Topic 3: patterns of inheritance Flashcards
What is a gene in terms of DNA?
An open reading frame (ORF) with start (ATG) and stop codons (TAG, TAA, TGA), encoding a protein with 100 or more amino acids. ORF is often preceded by a promoter.
What is the process from DNA to protein?
DNA is transcribed to RNA, which travels to ribosomes that assemble amino acid sequences to form proteins.
What are exons and introns in DNA?
Alternating segments where introns are spliced out via the spliceosome before RNA is translated into protein.
What are mutations?
Genetic variations defined as changes in the genetic material, which can be heritable or not. Most occur spontaneously through errors in DNA replication and repair.
What are polymorphisms?
Germline sequence variants with no obvious effects on phenotypes.
What are the types of mutations?
Silent: same amino acid
Missense mutation: single altered amino acid affecting protein function or stability
Nonsense mutation: stop codon inserted, leading to loss of function
Insertion/deletion: disrupts the reading frame, causing a frameshift.
What is nonsense mediated RNA decay?
A process that destroys RNA molecules before translation if an error is detected, preventing faulty protein production.
What are splice site alterations and their effects?
Alterations that weaken or abolish the native splice site, causing exon skipping. Type I: 3’ Acceptor alterations cause skipping of the following exon. Type IV: Synonymous mutations may lead to splicing defects (e.g., cryptic splice site).
What is the difference between loss of function and gain of function mutations?
Loss of function: Reduces gene activity or product production.
Gain of function: Causes normal gene product to be expressed inappropriately or acquire a new abnormal function. Example: Sickle cell disease.
Who is the proband in a pedigree analysis?
The person coming in for counseling. Start with the proband and work around them, gathering relationships for at least 3 generations.
What ancestry/history information should be collected in a pedigree analysis?
Origin, diseases (cancers, intellectual disabilities, autism, vision or hearing impairment, movement disorders, etc.). Some illnesses may be related, others coincidental.
What is pattern recognition in pedigree analysis?
Awareness of specific syndromes and recognition of inheritance patterns to identify at-risk families.
What example points to Fragile X syndrome in pattern recognition?
Child (boy) with developmental delay and autistic features, mother with premature ovarian failure, and grandfather with tremor/ataxia.
What complexities can influence pedigrees?
Pleiotropy, genetic (locus) heterogeneity, allelic heterogeneity, penetrance, variable expressivity, consanguinity.
What is autosomal dominant inheritance pattern?
Males and females affected equally, male-to-male transmission, disease in every generation.
Example: Marfan syndrome.
What is reduced penetrance in autosomal dominant inheritance?
When a generation is skipped, it may be due to reduced penetrance where individuals have the gene but do not develop the disease.
What is pleiotropy?
A single gene causing multiple effects in different organs or systems.
Example: Marfan syndrome.
What is variable expressivity?
The same genetic mutation causing varying degrees of severity in different individuals.
Example: Marfan syndrome.
What is de novo mutation?
A new mutation that occurs spontaneously, not inherited from parents.
25% of Marfan syndrome mutations are de novo.
What is penetrance?
A yes or no phenomenon. If everyone with the genotype presents with symptoms, it is fully penetrant. Reduced penetrance occurs when not all individuals with the genotype show symptoms.
How is penetrance expressed?
As a percentage – the proportion of individuals with the genotype who exhibit the expected clinical symptoms by a certain age.
What factors are linked to penetrance?
Age, sex, environment, epigenetic modifiers, and modifier genes.
what gene is affect in Marfan Syndrome?
FBN1
what are mendelian inheritance patterns?
- autosomal domninant
- autosomal recessive
- X-linked recessive
- x-linked dominant
- y-linked inheritance
What is the inheritance pattern of autosomal recessive disorders?
If both parents are carriers, there is a 25% chance of the disease, 50% chance to become a carrier (2/3 chance to be a carrier), with males and females equally affected.
What is compound heterozygous?
A different pathogenic variant on each allele.
What is homozygous in the context of genetic variants?
The same pathogenic variant on both alleles.
Why do most patients with autosomal recessive disorders not have affected relatives?
Due to the carrier frequency.
