genetic diseases

what are promoters and enhancers of non-protein coding sequences?

• bind transcription factors

• binding sites for DNA-binding proteins that organize and maintain chromatic structure

what are non-coding regulatory RNAs?

genes that are transcribed but not translated (including microRNAs, long non-coding RNAs)

what are transposons?

mobile genetic elements

what are telomeres and centromeres?

structural regions of DNA

what are the epigenetic mechanisms?

• covalent modifications of DNA (5-methylcytosine, 5-hydroxymethylcytosine)
• post-translational modifications of histones
• 3D chromatin structure

what are single nucleotide polymorphisms (SNPs)?

• variants at single nucleotide positions
• in coding and non-coding regions
• non-coding SNPs may alter the regulation of gene expression
• coding SNPs do not affect gene function or phenotype

what is the effect of individual SNPs on disease susceptibility?

weak, particularly for complex diseases (e.g. diabetes, heart disease, or cancer)

what are copy number variations (CNVs)?

• variations in number of large contiguous stretches of DNA
• ~50% of CNVs involve coding sequences
• duplications, triplications, deletions, inversions

what are point mutations in protein-coding genes?

substitution of a single nucleotide base by a different base

what is missense mutation?

changes in an amino acid

what is nonsense mutation?

creates a stop coding

what is gene editing (CRISPR)?

• clustered regularly interspaced short palindromic repeats
• form of bacterial "immunity"
• using artificial guide RNAs that target a DNA sequence of interest to introduce mutations
• first CRISPR/Cas9-based therapy approved to treat sickle cell disease

what are frameshift mutations?

• insertion/deletion of 1-2 base pairs alters the reading frame of the DNA strand
• wild type, base-pair deletion, base-pair insertion

what is mild-type mutation?

mRNA sequence without any mutation

what is base-pair deletion?

frameshift causing extensive missence

what is base-pair insertion?

frameshift causing immediate nonsense

what is trinucleotide repeat mutation?

• amplification of repeated sequence of 3 bases
• repeat expansion/amplification

what is repeat expansion/amplification?

number of repeats increases during gametogenesis

what are structural variations?

• genomic rearrangement leads to amplifications, deletions, or translocations of chromosomal segments
• single genes to entire chromosomes
• intra- or inter-chromosomal

what are mutations?

changes in DNA sequence

what are epimutations?

• changes in epigenetic mechanisms that change gene expression
• can have the functional outcomes on gene expression and phenotype/disease

what are epigenetic and genetic mechanisms in cancer?

• inactivation of tumor suppressor genes (promoter hypermethylation)
• activation of oncogenes (promoter demethylation)

what are genetic disorders?

• disease-causing mutations: mendelian disorders, cytogenetic diseases, non-medelian genetic diseases
• disease-associated mutations: complex disorders

what are mendelian disorders?

resulting from mutations in single genes

what are cytogenetic disease?

arising from changes in chromosomal number or structure

what are non-mendelian genetic diseases?

arise from single gene mutations with atypical patterns of expression

what are complex disorders?

involving multiple genes as well as environmental influences

what are patterns of inheritance of medelian disorders?

autosomal dominant/recessive, sex-linked

what is autosomal dominant?

• one copy is sufficient to cause disease
• disease manifests in heterozygous state
• does not skip a generation
• affected offspring have affected parents
• male and female offspring are equally likely to be affected

what is autosomal recessive?

• 2 copies are needed to cause disease
• disease manifests in homozygous state
• typically skips a generation
• affected offspring may have unaffected parents
• male and female offspring are equally likely to be affected

what is sex-linked?

• most are X-linked
• heterozygous females can transmit only to sons, while daughters may be carriers
• affected males cannot transmit the disorder to sons

what is X-linked recessive?

• typically skips a generation
• affects sons may have unaffected mothers (carrier)
• affected daughters must have an affected father and affected/carrier mother
• cannot be passed from father to son
• male offspring are more likely to be affected

what is pleiotrophy?

a single gene mutation has many phenotypic effects

what is genetic heterogeneity?

multiple genes cause the same trait

what is penetrance?

• the proportion of individuals with the mutation that exhibit clinical symptoms among all individuals with such mutation
• incomplete penetrance: BRCA1 mutations

what is expressivity?

• the degree to which a phenotype is expressed by individuals having a particular genotype
• e.g. sickle cell anemia

what are patterns of inheritance of ehler-danlos syndrome?

• autosomal dominant inheritance
• abnormal protein: collagen
• protein function: structural support (ECM)
• genetic features: dominant/recessive, genetic heterogeneity

what are patterns of inheritance of huntington's disease?

• autosomal dominant inheritance
• abnormal protein: huntingtin (trinucleotide repeat)
• protein type/function: unknown
• genetic features: genetic anticipation

what are the patterns of inheritance of cystic fibrosis?

• autosomal recessive inheritance
• abnormal protein: cystic fibrosis transmembrane regulator
• protein type: ion channel
• genetic features: genetic anticipation

what are the patterns of inheritance of sickle cell disease?

