Inheritance of Genetic Disease Flashcards
What is a genetic pedigree?
A visual representation of a multigenerational family, uses a set of internationally recognised symbols and lines
What are Mendelian conditions of inheritance?
Mendelian conditions are inherited in patterns which depend on a number of factors
- the location of the associated gene (autosome, sex chromosome, mitochondrial genome)
- whether one or two altered copies of the gene are needed for the disease
What is the locus?
specific location of a gene on a chromosome
What is an allele?
alternate forms of a gene at the same locus
What is homozygous?
both alleles at a gene locus are the same
What is heterozygous?
the two alleles at a gene locus are different from one another
What is Mendel’s law of segregation?
- Each inherited trait is defined by a gene pair
- Parental genes are randomly separated to the sex cells which contain only one gene of the pair
- Offspring inherit one allele from each parent when sex cells unite in fertilisation
What is Mendel’s law of dominance in a heterozygote?
One trait will hide the presence of another trait for the same characteristic (dominant allele expressed exclusively)
What is the genotype?
A person’s DNA sequence at a particular locus
What is the phenotype?
A person’s clinical features
What is a genetic syndrome?
A group of traits or conditions that tend to occur together and characterise a recognisable disease
What is dominant inheritance?
Having one altered copy of the associated gene is enough to cause the disease phenotype, one altered and one normal copy in affected individuals
What is recessive inheritance?
Both copies of the associated gene must be altered for disease phenotype to manifest, affected individuals have two altered copies, carriers have one normal & one altered
What are autosomes?
- Chromosomes 1- 22
- Conditions due to alterations in genes on autosomes are the same in males and females
Common autosomal dominant conditions (5 conditions)
- Huntington’s disease
- BRCA 1&2
- Neurofibromatosis type 1 (NF1)
- Autosomal dominant polycystic kidney disease (ADPKD)
- Marfan syndrome
What can autosomal dominant conditions arise from?
- Be inherited from an affected parent
- Arise de novo (occur for first time without family history)
What are the clues for autosomal dominant inheritance?
- Males and females equally affected
- Affected individuals in every generation or first in family
- Condition inherited from both affected mothers and affected fathers
What can recessive conditions be caused by?
Homozygous pathogenic variants
Compound heterozygous pathogenic variants
What are homozygous pathogenic variants?
- 2 identical pathogenic changes at a locus, more common in consanguineous families
What are compound heterozygous pathogenic variants?
- 2 different pathogenic changes in a gene which are in trans, one on each chromosome
What are 4 common autosomal recessive conditions?
- Cystic fibrosis
- Sickle cell anaemia
- Spinal muscular atrophy
- Phenylketonuria (PKU)
What are the clues for autosomal recessive inheritance?
- Affected siblings in same generation with healthy parents
- Parental consanguinity
- Males and females equally affected
What are X-linked conditions?
- Caused by pathogenic alterations of genes on the X chromosome
- Affect males and females differently
What are X- linked recessive conditions?
- More common
- manifest when no normal copy of gene present, mostly in males
What are X- linked dominant conditions?
- Rare
- Manifest when one altered copy of the gene is present, mostly affect females (mostly lethal in males)
Why is X linked recessive less severe in females?
Two X chromosomes, with pathogenic alteration on one X, normal X can compensate, so female= carrier & most likely unaffected/mild
Why is X-linked recessive more severe for males?
One X chromosome, only one copy of genes on the X chromosome, with a pathogenic alteration on the single X there is no second to compensate= males affected
Common X linked recessive conditions
- Duchenne muscular dystrophy
- Fragile X syndrome
- Haemophilia A
What are X- linked recessive inheritance clues?
- Only males affected
- Condition inherited from carrier females only (not affected males)
- All daughters of an affected male are carriers
What happens for females with X linked dominant conditions?
Two X chromosomes, with pathogenic alteration on one X= condition manifests
Healthy second copy= mild protection so prevents condition becoming lethal
What happens to males with X linked dominant conditions?
One X chromosome, with a pathogenic alteration on the single X chromosome and without second protective copy= usually lethal
What are common X- linked dominant conditions?
- Rett syndrome
- Craniofrontonasal syndrome
What is the mitochondrial genome?
- Single circular mitochondrial chromosome containing 37 genes
- Mitocondria present in egg cells but not the sperm head
- Pathogenic alterations in the mitochondrial genome passed via mothers eggs only
What are mitocondrial conditions dependent on?
- Severity depends on proportion of mutant mitochondria (low=mild, high= severe)
- Affected female will always pass on some mutant mitochondria (prop is random)
- Affected males do not pass on the condition
Clues for mitochondrial inheritance
- All offspring of affected female affected
- No offspring of affected male affected
- Condition passed via female line
More genetic conditions are…
rarer, genetics simple, unifactorial, high recurrence rate in family line
More environmental conditions are…
common, genetics complex, multifactorial, low recurrence rate
What is meiosis?
Process to produce haploid egg and sperm cells
During meiosis, one diploid cell divides twice to form four haploid daughter cells, containing half the number of chromosomes of the parent cell
How does advanced maternal age contribute to disease?
- Increase chromosome segregation errors during meiosis (nondisjunction)
- Produces egg cells with missing or extra chromosomes
- When fertilised produce aneuploid embryos
- Resulting aneuploid embryos may be compatible or incompatible with life
How does advanced paternal age contribute to disease?
- Selfish sperm hypothesis
- sperm production is a lifelong process
- volume and quality decreases with age
- Copying errors can happen during DNA replication preceding these sperm cell division during meiosis, which may lead to new (de novo) mutations in the sperm DNA
- Certain genetic errors may= selective advantage= these increase in number via clonal expansion (selfish sperm)
What is Penetrance?
likelihood that a clinical condition will occur when a particular genotype is present
What is complete penetrance?
Every person with a causative genetic variant will develop symptoms of the condition within their lifetime
What is reduced penetrance?
some individuals who carry the pathogenic variant express the associated trait while others do not
What is variable expressivity?
the range of signs and symptoms that can occur in different people with the same genetic condition (e.g. marfan syndrome)
What is genetic heterogeneity?
- Allelic heterogeneity
- Locus heterogeneity
What is allelic heterogeneity?
different pathogenic variants in a single gene associated with multiple different phenotypes
What is locus heterogeneity?
one phenotype can be caused by pathogenic variants in multiple different genes
What is Mosaicism?
When only some of an individual’s cells have a specific variant
Errors occurs post- zygotically during mitosis
Affected cells descend from mutated line
