Genetics 1 - Inheritance Patterns Flashcards
essential learning outcomes
Klippel-Feil Syndrome clinical symptoms
webbed neck
high arched palate
normal carrying angle
low set hairline - mid thoracic spine
congenital protrusion from skull
pectus excavatum
no organomegaly
kyphoscoliosis
significant restricted range of movement cervical and thoracic spine
SOB - minimal exertion
acute kidney injury
thoracic aortic aneurysm and thoracoabdominal aneurysm
dilation of aortic arch
bilateral pulmonary hyperinflation
what causes symptoms of Kippel-Feil Syndrome
congenital fusion of any 2 of 7 cervical vertebrae
Klippel-Feil Syndrome - mutations of what genes
GDF6
GDF3
MEOX1
(bone development)
Klippel-Feil Syndrome inheritance pattern
can be autosomal dominant or recessive (depends on gene involved)
Huntington disease inheritance pattern
autosomal dominant pattern
characteristics of Huntington
progressive neuronal loss - loss of neurons in basal ganglia
disease onset usually 30’s or 40’s
survival for 15-20 yrs after 1st symptoms
gene associated with Huntington
what sort of mutation is it
HTT gene
Polyglutamine/repeat expansion mutation
Trinucleotide repeat - repeat for CAG (makes glutamine)
Multiple copies of CAG
Non functional huntington protein
The more repeats you have, the earlier you are likely to display symptoms and more severe the phenotype will be
anticipation of Huntington
offspring may have earlier onset/more severe phenotype than parent due to further expansion of the repeat
risk for children - Huntington
27-35 repeats
incomplete penetrance - Huntington
36-39 repeats
no of repeats needed to develop Huntington
40+
how to screen for Huntington
preimplantation and prenatal diagnosis
select the non-hereditary, congenital diseases from the following list
rank these concepts in order of appearance
autosomal inheritance
not sex dependent
allele located on 1 of 22 autosomes
X-linked inheritance
clear pattern of sex dependent inheritance
allele located on the X chromosome
pedigree interpretation
what’s the pattern of mendelian inheritance
recessive
neither of Alexei’s parents have the condition
X linked recessive pattern - Mendelian inheritance
character is typically manifested in male offspring of UNAFFECTED offspring
not in offspring of affected males
X linked recessive basis - Mendelian inheritance
genetic locus is on an X chromosome
female has 2 X chromosomes
non-functional allele on 1 X chromosome means
- 1 functional allele for a woman
- no functional allele for a man
how can a female with carrier mother display classical haemophilia A
de novo mutation in the “good” allele
or
daughter of haemophiliac father and carrier mother
also by UPD of maternal X or by skewed X-inactivation of paternal X
vit D resistant rickets also known as
inheritance pattern
X-linked hypophosphatemic rickets (XLH)
X linked dominant
what is the only known Y linked character
maleness
50% chance that each child of an affected male will manifest the character
what pattern of mendelian inheritance is this
autosomal recessive
what pattern of mendelian inheritance is this
both males and females affected so probably not X linked
affected in every generation
AUTOSOMAL DOMINANT
e.g. of a dichotomous trait
cleft chin - dominant
1 gene (MENDELIAN)
mendelian
1 gene involved
polygenic/multifactorial
character is determined by a large no of genes and the interaction of expression of those genes with the environment - not Mendelian
height
shoe size
eye colour
intelligence
environmental influence - trait independent of such factors
Huntington
always associated with an expressed trait
T2D and environment
genetic predisposition to develop T2D but if one watches their diet, unlikely to develop it
incomplete penetrance
penetrance = probability of a genotype/trait being expressed
phenotype only expressed in a fraction of the population with the genotype
variable expressivity
variation in phenotype expression when penetrance is complete
a range of symptoms displayed in individuals with the same fully penetrant genotype
what happens when penetrance is incomplete but high
the disease will appear to be Mendelian but may occasionally appear to skip a generation
most obvious for autosomal dominant inheritance
what happens when penetrance is low
mendelian patterns are often very difficult to appreciate in the absence of large extended pedigrees
prevalence of variable expressivity
the norm among genetic diseases and is particularly common for disorders that affect multiple organ systems
