsible for the cancer
An individual can inherit a BRCA1 or BRCA2 mutation yet never develop cancer
Colorectal cancer
Genetic+ environmental factors
Genetic predisposition is the main risk factor in only a small proportion of people
Diet, exercise, smoking, obesity are stronger risk factors in most people
Colorectal cancer- familial inheritance
May occur sporadically or from familial inheritance
- Most are from sporadic mutations and occur randomly
- Many cancer syndromes include colon cancer
Types of colon cancer
- Familial colorectal cancer
2. Hereditary colorectal cancer syndromes
Hereditary colorectal cancer syndromes
Arise from specific mutations in genes that code for susceptibility to cancer
- ->Familial adenomatous polyposis (FAP) <1% of colon cancers
- ->Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch Syndrome) 2-3%
Familial colorectal cancers
Patterns within a family that exist without identifying a specific mutation are labeled as familial colorectal cancers
A family history of 1+ people with colorectal cancer or premalignant polyps is considered a positive FH
Familial colorectal cancer- causes
May be due to:
- Chance alone
- Shared exposure to a carcinogen or diet/lifestyle factors
- Combination of gene mutations and environmental risk factors
\Familial adenomatous Polyposis (FAP) gene
<1% of all colorectal cancers
Genetic mutation: mutation in APC (adenomatous polyposis coli) gene
- ->Hundreds to thousands of polyps in colon beginning in adolescence
- ->APC is a tumor suppressor gene on chromosome 5
- ->Cancers develop in 20’s
- ->Risk of developing colorectal cancer is near 100%, usually before age 50
- ->Time from polyp to cancer development is 10+ years
Mode of inheritance of Familial adenomatous Polyposis (FAP) gene
autosomal dominant
50% chance of passing it to each offspring
Mode of inheritance of Familial adenomatous Polyposis (FAP) gene–> genetic counseling and testing
Should be offered to all patients with a suspected diagnosis of FAP as identified by colonoscopy
Should also be offered to all relatives at risk
Children of patient with FAP should have genetic screening by age 10 years
Tx of FAP
Once diagnosis of FAP is established, total colectomy is recommended before age 20 years
Hereditary Nonpolyposis colorectal cancer (HNPCC)
Also called Lynch Syndrome
2-3% of all colorectal cancers
Pattern of inheritance of Hereditary Nonpolyposis colorectal cancer (HNPCC)
autosomal dominant
Genetic mutation: a mutation in one of many genes that code for DNA repair
More rapid transition from adenoma to cancer than FAP – cancers occur earlier, 30’s and 40’s
Hereditary Nonpolyposis colorectal cancer (HNPCC) –> Nonpolyposis
refers to the fact that colorectal cancer can occur when a small number or no polyps are present
Rate of incidence of Hereditary Nonpolyposis colorectal cancer (HNPCC)
Approx. 50% chance of cancer in women, approx. 70% in men
Hereditary Nonpolyposis colorectal cancer (HNPCC)-Association with other cancers
Associated with the formation of other cancers
Uterus, ovaries, stomach, urinary tract, small bowel, bile ducts
What to do if genetic testing + for Hereditary Nonpolyposis colorectal cancer (HNPCC) gene mutation
Regular colonoscopy starting age 25 for relatives
–>Or beginning 5 years younger than the age of diagnosis of the youngest affected family member
Upper endoscopy every 2 years to screen for gastric cancer
Screening for endometrial and ovarian cancer in women at age 25-35
Chronic Myelogenous leukemia
A myeloproliferative disorder
Genetic defect Translocation between chromosomes 9 and 22 Philadelphia chromosome (22)
**Produces a protein that codes for an enzyme that causes too many stem cells to develop into WBCs
Acute myelogenous leukemia is life threatening
Chronic Myelogenous leukemia- rate of incidence
More common in men
Median age at presentation is 55 years
Pathophysiology of Chronic Myelogenous leukemia-
Increased production of abnormal white blood cells that are nonfunctional
These large numbers of abnormal WBCs take up bone marrow space meant for healthy WBCs, RBCs, and platelets
Clinical presentation of Chronic Myelogenous leukemia
Insidious onset, slow progression over months to years of infections, anemia, complications of bleeding (most likely have low platelet counts)
