Unit 4 - Pathogenic Phenotypes: Single Gene Disorders

proband

index case/individual who has come to clinical attention, affected individual through whom a family with a genetic disorder is first brought to the attention of the geneticist

example of family history analysis

the proband (the person being studied) is a 6 yr old female with moderate muscle weakness and exercise intolerance, her 1 year old sister has weakness and delayed development, 10 year old brother in good health is unaffected, mother with exercise intolerance and myalgias (muscle pain) also had spontaneous abortion at 15 weeks, father with no muscle symptoms but with hypercholesterolemia, maternal uncle with mental retardation, seizures and myalgias, paternal aunt healthy, maternal grandmother with exercise intolerance, myalgias, diabetes and high blood pressure, maternal grandfather deceased (age 59, colon cancer), paternal grandmother with high blood pressure and history of breast cancer, paternal grandfather deceased (age 63, heart attack), the muscle biopsy of the kid shows congenital myopathy

autosomal dominant congenital myopathy

the maternal grandfather is affected, maternal uncle is affected and mother is affected making both of her daughters affected, it could be X linked cause there’s no male to male transmission

mendelian inheritance

only includes conditions related to mutations or result from abnormalities in nuclear genome, when the primary determinant occurs at a single locus of the nuclear genome and alleles (which of two chromosomes the mutation arrives on), at that locus (genetic part of chromosome where mutation arises) are necessary and sufficient for the expression of that disease

the five patterns of mendelian inheritance

autosomal dominant or recessive, X-linked recessive or dominant and Y-linked traits, includes diseases/conditions with mutations in nuclear encoded genes that exhibit autosomal or x-linked inheritance in pedigrees

autosomal dominant

direct transmission of allele to offspring causing disease (only need one allele), an affected individual usually has one affected parent, affects either sex, transmitted by either sex, mutations are heterozygous (one normal allele and one mutated), a child of an affected person has a 50% chance of being affected (assuming the affected parent is heterozygous for the trait, generally true for rare conditions, risk for recessive is 25%), typically less severe (affected individuals able to have offspring), exception is with severe de novo heterozygous mutations which can be more severe than recessive, ex: huntington’s, charcot marie tooth disease and myotonic dystrophy (risk of incomplete dominance + penetrance)

x-linked dominant

females and males affected but more females than males, females may be more mildly and variably affected than males, a child of an affected mother, regardless of sex, has a 50% chance of being affected, for an affected male, daughters may be affected but not his sons (ex: Rett Syndrome and Aicardi Syndrome)

autosomal recessive

affected individuals usually born to unaffected parents (parents are carriers but asymptomatic), increased likelihood of recessive disease when parents are consanguineous (degree of relatedness can affect risk of child getting disease), affects either sex, following birth of an affected child, each subsequent kid has a 25% chance of being affected, typically more severe that dominant disease (ex: cystic fibrosis, sickle cell anemia, PKU, and most inborn errors of metabolism

X-linked recessive

no direct male to male transmission, affects males mainly who are usually born to unaffected parents, the mother is usually asymptomatic and may have affected male relatives, females may be affected if the father is affected and the mother is a carrier or occasionally as a result of non-random X inactivation (ex: Duchenne muscular dystrophy, fragile X)

Y-linked

only see affected males

why use pedigrees?

helps to determine if a disease state is likely to be genetic and/or inherited, establish pattern of inheritance, guides diagnostic evaluation, helps with understanding and establishing recurrence risk (risk to future children), transmission is defined as one generation passing along an affected condition to the next one (implies vertical inheritance)

compound heterozygotes

autosomal recessive inheritance, 2 affected kids, heterozygote at each allele and put together you have the disease (comes from having parents that are both carriers, get one disease allele from each to be affected)

true homozygotes

comes from consangeanous mating (incest, 1st cousins 1/8 genetically identical, makes founder allele of mutation), this results in having 2 mutations at the same gene and both mutations have same allele mutated

