Genetics Flashcards
When is consanguinity particularly significant?
If you suspect a recessive disease
What types of diseases are always important to ask about in the family because of their strong genetic component?
Heart disease
Diabetes
Cancer
Why is it important to ask about miscarriages, abortions, and stillbirths when evaluating genetic diseases?
As many as 50% of miscarriages and 4% of stillbirths are due to chromosomal aberrations
What are two reasons why it is important to keep updating the family history?
Some diseases manifest later in life
Adding new members to the family
What are common symptoms of Prader Willi syndrome?
Short height Small hands and feet Hypogonadism Generalized obesity Mental retardation
What arm span to height ration begins to suggest Marfans?
> 1.05
What is acrocephaly? Scaphocephaly?
Pointed head
Narrow head
What is hyper or hypotelorism?
Too much or too little space between the eyes
What does a blue sclera suggest?
Osteogenesis imperfecta
What are things to look for in the physical exam of the iris?
Lisch nodules in neurofibromatosis
Brushfield spots in trisomy 21
Kayser fleischer rings in Wilson’s disease
What does a woolly, low hairline suggest?
Noonan’s syndrome
What are macro and microglossia?
Large and small tongue
What are macro and micrognathia?
Large and small jaw
What are prognathia and retrognathia?
Protruding jaw
Pulled back jaw
What two syndromes can webbing of the neck suggest?
Pterygium colli in Turner syndrome
Noonan’s syndrome
What are arachnodactyly and bradydachtyly?
Long and short fingers
What is clinodactyly?
Finger kinked inward - common in pinky finger in downs
What is genu varum and genu valgum?
Bow legged
Knock knees
What is cryptorchidism?
Undescended testes
What is hypospadia?
Urethra opens on ventral side of penis rather than tip
What is dysmorphology?
Diagnosis and management of congenital anatomic anomalies due to abnormal physical development
2/3 are multifactorial or unknown cause
Only 30% have identifiable genetic component
What are six clues the the patient has a genetic disease?
Disease occur in definite proportions in the family
Not present in spouses or in laws
Characteristic age of onset (often young) and course
Presence of multiple somatic abnormalities +/- mental retardation
Higher incidence in monozygotic than dizygotic twins
Presence of multifocal tumors
What is an example of a maternally imprinted syndrome? Paternally imprinted?
Prader Willi
Anglemans
What is pleiotropy?
Different manifestations of the disease-causing gene defect
What are two databases useful in determining if a congenital abnormality is isolated or part of a pattern?
Gene tests
Mendelian inheritance in man
What are four types of diagnostic tests for genetic diseases?
Screening tests for metabolic disease (urine or serum)
Functional tests (enzymatic assays)
Structural assays
Molecular diagnosis
What are five methods of molecular diagnosis?
Cytogenetics Comparative genome hybridization Direct detection of gene mutations Detection of mutations in diseases in which there is allelic genetic heterogeneity Indirect detection of diseased allele
What are cytogenetics and what are the problems with it?
Detection of chromosomal rearrangement/deletion by using karyotype or FISH
Problem - doesn’t detect single gene mutations or small deletions unless specific probes to the region deleted are available
What is comparative genomic hybridization (CMA) and what are the problems with it?
Augmenting conventional cytogenetics to detect variations in copy number of regions of the genome
Problem - doesn’t detect when no net gain or loss of genetic material (balanced translocations or inversion), detects many variants of unknown significance even in normal people
When is direct detection of gene mutations useful?
Genetic diseases for which single mutation in single gene responsible - use molecular assays
Ex: sickle cell, factor v Leiden
What is an example of detection of mutations in diseases in which there is an allelic genetic heterogeneity?
DNA chip resequencing
Ex: BRCA 1
Problem - not all possible mutations are screened, technology still not at stage when it is routine
What is indirect detection of diseased alleles and what is the problem with it?
Segregation of linked markers in a family
Problem - must get genomic DNA from family members
Where can genomic DNA be extracted from?
WBCs most common
Buccal cells
Cultured cells
Biopsy specimens
What is mosaicism?
Not every cell or tissue has the same exact genetic composition due to mutation that arose in one cell of multicellular embryo
What are 8 indications for referral to a genetic counselor?
