Modes of Inheritance Definitions Flashcards
Define locus heterogeneity
Where the same clinical phenotype can result from mutations at any one of several different loci. This may be due to epistasis (where gene A controls the action of gene B) or lies upstream of gene B in a pathway; alternatively genes A and B ay function in separate pathways that affect the same phenotype. Think about the biological role or a gene product and the molecules with which it interacts rather than expecting a one-to-one relationship between genes and syndromes. Rule rather than exception. Clinical syndromes often result from a failure of a developental or physiological pathway. If the correct function of several genes is reuired, mutations in any one of these genes ay cause the same or similar phenotype. Most extreme example is mental retardation. More than 10,000 genes expressed in the CNS all candidate genes for MR. Extreme, almost all depend on the action of more than one gene. Good example hearing loss.
Define Allelic heterogeneity
where many different mutations within a given gene can be seen in different patients with a certain genetic condition. Many diseases show both locus and allelic heterogeneity.
Define clinical heterogeneity
mutations in the same gene produce two or more different diseases in different people. eg mutations in the HPRT gene can produce either a form of gout or Lesch-Nyhan syndrome.
what are the features of X linked dominant conditions and examples
The inheritance pattern describing a dominant trait or condition caused by a mutation in a gene on the X chromosome. Features:
Affects either sex. Females are more midly and variable affected, males more severely.
Usually at least one parent affected
for an affected male all daughters but no sons affected
50% risk to child
Less X-linked dominant conditions compared to recessive
E.g. FraX
Alports - 80-85% cases. Condition characterised by kidney disease, hearing loss, eye abnormalities. Mutations in COL4A5 type IV collagen.
What are the features of X-linked recessive inheritance and examples
Affects mainly males
Vertical transmission where the carrier females pass disorder to affected sons
Affected males born to unaffected parents; mother may be asymptomatic
fameles may be affected if father affected and mother a carrier, or due to non-random X inactivation. Affected homozygous females very rare.
no male to male transmission
e.g DMD/BMD
SBMA degeneration of motor neurons leads to progressive proximal muscle weakness and wasting (arms and legs), swallowing, reduced fertility. CAG expansion in exon 1 of GOF mechanis. androgen receptor AR.
Seq variants in AR result in androgen insensitivity syndrome. Androgen receptors allow cells to respond to androgens (hormones eg testosterone) that direct male sexual development. characterised by feminisation of external genitalia at birth (genetically male), abnormal secondary sexual development at puberty. Point mutations result in lower ligand-binding or reduced transactivation potential of mutant receptor molecule.
Haemophilia A and B - bleeding disorders in coagulation factor VIII (F8) in haemophilia A
coagulation factor IX gene (F9) in haemophila B. Adverse qualitative or quantitative changes in circulating FVIII causing them to be inefficient in the coagulation cascade = deficiency of clotting.
F8 single base pathogenic substitutions to large insertions and deletions to gene rearrangements and whole gene deletions. Inversions are most common (intron 22 inversion in 45%). Molecular genetic testing of F8 identifies pathogenic variants in as many as 98% of individuals with haemophilia A.
F9 is smaller single base pathogenic substitutions predominate (approximately 90 % of patients). Molecular genetic testing of F9 identifies pathogenic variants in as many as 90% of individuals with haemophilia B.
X-linked retinitis pigmentosa (XLRP) and X-linked cone dystrophy (Xp21.1) XLRP is characterised by night blindness and a decrease in peripheral vision in the third/fourth decade of life. Genetically heterogeneous; however, >70% patients have a RPGR mutation and 15-20% of patients have a RP2 mutation.
What are the features of AR and examples
Affected person usually born to unaffected parents (asymptomatic carriers)
increased consanguinity
affects either sex
25% risk
What are the features of AD
Affected person usually has at least one affected parent
Affects either sex and transmitted by either sex
childe 50% chance of being affected
What can complicate the basic pattern of inheritance
Penetrance and variable expression anticipation imprinting male lethality in X-linked pedigrees e.g. IP and Rett New mutation (particularly in X linked) Mosaicism
Provide examples of X-linked lethality in males disorders
Incontinentia Pigmenti
affects skin, hair, teeth, nails, eyes and CNS. Blistering rash at birth. Skin lesions throughout life following defined patterns, majority of males abort after first trimester. IKBKG gene regulates NF-kappa-B a group of proteins that help protect cells from self-destructing in response to certain signals. Cells are more sensitive to signals that trigger them to apoptose.
2) Rett syndrome. Progressive neurodevelopmental disorder almost exclusively affects feales. MECP2 (80% 8 common missense and nonsense mutations caused by C>T transitions at CpG cause 60%), FOXG1 and CDKL5. Normal at birth, developental stagnation and rapid regression in language and motor skills. Repetitive hand movements hallmark. Sudden death in females. But phenotype normal to severe. Males born with severe neonatal encephalopathy resulting in death before age 2. Exist due to 47,XXY, post-zygotic MECP2 somatic mosaicism, mild MECP2 missense change.
How can clinical manifestations of X-linked disorders arise in females?
Skewed X-inactivation Somatic mosaicism Deletion involving X chromosome Turners or X-chromosome rearrangement Females with two pathogenic sequence changes (eg compound het DMD) UPD of the X chromosome
what types of genes show haploinsufficiency?
Highly expressed genes e.g. elastin. Loss of one copy has no effect in skin and lung (low levels of product required), but can cause supraventricular aortic stenosis because the aorta requires high expression levels.
Dosage-sensitive genes (majority of haploinsufficient genes)
o Gene products that are part of a quantitative signalling system depending on partial occupancy or competition for a receptor or DNA binding site (e.g. a promoter or enhancer region).
o Gene products that compete to determine a developmental or metabolic switch.
Genes whose products act essentially alone, eg soluble enzymes of metabolism, seldom show dosage effects.
transcriptional regulation. Around two-thirds of mutations in transcription factor genes are dominant or semi-dominant.
Define a GOF mutation
Result in either an increase in gene expression or the gene product developing a new function(s).
-Hypermorph: an allele that produces an increase in quantity or activity of its product
-Neomorph: an allele with a novel activity or product.
Usually cause dominant phenotypes as the presence of a normal allele does not prevent the mutant allele from functioning abnormally.
Often involves a control or signalling system behaving aberrantly; signalling when it should not, or failing to switch a process off when it should.
The product may acquire a novel function; a chromosome rearrangement may create a novel chimeric gene by fusing the exons of two different genes. For example, the BCR-ABL1 translocation in chronic myeloid leukaemia (CML)
Give exaples of a GOF mutation
Receptor permananetly on
Acquire a new substrate (alpha 1 anti trypsin (PI gene)
Ion channel permanently open (SCN4A) paramyotonia congenital
Protein aggregation HTT
Chimeric gene BCR-ABL
Define dominant-negative effect
pccur when a mutated gene product interferes with the function of the normal product. Dominant-negative mutations are those that generally impair the function of the protein encoded by the mutant gene copy and also, as a result of protein–protein interactions (e.g. in a multi-subunit protein complex), reduce the function of the protein encoded by the normal copy of the gene.