Tay Sach Disease

example of an autosomal recessive disease, affected individuals typically present in infancy with severe developmental delay, irritability, vision loss, seizures and white matter changes on brain MRI (death usually by age 2, very severe), caused by mutations in HEXA which encodes a lysosomal enzyme (need mutations on both alleles of the gene), parents are typically obligate carriers (very high carrier rate in jewish ppl due to founder mutation via consingeanous mating), prenatal screening in this population has greatly reduced the incidence of the disease, several other diseases that have high prevalence in this population, clondoscopy looks into the ey with opthomascope showing classical retinal abnormalities

founder mutations

often present in genetically isolated populations, cause mutations dont have possibility to be diluted out with other genotypes of individuals from other populations

relatedness

its important to know about relatedness in a pedigree because it helps predict if you are dealing with a homozygous recessive disease, the more relatedness there is the higher risk of recessive disease, increasing degrees of consanguinity can bring out recessive diseases in particular, helpful for understanding/estimatiing disease risk in relatives (look at degree of relatedness between different people/who might be a carrier), consanguinity is common in some ethno-regional areas (not considered abnormal or stigmatizing), could also be a denovo mutation or other type resulting from consanguineous mating, not necessarily recessive disease

myotonic dystrophy type 1

multisystem disease affecting skeletal muscle, heart, brain, kidneys and endocrine system (classic one to consider in terms of variable expressivity), due to trinucleotide repeat expansion in the 3’UTR of the DMPK gene, shows anticipation (example of autosomal dominant disorder, parent is associated with the disease get direct vertical transmission of disease)

anticipation

phenomenon where clinical phenotype presents earlier and more severely in sucessive generations, often tied to unstable gene mutations like trinucleotide repeats (gets larger with each generation), examples include myotonic dystrophy, huntington’s and machado joseph disease, the maternal grandmother who is affected has very mild symptoms, age of onset is earlier with each generation so grandchild has the worst symptoms due to repeat getting larger and larger

de novo dominant disease

2 year old boy born with hypotonia (low muscle tone) and weakness, required ventilator support at birth, at present cannot walk, breathe or feed independently, muscle biopsy consistent with central core disease, family history negative (no one else had muscle disease), found to have a het mutation in RYR1 (I4898T) so neither parent carries the mutation (new mutation arising in her genetic material means its de novo, severe dominant disease), the kids of the boy would be at 50% risk of getting the disease

duchenne muscular dystrophy

mutation in the dystrophin gene on Xp21.2, males have progressive muscle weakness, cardiomyopathy and early death, females are typically asymptomatic (maybe develop mild muscle weakness + higher probability of developing cardiac disease later in life), 66% of mothers are germline carriers or mosaics, 33% of mutations are de novo

Rett syndrome

an example of X linked dominant disease, caused by mutations in theMECP2 gene on Xq28, females heterozygous for mutations have a stereotypical syndrome involving acquired microencephaly, neurodevelopmental regression and stereotypical hand wringing movements (loss of fine motor movement), males are either non viable or born with severe encephalopathy

X linked recessive exception

in rare cases, females can have symptoms and even if present with a condition similar to affected males, this is most often due to skewed C inactivation or excessive lionization, females will have such significant skewing they present with the same condition as typical male so for example female with duchenne muscular disease with dystrophy mutation, normal X chromosome inactive so only mutant dystrophine is expressed due to severe skewing X inactivation)

mutation in mitochondrial DNA (mtDNA) maternal inheritance

both sexes can be affected, wide range of clinical variability, inherited from mother (the diseases show exclusive maternal inheritance) or involve de novo mutations on mtDNA from mother (mother may not be affected), fathers do not transmit

genotype

the actual genetic change responsible for disease, the mutation itself (so deletion of exon 44 in dystrophin gene is an example)

phenotype

the clinical manifestations of the genetic change, this will be the outward presentation of the disease (ex: duchenne muscular dystrophy caused by exon 44 deletion in DMD, cardiac myopathy, muscular dystrophy, etc)

expressivity

differences in phenotype for same disease genotype, think of it as disease severity range, the extent to which an individual with a given genotype manifests all known aspects of the clinical phenotype, variable expressivity means there are different clinical phenotypes resulting from the same primary genotype

penetrance

either you have the phenotype or you dont, basically how true the phenotype runs in all affected individuals, in a fully penetrant disease, all inidviduals with the mutation will manifest at least some signs/symptoms, if its incomplete it means you could have the disease genotype but no clinical manifestations at all, absence of clinical phenotype in some individuals despite having a genotype associated with a particular disease state would be incomplete penetrance