Fever, night sweats fatigue (“B symptoms”)
Diagnosis of Chronic Myelogenous leukemia
Bone marrow aspiration and then assess for karyotype
Hemophilia
Bleeding disorders caused by mutations in genes that code for coagulation proteins
Mutation on F8 or F9 genes, located on the X chromosome
Hemophilia- Mutation on F8 gene
Mutation in F8 gene causes factor VIII deficiency
Results in hemophilia A (classic hemophilia)
More common
Hemophilia- Mutation on F9 gene
Mutation in F9 gene causes factor IX deficiency
Results in hemophilia B (Christmas Disease)
Pattern of inheritance of Hemophilia
X-linked recessive pattern
Genes associated are on the X chromosome
Most people affected are males
Clinical manifestations of Hemophilia
hemarthrosis (spontaneous bleeding into a joint)–> most common clinical manifestation
bleeding into muscles, and other soft tissues after injury or trauma;
prolonged bleeding or oozing of blood after injury or surgery
Severity of symptoms can be variable
Sickle Cell disease- pathophysiology
Atypical hemoglobin molecules (hemoglobin S)
Distorts the red blood cell into a crescent shape
Abnormally shaped RBCs break down prematurely
Mutation on HBB gene
Sickle Cell disease- Clinical manifestations
CP
Anemia, infections, episodic pain
Shortness of breath, fatigue, delayed growth
Generally will present with sickle cell crisis
Inheritance of Sickle cell disease
Autosomal recessive
Most common in people whose ancestors came from:
Greece, Africa, Turkey, Italy, Arabian Peninsula, India, South America, Central America, Caribbean
Cystic Fibrosis- Pattern of inheritance
autosomal recessive
Two copies of mutated gene are needed for disease to be expressed
Cystic Fibrosis- Genetic mutation involved
mutation in the CFTR gene (cystic fibrosis transmembrane conductance regulator)
CFTR codes for a protein that regulates chloride channels in epithelial cells
When mutated, a defective protein is made, causing a disruption of chloride and water transport - water balance in secretions is disrupted
Clinical manifestations of Cystic Fibrosis
Causes thick, sticky mucous obstructing airways in lungs and ducts in pancreas
Can affect pancreas, intestines, GU tract, hepatobiliary system, and exocrine glands
Clinical manifestations of Cystic Fibrosis–> symptoms
Difficulty breathing, infections in lungs
Problems with nutrient digestion
Buildup of mucous prevents pancreatic enzymes from reaching intestine
Failure to thrive, poor growth rate
Meconium ileus – newborn intestinal obstruction due to thick fecal waste products
What is the most common cause of morbidity associated with Cystic fibrosis
pulmonary disease
Pulmonary system can’t defend against pathogens well – leads to sinusitis and bronchitis
Nasal polyps, nosebleeds, chronic sinus infections common in CF patients
Thick mucous builds up in lower airways causing obstruction
Disease incidence of Cystic Fibrosis
Common genetic disease in the white population in the US
Disease incidence: 1 in 3500 white newborns
Carrier incidence: 1 in 25
Most cases diagnosed by age 1
How do you diagnose Cystic Fibrosis
Sweat chloride test – primary test for diagnosis
Defective chloride channel doesn’t allow chloride to be reabsorbed
-Concentration of chloride in sweat is elevated in CF
Genetic testing used to confirm results
Marfan syndrom- mode of inheritance
autosomal dominant
Results from either an inherited mutation or a new mutation of the fibrillin-1 gene (FBN1)
Results of Marfan Syndrome
Causes defects in connective tissue affecting multiple systems Bones Ligaments Muscles Blood vessels Heart valves
Clinical Manifestations of Marfan Syndrome
Tall stature Long, thin arms and legs Arm span wider than body height Long, narrow face High arched palate Overcrowded teeth Scoliosis Hyperflexible joints Chest deformities (barrel chest)
Primary features of Marfan syndrome
- vision problems because of dislocated lens
- Aortic aneurysm/dissection
What is the major cause of morbidity and mortality in Marfan Syndrome
Heart defects
Mitral valve prolapse, aortic valve regurgitation
–>Both of these can cause SOB, fatigue, palpitations
What do you advise patients with Marfan Syndrome
