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72 Cards in this Set
- Front
- Back
define allelic heterogeneity
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existence of different mutant alleles of the same gene
(e.g. different mutations on the same gene can cause the same disease) |
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define locus heterogeneity
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occurrence of similar/identical phenotypes due to mutations at two or more different loci/genes
(e.g. different mutations on different genes can cause the same disease) |
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define phenotypic/clinical heterogeneity
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different mutations in the same gene give rise to different phenotypes/clinical pictures
(e.g. different mutations on the same gene cause different diseases) |
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define autosomal dominant
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gene is located on a chromosome other than the X or Y chromosome
need only one dose of a mutant allele to present with the disease/trait affecteds are usually heterozygotes, but homozygotes may occur and may be more severely affected |
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how does autosomal dominant appear in a pedigree?
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the trait typically appears in each generation (vertical transmission); isolated cases may be caused by new mutation
males and females are equally likely to inherit the mutant allele and either parental sex can transmit the mutant allele to either offspring sex phenotypically "normal" family members don't transmit generally |
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what are the chances that the offspring of a pt with an autosomal dominant disorder will be affected?
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50% if parent is A/a
100% if parent is A/A |
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define penetrance
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the fraction of individuals with a genotype known to cause a disease who have any sign or symptoms of the disease
(# of affecteds) ----------------------------------------- (# with "affected genotype") |
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compare penetrance at an individual level to penetrance at a population level
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individual level: a disease gene (allele) is either penetrant or not
population level: fraction/percent of pts affected out of those who should be affected (eg. fully penetrant AD disease means that everyone with a disease allele has the disease; fully penetrant AR disease means that everyone with homozygous mutant alleles has the disease) |
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define pleiotropy
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presence of multiple phenotypic effects of a single allele or pair of alleles
**particularly used when the effects are not obviously related (e.g. impact different systems)** |
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define expressivity
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extent or degree of expression (e.g. mild to severe)
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compare penetrance with expressivity
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penetrance is a measure of how many ppl are affected by the mutant allele, no matter the extent/severity of disease in the pts
expressivity is the range across which the extent/severity to which an individual can be affected by the disease can vary |
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in a pedigree, there are six ppl with an autosomal dominant disorder, six ppl heterozygous for the mutant allele, and two people who are homozygous for the allele.
what is the chance that an unaffected heterozygous male, with a female who is homozygous for the normal allele, will have a child who is affected? |
risk = (chance that dad will pass on the mutant allele) x (penetrance)
risk = (1/2) x (6/8) = 3/8 = 0.375 |
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in a pedigree, there are 3 ppl with an autosomal recessive disorder, twelve ppl heterozygous for the mutant allele, and five people who are homozygous for the allele.
what is the chance that an unaffected heterozygous male, with a female who is homozygous for the mutant allele, will have a child who is affected? |
risk = (chance that dad will pass on the mutant allele) x (chance that mom will pass on the mutant allele) x (penetrance)
risk = (1/2) x (2/2) x (3/5) = 3/10 = 0.30 |
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what is the effect of late age of onset on a pedigree?
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if one/more generations/persons with the "affected genotype" is younger than the typical age of onset for the disorder, they may not be presenting yet; they may be mistakenly labeled non-penetrant individuals
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what is the inheritance pattern for achondroplasia?
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autosomal dominant
complete penetrance |
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what is the inheritance pattern for osteogenesis imperfecta?
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autosomal dominant
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what is the inheritance pattern for marfan syndrome?
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autosomal dominant
variable expressivity pleiotropy |
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what is the inheritance pattern for neurofibromatosis?
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autosomal dominant
full penetrance variable expressivity often caused by new mutation |
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what is the inheritance pattern for Huntington Disease?
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autosomal dominant
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what is the inheritance pattern for familial alzheimer disease?
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autosomal dominant
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what is the inheritance pattern for familial hypercholesterolemia?
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autosomal dominant
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what is the inheritance pattern for blood types?