Known genetic disease in patient or family member Single or multiple malformations Mental retardation or developmental delay Advanced maternal age Family history of early onset tumor Recurrent pregnancy loss Teratogens exposure Consanguinity
What is anticipation a clinical hallmark of?
Trinucleotide repeat expansion
What are codominant alleles?
Both expressed in heterozygous and homozygous state
What can gonadal mosaicism result in?
Autosomal dominant disorder when mutation is present in more than one child but not either parent
What is heteroplasmy?
Having different DNA sequences in the same cell
Term for mitochondrial disorders
What is a phenocopy?
When an identical phenotype is produced by defects in different genes or by gene defect and an environmental factor
What is acromelia?
Shortening of distal parts of limbs as in achondroplasia
What is the incidence of chromosome disorders in humans?
Newborns: 4/1000 autosomal abnormality, 2/1000 with sex chromosome abnormality
Disease with a genetic component in <25 YO is 5%
How much of the genome encodes proteins? How much is of unknown function?
Less than 2%
More than 50%
How many genes and base pairs are in the human genome?
About 25,000 genes
About 3.2 billion base pairs
What are three alterations in protein coding genes other than mutations?
Sequence and copy number variations - SNP, CNVs
Epigenetic changes - methylation, histone modification, imprinting
Alteration in non coding RNAs that inhibit translation - miRNAs and lncRNAs (long non coding)
What are the four categories of mutations?
Missense mutations - conservative and non-conservative
Nonsense mutations (beta thalassemia)
Frame shift mutation (ABO blood system, Tay Sachs)
Trinucleotide repeat mutations
What are the four major categories of genetic disease?
Mendelian disorders
Complex multigenic disorders
Cytogenetic disorders
Single gene disorders with atypical pattern of inheritance
What are the four categories of Mendelian disorders caused by single gene defects?
Defects in structural proteins (Marfans and ehlers-danlos syndrome)
Defects in receptor proteins or channels
Defects in enzymes
Defects in proteins that regulate cell growth
What is the pathology of Marfans syndrome?
Defect in fibrillin 1 that is normally scaffolding for elastin
600 causative mutations
What are clinical features of Marfans?
Tall stature Arachnodactyly Bilateral subluxation of Lens Aortic dissection Cystic media necrosis of aorta due to deposition of ground substance Mitral valve prolapse Pectus excavatum
What is the inheritance pattern of Marfans?
Autosomal dominant
15-30% are new mutations
What is the pathology of ehlers-danlos syndrome?
Various defects in collagen molecule
Six different variants
What is the inheritance of ehlers-danlos syndrome?
Collagen defects are autosomal dominant
Enzyme defects are autosomal recessive
What are the clinical features of ehlers-danlos syndrome?
Hyper extensible joints and skin Cigarette paper scars Aortic and colonic rupture Ocular fragility with rupture of cornea and retinal detachment Diaphragmatic hernia
What are the six different types of ehlers-danlos syndrome and the gene defect responsible for each?
Classical (1,2) - COL5A1, COL5A2 Hyper mobility (3) - unknown but AD vascular (4) - COL3A1 Kyphoscoliosis (6) - Lysyl hydroxylase Arthrochalasia (7a,b) - COL1A1, COL1A2 Dermatosparaxsis (7c) - procollagen, N-peptidase
What is the inheritance of cystic fibrosis?
1/3200 live births
Autosomal recessive - doesn’t affect heterozygotes
What happens with mutated CTFR in the airway (pancreas, lung epithelium)?
Normal mucus becomes dehydrated and thick - can plug up and damage organs as well as provide hotbed for bacterial infection
What happens with mutated CTFR in sweat ducts?
Normally no increase in sweat chloride but sweat test positive means increased sweat chloride
What are the mutation classifications for CF?
Class I - defective protein synthesis
Class II - abnormal protein folding and trafficking
Class III - defective regulation
Class IV - decreased conductance
Class v - reduced abundance
Class vi - altered regulation of separate ion
What are genetic and environmental modifiers of CF?
Genetic - mannose binding pectin immunity involved in opsonizaton
Environmental - organism virulence (pseudomonas and burkholderia cepacia very virulent), infections by multiple organisms, exposure to smoking and allergens
What pathological changes are associated with a severe phenotype of CF?
Bronchiectasis
Hepatic cirrhosis
Pancreatic insufficiency
Male infertility
What pathological changes are associated with a mild phenotype of CF?