factors that influence penetrance and expressivity
age
gender
environmental risk factors
lifestyle risk factors
modifier genes
parents of origin (epigenetic) effects
clinical case
inheritance pattern of hypercholesterolemia
associated genes
dominant pattern of inheritance
LDLR gene on Chr 19
clinical symptoms of hypercholesterolemia
skin lesions (xanthelasmata) present on eyelids and under eyes
MI
xanthomas
things to remember
genome
all of the hereditary info that an organism has encoded in its DNA (or for some viruses DNA)
chromosome
a threadlike structure of DNA and protein (chromatin) found in the nucleus of most living cells
each chromosome has many genes which carry genetic info
human cells have 23 pairs of chromosomes (22 autosomes + our sex chromosomes)
gene
unit of heredity which is transferred from a parent to offspring and is responsible for a character/trait of the offspring
or a DNA sequence associated with a particular property/encoding for a particular protein
allele
each of 2 or more alternative forms of a gene that arise by mutation and are found at the same place (locus) on a chromosome
homozygous
refers to a gene with identical alleles on both homologous chromosomes
heterozygous
refers to a gene with different alleles on each homologous chromosome
phenotype
observable physical or biochemical characteristics of an organism, as determined by both genetic makeup and environmental influences
genotype of an organism
the entire set of allels in an organism that determines the expression of its characteristics or traits
(Which allele do you have at each locus on your chromosomes)
trait/character
a specific part/relatively discrete element of total phenotype
dichotomous characters
yes/no
extra fingers, presence or absence of a disease
quantitative/continuous characters
height
IQ
mendelian characters
synonym
specific identifiable characters/traits (normal or pathological) that show a fairly clear cut pattern of inheritance
monogenic
the specific character/trait depends mostly on genotype at a single gene locus
given an otherwise normal genetic and environmental background 1 allele at 1 specific locus determines the character
In HETEROZYGOUS state he was able to tell if traits were recessive or dominant
mendelian disease
Huntington
4p16.3
punnett square
mother is heterozygous for H allele (dominant pattern of inheritance for monogenic Huntington’s disease character)
father is homozygous for h allele (recessive pattern of inheritance for non HD character)
inheritance pattern - CF
recessive
terms generally refer to pattern of inheritance of character (phenotype) rather than to the gene
dominant and recessive describe
functional relationship of 2 different alleles of the same gene in a (compound) heterozygous organism
dominant genetic characters
recessive genetic characters
fully penetrant condition
e.g. Huntington
clinical phenotype is manifested in 100% of the offspring with the appropriate genotype
incomplete/reduced penetrance condition
e.g. breast cancer in carriers of BRCA1 and BRCA2 genes
clinical phenotype is not observed among all individuals
High risk for breast cancer, but not 100% guaranteed to display breast cancer
what influences penetrance
penetrance is a complex continuum influenced by other (modifier) genes and non-genetic factors (environment, lifestyle, age, epigenetics)
penetrance of mendelian conditions vs multi-factorial
Mendelian single gene conditions - more likely to be fully penetrant
Multi-factorial - less than 100% penetrance
e.g. variable expressivity
even siblings with the same mutation for Cystic Fibrosis have varying degrees of lung and pancreas dysfunction
variable expressivity in neurofibromatosis type 1
incomplete dominance
intermediate inheritance in dominant disorders in which 1 allele is not completely expressed over its paired allele (blending of traits)
clinical phenotype of MOST DOMINANT genetic traits in heterozygotes (Aa) is in-between that of wild-type (aa) and mutant homozygotes (AA)
homozygosity for a disease causing mutation (AA) with dominant pattern of inheritance often results in much more severe clinical phenotype
e.g. incomplete dominance
e.g. achondroplasia (short limbed dwarfism)
heterozygosity for FGFR3 mutation (Ff) = short limbed dwarfism
homozygosity for FGFR3 mutation (FF) = stillborn/early death due to resp failure (underdeveloped ribcage)
clinical case - Marfan syndrome
associated gene
symptoms
MCQ
things to remember