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autosomal dominant
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define qualitative mutation
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mutation that causes a structural change in a protein (or RNA) that results in an abnormal gain of function that leads to disease
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define quantitative mutation
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mutation that causes a reduction in the amounts/levels of normal protein
**the body may need to have a certain minimal amount (threshold) of a particular protein (or gene expression); if both alleles of a specific gene need to be functional/normal to achieve the level, then mutation of one allele would result in a drop below the threshold level (haploinsufficiency)** |
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what is the most common cause of dwarfism in man?
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achondroplasia
**causes short-limbed dwarfism in 1/15,000-40,000 live births** |
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what are the clinical features of achondroplasia?
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short stature
macrocephaly (lg head) frontal bossing (prominent forehead) reduced fertility limbs that are short proximally curvature of the spine (lumbar lordosis) depressed nasal bridge AFFECTED PERSONS ARE OF NORMAL INTELLIGENCE |
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what gene/protein is affected in achondroplasia?
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FGFR3 (Fibroblast Growth Factor Receptor 3)
**typically a G380R substitution** (G->C or G->A in first position of codon 380) |
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what is the most common single base mutation in humans?
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C to T transition
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what does it mean for the genetic code to be degenerate?
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different sequences of nucleotide bases can code for the same amino acid
e.g. AGG=Arg and CGG=Arg |
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define transition
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substitution of a purine for another purine or of a pyrimidine for another pyrimidine
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define transversion
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substitution of a purine for a pyrimidine or vice versa
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describe the heterogeneity of achondroplasia
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no locus heterogeneity (ONLY a mutation in the FGFR3 gene can cause achondroplasia
very little allelic heterogeneity (90% of the mutations of FGFR3 are G380R substitutions) |
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what is the normal function of FGFR3? how is it altered in achondroplasia?
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fibroblast growth factor receptor 3 (FGFR3) is a transmembrane tyrosine kinase receptor that, on activation by FGF, inhibits the proliferation of chondrocytes and thereby arrests growth
in achondroplasia, a G380R substitution causes FGFR3 to be constitutively active and to always inhibit growth rather than only in response to signal |
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how do most pts with achondroplasia inherit the disorder?
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in most cases, the parents of the pt with achondroplasia are not affected b/c about 80% of cases are caused by new mutations
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when does the risk of new achondroplasia-causing mutations increase?
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advanced paternal age (>35 yrs)
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in what types of disorders are new mutations likely to be the cause of the majority of cases?
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more likely in severe disorders (e.g. those that are lethal in childhood or that prevent reproduction for some reason)
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what is the most severe type of osteogenesis imperfecta?
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type II
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where do most cases of type II osteogenesis imperfecta arise?
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new mutations
type II OI is perinatal lethal |
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what are the clinical features of type II osteogenesis imperfecta?
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generally lethal perinatally
- large, unmineralized skull - small thoracic cavity - short & deformed long bones of arms and legs - flattened vertebral bodies - undermineralization of all bones - many congenital or prenatal fractures |
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define true/pure dominant
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individuals present with the same phenotype whether they are heterozygous or homozygous for the mutant allele(s)
ex. Huntington's Disease |
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define incomplete dominant
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trait that is inherited in a dominant manner, but that is more severe/extreme in a homozygote than in a heterozygote
ex. achondroplasia |
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define codominant
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a trait where if both alleles of a pair are expressed in the heterozygous state, then the alleles (or traits determined by them) are both presented to some degree
ex. A and B blood types |
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achondroplasia homozygotes
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more severe disease than heterozygotes
lethal in utero or in early infancy incomplete dominant |
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familial hypercholesterolemia homozygotes
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more severe disease than in heterozygotes
heterozygotes have elevated cholesterol levels, but homozygotes have astronomical levels incomplete dominant |
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Huntington disease homozygotes
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homozygotes and heterozygotes have similar phenotype
true dominant |
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what disorders involve mutations of FGFR3?
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1. achondroplasia
2. thanatophoric dysplasia 3. hypochondroplasia 4. severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) 5. muenke coronal craniosynostosis 6. crouzon syndrome with acanthosis nigricans significant phenotypic/clinical heterogeneity |
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thanatophoric dysplasia
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caused by mutation of FGFR3
severe perinatal lethal similar disease to achondroplasia homozygotes |
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hypochondroplasia
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caused by mutation of FGFR3
milder disease than achondroplasia |
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what is the most common type of osteogenesis imperfecta?