Azospermia
Sinusitis
Absence of vas deferens
All as sole abnormalities
What is the biochemical pathway involved in phenylketonuria?
Phenylalanine normally converted to tyrosine by phenylalanine hydroxylase
What is the biochemical abnormality in classic phenylketonuria?
500 mutant alleles in phenylalanine hydroxylase identified
Diagnosis requires measurement of phenylalanine in blood
What is the inheritance pattern of classic phenylketonuria?
Autosomal recessive
1/12,000
Scandinavian descent
What are the clinical features of classic phenylketonuria?
Mental retardation evident by 6 mos Mousy odor Light skin and hair Eczema Gait disturbances and seizure
What is maternal PKU?
Teratogenic effect of phenylalanine
Clinically normal female PKU patient of childbearing age that discontinues dietary control
75-90% children are mentally retarded, microcephalic, 15% congenital heart disease
Children heterozygotes
Fetal anomalies directly correlate with phenylalanine level
What is the biochemical pathway involved in galactose metabolism and galactosemia?
Galactose 1 phosphate + ADP is converted to UDP galactose + glucose 1 phosphate by GALT (galactose 1 phosphate uridyl transferase)
Most common form is due to deficiency in this enzyme
What is the inheritance pattern of galactosemia?
Autosomal recessive
1/60,000
What are the clinical features of galactosemia?
Vomiting and diarrhea
Neonatal jaundice and FTT, liver failure, hepatomegaly
Cataracts
Mental retardation
Susceptibility to infection (e. coli septicemia)
Aminoaciduria (impaired AA transport)
What is the diagnosis and treatment of galactosemia?
Reducing sugar other than glucose in urine
Direct enzyme assay in leukocytes
Prenatal diagnosis - GALT or galacitol level in amniotic fluid
Early removal of galactose in first two years can prevent cataract and liver damage but not speech disorders, gonadal failure, and ataxia
What are the anatomic change of untreated galactosemia?
Organomegaly
Fatty change and fibrosis in liver
Cataracts
Why are newborns screened for PKU and galactosemia?
Treatment available and early institution better
Testing required to reveal - exam wont
Rapid economical test is available that is highly sensitive and specific
Condition frequent and serious enough to justify it
Infrastructure in place to deal with results
What are 4 common features of lysosomal storage diseases?
Autosomal recessive
Pediatric age group affected
Hepatosplenomegaly, CNS damage with neuronal damage
Damage caused by storage of undigested material and secondary events (cytokine release and macrophage activation)
What is Tay Sachs disease?
Mutations in b subunit of hexosaminidase A leads to inability to degrade GM2 gangliosides
How can heterozygotes Tay Sachs carriers be identified?
Serum hex A level or DNA analysis
What are the histological features of Tay Sachs disease?
Lipid vacuolization in large neurons
EM lysosomes filled with whorled configurations
What are clinical features of Tay Sachs disease?
Onset 3-6 months, death 2-3 yrs Primarily CNS Cherry red spot in retina Blindness (retinal involvement) Motor and mental deterioration
What is the pathogenesis of damage presumed to be due to in Tay Sachs?
Unfolded protein response
Lack of chaperone stabilization
What are features common to Neimann pick types A and B?
Most severely affected organs have high phagocytic function (spleen, liver, bone marrow, lymph nodes and lungs)
Acid sphingomyelinase deficiency resulting in sphingomyelin accumulation
What are features of Neimann pick type A?
Severe infantile form
Missense mutation leads to complete deficiency of sphingomyelinase and visceral accumulation of sphingomyelin
Extensive neurological involvement
Death by age of 3
What is Neimann pick type B?
Survival into adulthood
Organomegaly but no CNS involvement
What is the histology of Neimann pick types A and B?
Foamy and vacuolated hepatocytes and kupffer cells
EM shows zebra bodies - lamellated myelin figures
How do you diagnose Neimann pick types A and B?
Enzyme analysis
Biochemical assay for sphingomyelinase activity in liver or bone marrow biopsy
Direct DNA analysis
What is Neimann pick type C?
More common than A and B combined
Lipid accumulation due to NPC1 and NPC2 mutations
Terminal axons and dendrites degenerate due to accumulation of cholesterol, GM1 and/or GM2
What are the clinical features of Neimann pick disease type C?