• autosomal recessive inheritance
• abnormal protein: hemoglobin
• protein function: oxygen transport

what are the patterns of inheritance of fragile X syndrome?

• X-linked recessive inheritance
• abnormal protein: FMRP (trinucleotide repeat)
• protein function: RNA translation
• genetic features: genetic anticipation

what is cystic fibrosis?

• most common life-limiting disease in the US
• disorder of epithelial ion transport that affects fluid secretion in the lining of the respiratory, GI, and reproductive tracts
• recurrent and chronic pulmonary infections
• pancreatic insufficiency
• male infertility
• high NaCl in sweat

what are the effects of cystic fibrosis in sweat glands?

increased sweat chloride [ ]

what are the effects of cystic fibrosis in sinuses?

sinusitis

what are the effects of cystic fibrosis in lungs?

inflammation, pseudomonas infection, bronchiectasis

what are the effects of cystic fibrosis in the liver?

cirrhosis

what are the effects of cystic fibrosis in the pancreas?

exocrine dysfunction, pancreatitis, diabetes

what are the effects of cystic fibrosis in intestine?

neonatal obstruction (meconium ileus), distal obstruction

what are the effects of cystic fibrosis in the male reproductive tract?

azoospermia, infertility, bilateral obstruction/absence of vas deferens

what is the primary defect in CF?

reduced production or abnormal function of CFTR (cystic fibrosis transmembrane regulator): an epithelial chloride and bicarbonate channel protein

what are the effecs of cystic fibrosis in the lumen of sweat duct and airway?

• lumen of sweat duct: hypertonic salty, sweet, mutated CFTR
• airway: defective mucociliary function, dehydrated mucus

what are the effects of cystic fibrosis in genetics?

• mutations (>2000 identified) in CTFR (CF treansmembrane conductance regulator) with autosomal recessive inheritance patterns

• 5 classes of mutations in CTFR

• F508del

• in 2010, all 50 states adopt universal newborn screening

what are the 5 classes of mutations in CTFR?

protein production, protein processing, gating, conduction, and insufficient protein

what is F508del?

• most common CF mutation
• ~90% of CF population
• protein processing mutation

what is trikafta?

• treatment that treats the underlying cause of disease (the defective CTFR) in a majority of the CF population
• combination of elexacaftor, ivacaftor, and tezacator
• approved in 2019 for carriers of the most common varient
• expanded to people with CF2 and older with F508del and 177 other mutations

what is ivacaftor?

chloride channel opener

what are elexacaftor and tezacaftor?

CFTR modulators

what is the impact of trikafta?

• the median age at death for those with CF was 66 yrs in 2022 vs 26 yrs in 2008
• 1 in 5 CF patients died before age 40 in 2022 vs almost 50% in 2016

what were treatments before trikafta?

• various pills including multivitamins, synthroid, ursodiol
• posutral drainage using the vest airway clearance system for 30 min, twice per day
• albuteol nebulizer twice daily
• inhaled antibiotic in nebulizer twice daily
• albuterol inhaler 3-4 times daily
• advair inhaler twice daily
• ensure plus twice daily
• enzymes with all snacks and meals

what are treatments after trikafta?

• 2 trikafta pills in the morning and 1 at night
• multivitamins, synthroid, and ursodiol
• no postural drainage
• inhaled antibiotic in nebulizer, every other month
• albuterol inhaler 1-2 times daily
• advair inhaler once per day

what is down syndrome?

• trisomy 21
• extra copy of chromosome 21: visible on karyotype
• multiple genes are disrupted, leading to intellectual disability and other symptoms
• 40% have congenital heart disease

what is the philadelphia chromosome?

• translocation event between the BCR (chr22) and ABL (chr9) genes
• almost all people with chronic myeloid leukemia and some people with acute lymphocytic leukemia or acute myelogenous leukemia
• gleevec: 10-yr survival rates increased from <20% to 85%

what is fragile X syndrome?

• trinucleotide (CGG) expansion mutation in the familial mental retardation I (FMR1) gene
• fragile-X-asociated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency
• primarly affects males (X-linked)
• full mutation blocks protein expression

what is genetic anticipation?

clinical features worsen or begin earlier with each successive generation

what complex multigenic disorders are there?

• hypertension/heart disease
• diabetes
• cancer
• autoimmune diseases
• parkinson's disease

what are non-disease traits?

• hair, eye, and skin color
• height
• intelligence

what are the genetics of complex multigenetic disorders?

• genetic variants, environmental factors, and the interactions between them
• polymorphism

what is polymorphism?

genetic variant that occurs in at least 1% of the population

what is the common disease-common variant hypothesis?

• complex diseases arise when many polymorphisms, each with a small effect and low penetrance, occur together
• different polymorphisms vary in significance
• polymorphisms can be disease-specific or shared by related diseases
• many disease-associated polymorphisms are in noncoding regions, so they may affect epigenetics and regulation of gene expression