tuberous sclerosis

this is an example of variable expressivity, its a neurocutaneous disease so neurological manifestations + skin changes caused by 1 of 2 tumor suppressor genes in the M4 pathway (TSC1 or 2), you could have incomplete penetrance in some ppl, clinical features include facial angiofibromas, renal angiomyolipomata, cardiac rhabdomyomata, infantile spasms and severe learning disability, learning and behavior difficulties, epilepsy (onset in childhood), rare to see all clinical features so example of variable expressivity cause someone could have all the features where someone else might only have some + severity of individual clinical phenotypes might differ

example of both variable expressivity + incomplete penetrance

proband (the one we first identify with the mutation) has very severe myopathy, the father is unaffected so incomplete penetrance (he’s an obligate carrier), and paternal uncle presents with very mild myopathy (variable expressivity

what factors could cause variable expressivity and incomplete penetrance?

intragenic variability, genetic heterogeneity, environment, second site genetic modifiers and epigenetic modifications

intragenic variability

often not even considered cause so common to be reason for variable expressivity, its the idea of different mutations in the same gene, ex: missense + non sense mutation causing different disease phenotype, could be enzymatic deficiency which is caused by pompeil disease (null mutation in maltase gene so no function, neurologic symptoms, cardiac myopathy), some could have excess activity present in early infancy

genetic heterogeneity

different genetic causes for the same disease, disease with common phenotype caused by many different gene mutation (might get variability in phenotype still)

environment

an example of it is charcot marie tooth disease, so motor function going from normal walking to needing a wheelchair due to chemotherapeutic symptoms getting worse

interfamilial variation

having different mutant alleles at gene locus (could be missense, nonsense or deletion)

intrafamilial variation

having 3 different people with same genotype but different second site changes causing different phenotypes (effect of different alleles at the modifier gene locus)’ could also be epigenetic regulation or environmental factors causing variation

LMNA (laminin A/C) mutations

they encode a nuclear envelope protein, broad range of clinical phenotypes including severe muscular dystrophy, peripheral neuropathy, cardiomyopathy and even progeria (premature aging syndrome), clear genotype correlation in some instances (ex: progeria associated only with mutation in the extreme C terminus of the gene, anywhere else mutated associated with other clinical features of disease)

nemaline myopathy

this is an example of genetic heterogeneity, 1 phenotype with many different causes, skeletal myopathy associated with facial and muscle weakness, severe childhood muscle disease with characteristic clinical appearance and muscle biopsy features, mutations in 11 genes are known to cause it, inheritance pattern and clinical severity varies with each genetic cause, they can fully close their mouth

examples of second site gene modifiers

in spinal muscular atrophy, all cases are caused by mutation in the SMN1 gene which is variable due to second site modifier, 4 clinical phenotypes ranging from severe weakness in infancy to adult onset disease, difference in phenotypes dictated by number of copies of SMN2 (more copies equals milder phenotype), basically influences proper splicing of SMN2 gene (all SMN1 proteins comes from this gene), its highly susceptible to gene rearrangements so you get variable copies of SMN2, so higher SMN2 processing leads to higher SMN2 expression cause causes milder symptoms leading to improved disease phenotype

SMA type 1

most severe form cause has the least copies of SMN2

SMA type 2

type of spinal muscular atrophy where they can sit but never stand or walk, they can live until adulthood

SMA type 3

can walk independently but can loose that ability in adulthood

SMA 4

may not even have symptoms till adulthood (very mild, has the most copies of SMN2

epigenetic influences on phenotype

the classical disorders where epigenetic changes influence phenotype are the imprinting diseases, in these conditions, the parental origin of the mutation is key because one allele is epigenetically silenced (through hypermethylation) and so expression comes only from the other allele, gene mutation on unsilenced gene unmasked cause no balancing expression from the other allele (Ex: angelman syndrome which is maternally inherited, prader willi which is paternally inherited, and beckwith weideman)

prader willi syndrome

6 month old female is born at term, has severe feeding issues at birth (needs tube), also had profound hypotonia (low muscle tone)’ work up included methylation PCR of PWS/AS region on 15q11-13, methylation PCR of SNRPN locus abnormal (uniparental pattern), microarray then uncovered deletion of the 15q11-13 region, later developed hyperphagia obesity and mental retardation