Example: Incidence of phenylketonuria (PKU) is 1/12,000 in North America, with a carrier frequency of 1/55.
What is uniparental disomy?
Two alleles come from the same parent. Types include isodisomy (identical sister chromatids) and heterodisomy (both homologues from one parent).
What is an example of an X-linked recessive disorder?
Duchenne muscular dystrophy (DMD), which is fully penetrant in boys ~4 yrs old and is considered to be lethal from a mendelian viewpoint
What are the symptoms of Duchenne muscular dystrophy?
Progressive muscle weakness, difficulty climbing stairs, ‘Coke’ colored urine after exercise, Gower sign, and elevated creatine kinase levels.
What is X chromosome inactivation (XCI)?
In each female somatic cell, one X chromosome is randomly inactivated early in development to equalize X chromosome gene expression between males and females.
What is skewed X chromosome inactivation (XCI)?
When the inactivation of one X chromosome is favored over the other. The ratio is considered skewed if it is ≥65:35.
What is the inheritance pattern of X-linked dominant disorders?
No direct male-to-male transmission. Males and females affected, more affected females than males, females usually less severely affected. Affected males transmit to all daughters, none to sons.
What is y-linked inheritance?
Never occurs in females and occurs in all male descendants of an affected male.
Examples include SRY gene, TDF, TSPY, and gene for excessive hair on the ear pinna.
Front: What are multifactorial inheritance patterns affected by? .
Back: Affected by several genetic factors and environmental factors. Recurrence risk is higher with multiple affected family members, severe disease expression in the proband, and if the proband is of the less commonly affected gender
Front: How can empirical recurrence risk in complex disorders be estimated?
Back: Using family population studies, estimation programs, and genome-wide association studies (GWASs) of single nucleotide polymorphisms (SNPs).
What are repeat expansion disorders?
Disorders arising from normally existing polymorphic repeats. Expansions are unstable, causing more severe and earlier onset diseases in successive generations, with clinical anticipation and highly variable phenotypes.
What are the three classes of repeat expansions?
CAG repeats: Huntington’s disease.
CGG repeats: FMR1-related disorders (Fragile X).
CUG repeats: myotonic dystrophy
where on the the genome does Huntington’s disease occurs and how is it inherited?
- Occurs in the 5’ end of the Huntington disease gene
- Paternal meiosis accounts for the increased risk of early-onset Huntington disease, occasionally in childhood or adolescence, when the gene is transmitted by the father
- due to chromosome “slipping”
how many CGG repeats cause fragile X, and which gene is affected?
the FMR1 gene on chromosome X:
* >200 repeats: Fragile X
* 55-200 repeats: fragile X tremor/ataxia or fragile X-associated primary ovarian insufficiency
* 45-54 repeats: may expand to pre-mutation
* 5-44 repeats: normal
What is genomic imprinting?
The differential expression of genes depending on whether they are inherited from the mother or father, regulated by DNA methylation.
What is Prader-Willi Syndrome (PWS) and its causes?
An endocrine and neurological disorder caused by loss of SNRPN gene via: paternal deletion (60-70%), maternal uniparental disomy (29-39%), or imprinting defect of ICR (imprinting control region)
What is Angelman Syndrome (AS) and its causes?
A neurological disorder caused by lack of UBE3A gene via: maternal deletion (65-75%), paternal uniparental disomy (3-7%), pathogenic variant of UBE3A on maternal gene (5-11%), or imprinting defect (3%).
where is the imprinting control region?
15q11.2-q13 (also called the PWS/AS region)
what are the differentially expressed/controlled genes on the ICR (or the PWS/AS region)?
The 5’ end of the ICR is methylated on the maternal side.
1 UBE3A gene (maternal) and 1 SNRPN gene expressed (paternal)
What are mitochondrial diseases and their inheritance pattern?
Disorders caused by pathogenic variants in mitochondrial DNA, inherited only from mothers, affecting all children with varying severity. Most susceptible organs are CNS, skeletal muscle, and heart
What is a genetic bottleneck in mitochondrial diseases?
A process where a person can inherit the same number of abnormal mitochondria but have different outcomes due to random selection of mitochondria.