Clinically heterogenous Hydrops fetalis and still birth Neonatal hepatitis Chronic, progressive neurologic damage Childhood presentations with ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria, and psychomotor regression
What are general features of gaucher disease?
Mutations in glucocerebrocidase gene
Most common lysosomal storage disorder
Glucocerebrocide accumulation in phagocytic system and sometimes CNS
Macrophage activation causes cytokine release
What is Gaucher type I?
Most common, chronic non-neuronopathic form
No brain involvement but spleen and skeletal
Reduced enzyme activity
Can live to adulthood
What is gaucher type II?
Acute neuronopathic form
Infantile acute cerebral form, death at early age
No enzyme activity
Some organomegaly but progressive CNS involvement
What is gaucher type III?
Chronic neuronopathic (intermediate between I and II) Juveniles with systemic involvement but also progressive CNS disease
What are the histological changes in Gaucher disease?
Gaucher cells not vacuolated, have fibrillary cytoplasm due to accumulation of glucocerebrocides in macrophages
Crumpled tissue paper cells in bone marrow but not pathognomonic
How is gaucher diagnosed?
Leukocyte or fibroblast glucocerebrosidase level
What is the therapy for gaucher disease?
Enzyme replacement Glucocerebroside synthase inhibition Symptomatic treatment Supportive care Sometimes bone marrow transplant
What are the mucopolysaccharidoses?
Hunter and hurler
Different deficiencies in lysosomal enzymes - I - IV exist
Mucopolysaccharides - part of ground substance of connective tissue produced by fibroblasts - accumulate
Autosomal recessive except x linked hunters
How are mucopolysaccharides degraded?
Lysosomal enzymes cleave terminal sugars from polysaccharide chain
Lack of degradation of terminal sugar prevents entire chain
What are abnormal clinical features in the MPSs?
Course facial features Cloudy corneas Joint stiffness Skeletal deformities Mental retardation Hepatosplenomegaly Cardiovascular involvement (MI most common cause of death)
What is hurler syndrome?
MPS I - deficiency of alpha-L-iduronidase
Dermatan sulfate and heparan sulfate accumulate
One of most severe
Hepatosplenomegaly by 6-24 mos
Death by 6-10 yrs, usually cardiovascular
What is hunters syndrome?
MPS II - deficiency of L-iduronate sulfatase
Dermatan sulfate and heparan sulfate accumulate
Milder clinical course - no CNS disease, less aggressive course, no corneal clouding
What are the three types of glycogen storage diseases?
Most autosomal recessive
- Von gierke - type I (hepatic form) due to defect in glucose-6-phosphotase - hepatomegaly, hypoglycemia, weakness
- McArdle - type v (myopathic form) due to defect in muscle phosphorylase - hypotonia, muscle cramps after exercise, weakness, failure of exercise to induce elevated blood lactate levels
- Pompe - type II (lysosomal storage disease) due to defect in lysosomal acid Maltase - cardiomegaly, enzyme replacement?
What is a feature of complex multigenic diseases?
Trait expression is determined when two or more polymorphisms are co inherited and conditioned by environmental influences
Polymorphisms and and quantitate trait loci
What is a polymorphism?
Genetic variant that has at least two alleles and occurs in at least 1% of the population
What are quantitative trait loci?
Characteristics governed by multigenic inheritance
What are some examples of complex multigenic diseases?
Diabetes, immune mediated inflammatory diseases, coronary heart disease, hypertension
What does aneuploid mean?
Any chromosome number not an exact multiple of n
What is anaphase lag?
Failure of pairing of homologues with random assortment
What are the two categories of cytogenetic disorders?
Numeric
Structural
What is the difference between a para centric inversion and a pericentric inversion?
Pericentric involves both sides of centromere
What is a robertsonian chromosome formation?
Two long arms join together leaving two short arms joined together
What are specimens that can be evaluated using FISH?
Prenatal specimens, peripheral blood, bone marrow, paraffin embedded tissue sections, non neoplastic tissue (fibroblasts) and tumors
What can be detected using FISH?
Numerical abnormalities Micro deletions Complex translocations Gene amplifications Gene mapping
What are the unique features of CMA?
Genome wide analysis
DNA from any source
What does CMA detect?