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type I (1/15,000 live births)
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clinical features of type I osteogenesis imperfecta
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mild disease
- brittle bones with tendency to fractures - fractures generally heal w/o deformity - blue sclerae - deafness |
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where do most cases of type II osteogenesis imperfecta come from?
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new mutations
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clinical features of type III osteogenesis imperfecta
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some fractures at birth
progressive deformity growth retardation some blue sclerae |
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clinical features of type IV osteogenesis imperfecta
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tendency for fractures
normal sclerae |
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how does the mutation in type I OI differ from the mutation in type II OI?
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in type I OI, the mutation is a null mutation (a mutation in the early coding or promoter region) in the alpha1 allele of collagen; this mutation doesn't allow production of proalpha1 collagen from this allele, but since normal proalpha1 collagen can be made from the other copy some normal collagen can still be made (though it is less)
in type II OI, the mutation is later in the coding sequence, so abnormal proalpha1 collagen is made and then pairs with other procollagen molecules; this results in destruction of the abnormal proteins rather than just producing insufficient protein, the abnormal protein actually causes the destruction of normal/good proteins |
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define dominant-negative mutation
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disease-causing allele, or the effect of such an allele, that results in disruption of the function of the wild-type allele or protein
aka protein suicide |
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what are the clinical features of Marfan syndrome?
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skeletal: long, thin extremities and fingers (arachnodactyly); arm span:height ratio>1.05; lax joints; bony deformities of the spine and sternum
eye: nearsightedness and lens dislocation (ectopia lentis) (usually upward) cardiovascular: widening/dilation of aortic root (dissecting aneurysms); valvular incompetence (mitral valve prolapse) |
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define genetic compound
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aka compound heterozygote
individual that is heterozygous for two different mutant alleles at a single gene |
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sex-limited vs. sex-influenced traits
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sex-limited: trait expressed in only one sex
sex-influenced: trait expressed differently (in degree/frequency) in males vs. females |
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male pattern baldness
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hair recedes in an "m" shape
the crown bald patch eventually meets the top points to form a horseshoe shape |
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define mosaicism
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presence in an individual (or a tissue) of two or more cell lines that differ genetically but that came from one zygote
can be somatic or germline mosaicism |
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what is the result of somatic mosaicism?
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segmental/modified disease expression
e.g. neurofibromatosis 1 (NF1) |
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what is the result of germline mosaicism?
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multiple affected offspring from two unaffected parents
e.g. osteogenesis imperfecta |
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what are the clinical features of neurofibromatosis 1 (NF1)?
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multiple neurofibromas (benign, fleshy skin tumors)
multiple cafe-au-lait spots (flat irregular pigmented skin lesions) Lisch nodules (small benign iris nodules) - not found in NF2 inc. risk for certain neoplasms (optic nerve gliomas, brain tumors, malignant myeloid disorders) axillary freckling |
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why is germline mosaicism a more plausible explanation than random mutations in a family where an unaffected couple has two children afflicted with an autosomal dominant disease (assuming complete penetrance)?
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mutations are RARE
- 1/10,000 to 1/1,000,000 gametes since mutations are so rare, it is HIGHLY unlikely that two mutations will occur in the same family |
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how can somatic and germline mosaicism coexist in the same individual?
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the mutation must occur during embryogenesis
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how does an autosomal recessive disease present in a pedigree?
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parents are usually not affected, but are probably carriers
the offspring of an affected individual can only be a carrier or an affected see multiple affected individuals only in sibship, with males and females affected equally see affecteds in one generation, therefore called horizontal transmission |
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what is the inheritance pattern of alkaptonuria?
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autosomal recessive
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what is the inheritance pattern of Tay-Sachs Disease?
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autosomal recessive
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what is the inheritance pattern of cystic fibrosis?
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autosomal recessive
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what is the inheritance pattern of sickle cell anemia?
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autosomal recessive
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what is the inheritance pattern of phenylketonuria?
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autosomal recessive
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what is a generalization about autosomal recessive conditions?
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most are caused by mutations that result in loss of function, esp. of an enzyme
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