Affected individuals are advised to avoid contact sports, caffeine, and decongestants due to increased stress placed on CV system
Neurofibromatosis Type I
Also called von Recklinghausen disease
Pattern of inheritance of Neurofibromatosis Type I
autosomal dominant
Tumor suppressor gene
Pattern of inheritance of Neurofibromatosis Type I –> what mutation results in
Growth of neurofibromas - benign tumors that grow on nerves of skin and brain
Changes in skin pigmentation
Pattern of inheritance of Neurofibromatosis Type I – what is the most common type (along with clinical manifestations)
NF-1 is most common type
- Subcutaneous tumors
- Hyperpigmented skin lesions called café-au-lait spots
- Flat patches on skin darker than surrounding area
- Lisch nodules in iris
- Freckles in axillae and groin
Diagnositic features of Neurofibromatosis Type I
1.5 cm or larger café-au-lait spot post puberty or 6 or more café-au-lait spots 0.5 cm or larger in before puberty
2 or more neurofibromas to be diagnosed
Axillary or inguinal freckling (Crowe sign)
Optic glioma
2 or more Lisch nodules
1st degree relative with NF1
Polycystic kidney disease- pathophysiology
Clusters of fluid filled sacs develop in kidneys
Affects ability to filter the blood properly
Kidneys become enlarged and can fail (2nd most common cause of kidney transplant)
Polycystic kidney disease- Clinical manifestations
Hypertension
Back pain (b/c kidneys getting bigger and putting strain on back)
Hematuria
UTIs, kidney stones
Other associations of Polycystic kidney disease
Liver cysts
Heart valve abnormalities
Increased risk of aortic aneurysm and brain aneurysm
Polycystic kidney disease- 2 forms
Autosomal dominant
Autosomal recessive
Polycystic kidney disease- Autosomal dominant
sx start in adulthood
1 in 1000; PKD1 and PKD2 genes
Usually inherited (90% of the time)
Polycystic kidney disease- Autosomal recessive
rare, lethal early in life
1 in 30,000
PKHD1 gene
Congenital abnormalities
Approximately 10% of all newborns have some birth defect
–>Ranges from minor biochemical problem to severe physical deformity
Caused by variety of biological, chemical, and physical agents
–>Contributors: mutant genes, chromosomal defects, multifactorial components
What is the biggest cause of birth defects?
unknown etiology!
Congenital abnormalities- teratology
Teratology= study of abnormal development
Teratogens- anything capable of disrupting embryonic or fetal development and producing malformations
Teratogenic, teratogenicity
Congenital abnormalities- What is the critical period for teratogenic effects
3-16 weeks
brain starts to develop at 3 weeks
Timing of exposure determines which systems are affected
Example – CNS begins to develop in 3rd week, while teeth and palate begin to form in 6th-7th week
Newborn screening
Performed on all newborns
Biochemical analysis that determines whether certain proteins (enzymes) are present or absent
These are typically autosomal recessive conditions
Referred to as “inborn errors of metabolism”
–>Inherited defect in one or more enzymes
Newborn screening checks for many of these metabolic disorders
A law in 2008 was enacted to increase testing and make more uniform among states
Newborn screening- the Arizona Panel
The federally recommended uniform screening panel of 30 disorders (including hearing loss): Endocrine Disorders Hemoglobinopathies Other Enzyme Deficiencies Amino Acid Disorders Fatty Acid Oxidation Disorders Organic Acid Disorders Cystic Fibrosis Hearing Loss
Newborn screening- First and second test
1st: baby is 24-36 hours old
2nd: 1st office visit, b/w 5-10 days
Who are genetic counselors employed by Employed by>
physician offices, medical centers, advocacy organizations, governmental agencies, public health departments, biotech companies
Medical geneticist
Clinical genetics specialist
Practice of clinical medicine with regard to hereditary disorders
Recognized by the American Board of Medical Specialties
Residencies in clinical genetics are accredited by the American Council of Graduate Medical Education
Applicants must be M.D. or D.O. who has already completed 24 months of another residency
Genetic counselor
Master’s trained health care professionals
Skilled in genetic risk assessment, education, counseling