environment as a phenotypic modifier

PKU is an autosomal recessive disorder caused by mutation in a liver processing enzyme that coverts phenylalanine, the typical phenotype is one of severe mental retardation, seizures, environmental regression and early death (occurs if unrecognized), however if recognized in infancy, patients can go on a PA free diet, this prevents the severe consequences of the disease

malignant hyperthermia

this is another example of environment as a phenotype modifier, the disease is pharmacogenetic so it requires pharmacologic stimulus to be created + underlying genetic predisposition, it is caused by dominant mutations in the RYR1 gene associated with anaesthesia, it is characterized by fever, muscle rigidity and complicated by abnormal heart rhythms and kidner failure if not promptly treated so people can die from it, it is only caused upon exposure to certain anesthetic agents (changes environment causing disease)

sex limited phenotypes

this is NOT the same thing as sex-linked diseases, some diseases caused by mutations in autosomes have a skewed presentation based on patient sex, for example hereditary hemochromatosis is an autosomal recessive disease that is 5-10x more common in males than females, the phenotype is influenced by amount of iron intake and males have more iron so they are more susceptible to developing the disease (sex limited + environmental influence affecting expressivity), this is different from imprinting where the parental origin of mutation matters, the key is the sex of the proband

what is bioethics?

involves critical reflection on moral/ethical problems faced in health care settings toward deciding what we should do, explaining why we should do it and describing how we should do it

why is bioethics important?

it can improve patient care and research, provides shared language to discuss and pursue quality health care, signs of an ethical issue include conflicting values, beliefs and goals or difficult alternatives, having conflicting obligations or responsabilities, concern that rights are being violated or persons are not being respected, concern with fairness and justice, unsure what we should do or why we should do it

engaging ethics

expressively through feelings and emotions, pre-reflectively by adherence to laws, religious tenets, conventions, codes of ethics, etc (responding in a way that complied with a rule without giving further thought) and reflectively (through reasoned analysis and choice of ethical principles, rules and values)

critical reflection

more careful attention to issues at hand, important to avoid knee jerk emotional responses and jumping to conclusions as well as failing to take other perspectives into account

ethical justification

there is no universally accepted ethical theory or top ranked principle, different theories and principles illuminate different concerns that can serve as points of reflection, ethical frameworks or lenses can be helpful in reflecting upon or in attempting to resolve problems

personal ethics

as moral ethics we act on the basis of values (concepts we used to explain how and why various realities matter), we might rank these differently depending on our upbringing, experiences, religious and cultural background and character

professional ethics

professional codes, institutional policies, law (statutes and case law) and ethics (what we look to when professional codes and law cant tell us the answer, entrenched in the above, also used to fill in the blanks)

principals of medical ethics (principalist approach)

justice (treat like cases alike, issues of non discrimination) autonomy (self governance, if something is being done to an individual, that person is consenting to it, decide what happens to their own body) beneficence (promote welfare/do good) and non maleficence (do no harm), principles are prima facie so an obligation that must be fulfilled unless it conflicts with an equal or stronger obligation, principal you pursue unless you have a stronger one leading you to act in a different way, always right and binding unless a competing moral obligation overrides or outweighs it in particular circumstances, specify principels and balance them (what takes primary consideration)

strengths of principalism

recognizes complexity of moral life, illuminates important moral dimensions at play in ethically challenging situations (ex: importance of autonomy/being able to decide what happens to their own body, minimize harm, be fair and good)

weaknesses of principalism

ambiguous so dont actually know what they entail, hard to weigh and balance them, there are competing principles (so multiple could be relevant but has opposing call for action)

utilitarianism

consequentialist theory, the rightness or wrongness of human action is exclusively a function of the consequences, a person ought to act so as to produce the greatest good for the greatest number of people

deontolgy

contrasted with utilitarianism, is the normative ethical position that judges the morality of an action based on the action’s adherence to a rule or rules, its the study of that which is an obligation or duty and consequent moral judgment on the actor on whether that person has complied

ethical practioner

reflects on what it means to be a good geneticist or genetic counsellor, engages in an ethical reasoning process to understand the ethical strength and ethical vulnerabilities associated with various options, understands that while these issues are complex and that reasonable people might disagree, not all options are equally defensible