Copy number gains and losses
Addition of SNPs can add ability to detect loss of heterozygosity
When is linkage analysis used?
For entities where direct DNA analysis is not possible because gene not identified or disease is multifactorial
What a linkage analysis lead to formation of?
A disease haplotype based on panel of SNPs co segregating with disease allele
What is the incidence of downs?
1/1550 live births in women 45
What is downs associated with?
Advanced maternal age
Meiotic I nondisjunction event
What led to the thinking that the gene for Alzheimer’s might be on chromosome 21?
Almost without exception if a downs patient lives until 40 they will develop Alzheimer’s
What is trisomy 18?
Edwards syndrome
1/8000
Heart defects, hypertonicity (unique to this disorder), overlapping fingers, clenched fist, intrauterine growth retardation
What is trisomy 13?
Patau syndrome
1/4000
Cleft lip and palate, brain abnormalities, midline skeletal defects
Polydactyly with midline defect is trisomy 13 until proven otherwise
What is a micro deletion syndrome?
Large class of genetic disorders that involve deletion of very small chromosomal regions that cannot be seen by conventional cytogenetic analysis
Diagnosed by FISH
first one discovered involved chromosome 22
What is chromosome 22q11.2 deletion syndrome?
1/4000
Unique facial problems resulting in nasal sounding speech, heart defects, developmental delay, hypocalcemia due to parathyroid hypoplasia, T cell immunodeficiency, and predisposition to schizophrenia or bipolar disorder
Why are sex chromosome abnormalities better tolerated than autosomal?
Inactivation of one x
Little genetic material on y
What are the tenets of the Lyon hypothesis?
Only one X chromosome is genetically active
Other X undergoes heteropyknosis and is inactive
Inactivation is random
Inactivation of same X persists
What are general features of sex chromosome disorders?
Subtle, chronic problems
Difficult to diagnose at birth
Higher number of X chromosomes can be associated with greater likelihood of phenotypic effect and mental retardation
What is Turner syndrome?
1/2000-3000
Short stature, coarctation of aorta, horseshoe kidney, streak ovaries, hypothyroidism
Sometimes not recognized until fail to go through puberty
SHOX haplosufficiency causes short stature with no mental compromise
What is Klinefelter syndrome?
1/500 males
Two or more X chromosomes and one or more Y
Hypogonadism, small testes and penis, pear shaped figure, long legs, predisposition to breast cancer, extra gonadal germ cell tumors and auto immune disease
What are true hermaphrodites?
Rare
Both ovarian and testicular tissue
Can have xx and xy bearing cell lines
What is a female psuedohermaphrodite?
XX with ovaries but male external genitalia
Can be virilization due to high numbers of androgens
Congenital adrenal hyperplasia - defect in enzyme that results in overproduction of androgens
What is a male psuedohermaphrodite?
Y chromosome and testes but external genitalia ambiguous or female
Androgen insensitivity - defects in androgen receptor, so androgens made but patients cannot respond
What are the clinical features of fragile x syndrome affected males?
Long face and mandible
Large, everted ears
Macro-orchidism
What is the incidence of fragile x syndrome?
X linked
1/1550 male births
1/8000 females
What is the cause of fragile x syndrome?
Mutation in FMR1 gene
Highly expressed in brain
Repeated CGG sequence - expansion during female but not male meiosis
What is the inheritance pattern of fragile x syndrome?
Transmitting males - roughly 20% carrying mutation are normal, all daughters inherit trait and pass it on
Carrier females may be affected - about 30-50% have mental retardation
What is the Sherman paradox?
The risk of being affected with fragile x syndrome depends on the persons position in the pedigree
What are the two categories of trinucleotide repeat disorders?
Expansions affecting noncoding regions - fragile x
Expansions affecting coding regions - Huntington
What is leber hereditary optic neuropathy?
Mitochondrial disorder
Affected organ systems involve oxidative phosphorylation
Threshold effect - minimum number of mutant mitochondrial DNA must be present to cause phenotypic effect
What chromosome are the genes for Prader Willi and Anglemans located on?
15
What is gonadal mosaicism and what is the mechanism for producing phenotypically abnormal offspring?
Results from post zygotic mutation that affects gonadal tissue
Transmission of abnormal gamete from phenotypically normal parent
