Modes of Inheritance II - Flashcards

50 vocabulary flashcards covering modes of atypical and multifactorial inheritance based on the lecture notes.

Mosaicism

The presence of at least two genetically different cell lines within an individual that derived from a single zygote.

Somatic mosaicism

A genetic change occurring during embryogenesis that affects morphogenesis, leading to segmental abnormalities or carcinogenesis in adult dividing cells.

Germline mosaicism

A condition in an unaffected individual where disease-causing mutations exist solely in germline cells, presenting a risk of passing highly penetrant autosomal dominant or X-linked traits to offspring.

Dynamic mutations

Unstable repeat expansions of nucleotide units within a DNA segment that increase in length across generations.

Anticipation

A phenomenon in unstable repeat expansion disorders where the onset of symptoms becomes earlier in successive generations.

Parental transmission bias

The phenomenon where anticipation and repeat expansion severity depend on whether the mutant allele is inherited from the mother or father.

Huntington's disease CAG repeat thresholds

Normal individuals have 5-35 CAG repeats, mild late-onset Huntington's disease presents with 36-39 repeats, and severe disease occurs with >40 repeats.

Fragile X syndrome

An X-linked dominant condition causing mild intellectual disability, characterized by massive CGG repeat expansion (>200) in the 5'-UTR of the FMR1 gene.

Maternal inheritance

The strict maternal pattern of mitochondrial DNA transmission resulting from the absence of sperm mitochondria in the zygote.

Replicative segregation

The random distribution of replicated mtDNA copies into newly synthesized mitochondria and daughter cells during cell division.

Homoplasmy

A cell or tissue state where all copies of mtDNA are purely wild-type or purely mutant.

Heteroplasmy

A cell or tissue state containing a mixed population of both wild-type and mutant mtDNA.

Mitochondrial genetic bottleneck

The temporary reduction of mtDNA copies in developing oocytes before expansion, causing variable mutant mtDNA proportions in offspring.

Multifactorial diseases

Conditions showing familial clustering without Mendelian patterns, caused by additive polygenic variants combined with environmental factors.

Discrete qualitative traits

Multifactorial characteristics or disorders that are either present or absent in an individual.

Continuous quantitative traits

Measurable physiological or biochemical parameters (such as height) that vary continuously in a population.

Gaussian distribution of quantitative traits

A bell-shaped curve distribution exhibited by continuous quantitative traits due to the additive contribution of multiple polygenic loci.

Liability threshold model

A model for qualitative traits where underlying genetic and environmental liability follows a normal distribution and disease manifests once a critical threshold is crossed.

Empirical risk

Recurrence risk determined from observational data of large family studies rather than calculated Mendelian ratios.

Concordant twins

Twin pairs where both individuals express the same disease or trait.

Discordant twins

Twin pairs where only one individual expresses a given disease or trait.

Heritability ($H^2$)

The proportion of total phenotypic variance attributable to genetic factors, calculated as $\frac{C_{MZ} - C_{DZ}}{1 - C_{DZ}}$.

Limitations of twin studies

Analytical constraints including the equal environment assumption, post-cleavage somatic mutations, and differences in epigenetic methylation or X-inactivation.

Adoption studies

Investigation strategy comparing disease rates in adopted offspring of affected versus unaffected biological parents to isolate genetic contributions.

Congenital heart defects

The most common congenital malformations, occurring in approximately 8 per 1000 births with multifactorial etiology and familial aggregation.

Cleft lip and palate

Congenital malformation occurring in 2.5 per 1000 births, categorized as syndromic or non-syndromic, and linked to environmental factors like maternal smoking and folic acid deficiency.

Coronary artery disease (CAD) recurrence risk factors

Familial risk factors including having >1 affected relative, an affected female relative, or an onset age <55 years in an affected relative.

Stroke genetics and concordance

A 2-3-fold risk increase with an affected parent, showing 10% monozygotic concordance versus 5% dizygotic concordance and links to clotting factor V.

Hypertension heritability

An estimated heritability of approximately 0.5 for systolic and diastolic blood pressure, linked to angiotensin system genes.

Breast cancer familial risk factors

A 2-fold increased risk with a first-degree affected relative, influenced by BRCA1, BRCA2, DNA repair genes, nulliparity, and late first childbirth.

Colorectal cancer genetic risk

A 2-3-fold increased risk with affected relatives, driven by APC gene mutations or DNA mismatch repair gene defects.

Prostate cancer genetic markers

Multifactorial cancer with heritability around 0.4 linked to SNPs surrounding an enhancer for the MYC oncogene.

Type 1 Diabetes Mellitus (T1DM) genetic components

Autoimmune disease with 50% MZ concordance, associated with HLA class II DR3/DR4 homozygotes and insulin gene variants, carrying higher risk from affected fathers (4-7%) than mothers (1-3%).

Type 2 Diabetes Mellitus (T2DM) genetic components

Metabolic disease with >90% MZ concordance, 15-30% recurrence risk, and candidate genes including TCF7L2, PPAR-g, and KCNJ11.

Obesity genetic risk factors

Heritable trait ($H^2$ = 0.6-0.8) linked to leptin, leptin receptor, neuropeptide Y, melanocortin-4 receptor, and FTO gene variants.

Early-onset Alzheimer's disease genes

Autosomal dominant form appearing before age 60, caused by mutations in Presenilin 1, Presenilin 2, or APP.

Late-onset Alzheimer's disease genetic risk factor

Genetic susceptibility factor associated with the apolipoprotein E $\epsilon 4$ allele (APOE-$\epsilon 4$).

Type I Alcoholism

Subtype characterized by onset after age 25, equal male/female distribution, lower severity, and better treatment response.

Type II Alcoholism

Severe alcoholism subtype primarily affecting males under age 25 that is difficult to treat.

Alcohol metabolic enzymes

Enzymes encoded by alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) genes involved in alcoholism risk.

Schizophrenia recurrence risk

An 8-10% recurrence risk for offspring of affected parents, with MZ concordance of 50% and DZ concordance of 15% involving glutamatergic and dopaminergic pathways.

Autism spectrum disorder (ASD) genetic features

Condition 3-4 times more common in males with heritability >0.7 and high risk associated with paternal age and paternally inherited mutations.

Polyglutamine disorders

Hereditary neurological conditions caused by repeating CAG nucleotide units in mutant proteins, following autosomal dominant inheritance patterns.

FMR1 gene silencing mechanism

Massive CGG expansion (>200) in the 5'-UTR of FMR1 leading to CpG island hypermethylation and gene silencing.

APP cleavage in Alzheimer disease

Aberrant cleavage of amyloid precursor protein by $\beta$ -secretase and $\gamma$-secretase generating $A\beta 40$ and $A\beta 42$ peptides that aggregate into $\beta$-amyloid plaques.

Mitochondrial disease manifestations

Pleiotropic multisystem symptoms resulting from defective mtDNA expression, including muscle weakness, cardiomyopathy, hearing loss, optic neuropathy, diabetes, and seizures.

Replicative segregation and heteroplasmy threshold

The mechanism where random mtDNA segregation yields varying proportions of mutant mtDNA that must surpass a phenotypic expression threshold to manifest disease.

Genetic versus Environmental disease spectrum

A continuum spanning rare unifactorial genetic disorders with high recurrence risk to common multifactorial disorders and purely environmental conditions.

Multifactorial recurrence risk criteria

Empirical risk principles stating recurrence risk increases if >1 family member is affected, if the proband has severe disease, or if the proband belongs to the less affected sex.

Embryonic somatic mosaicism origin

The development of genetically distinct cell populations in a mature organism originating from a mutation in a single embryonic cell.