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Genetics: Hereditary Pathologies - Coggle Diagram
Genetics: Hereditary Pathologies
Anomaly due to gene mutation (ID via bio/biomol, ++ susp.
histology
via discharge)
Anomaly due to cytological morpho changes
Definitions
Gene, Genotype, Phenotype, Locus, Allele
Gene =/= Pheno characteristic
Polyallelic gene; makes gene =/= allele
Syndrome = clinical condition w/ ++important pheno morpho mods (☑️recon) = "groupements de modifs phenotypiques"
subject can be phenotypically normal for most of lifetime despite abnormal gene (e.g. Huntington's)
Pleiotropism: 1 gene = ++ fx
Genic heterogeneity: ++ gene = 1 fx
Phenocopy: env. agents = fx
gene
Congenital disease =
birth
(hereditary or not)
Fetal alcoholisation = congenital non-hereditary
1/3 of hospit. kids
gene
anomalies
Heredity + Environment
Some differences = via genetic constitution (e.g. blood groups)
Others via constit. of gen + env (e.g.cancers, infections)
Some via env. only (e.g. Chernobyl)
Monozygote twin studies = means to see fx
Nucleosomes
Remodeling complexes = proteins using ATP to change confs
nucleosome
(condense/decondense)
Epigenetic modifs + chemical modifs:
Acetylation
Place histone-acetyltransferases (HATs) = + acetyl group = ++accessible genes
Methylation-Plation-Ubiquitinylation
Place Me groups
gene
= ↓accessible
Ribosomes translate RNA to proteins
RER
Mutations
Types of mutation
Punctual
(@3nucl
); respects reading frame
Deletion
Substitution
e.g. drepanocytose (sickle cell disease-missense mutation)
Insertion
Frameshift: altered reading frame (insertion/deletion non-3)
instab/degraded prot
gain of fx
protein
STOP mutation
Consequences
Regulation
over/under expression
Sequence change
over/under
STOP translation
Truncated prot = fx change
Maturing mRNA
Truncated prot = fx change
Change
a.a.
Fx change
Gain
Loss
Genetic mutation disorders
Dominant autosomal (Aa = disease)
e.g. Achondroplasia (dwarfism/nanisme)
croissance et un développement anormal des os longs
men: max 132cm
women: max 123cm
achondroplasia means "without cartilage formation"
no gen skipping = pt sick -> parent sick
parent healthy = 🚫transmission
♂️/♀️ same chances to transmit
e.g. Marfan's disease
(Recessive) X-linked
no corresponding (masking) locus in chromosome Y (hémizygote)
if ♀️gets it, is due to inactivation of X
1/2 ♂️ sick, 1/2 ♀️ carrier
most on recessive X gene
e.g. Duchenne's muscular dystrophy
: démarche chancelante
mutation du gène de la dystrophine
(Xp21.1)
most common children's myopathy
pseudo-hypertrophy
lordose
+ popliteal fossae
Gower's sign: difficulty getting up from sitting
Dominant X-linked
all
generations
normals don't pass it down
♀️ transmit to half male and fem children
♂️ transmit to all fem and no male chlidren
dinstincts from autosomal dominant
rare
Y-based heredity
rare: ~0 abnormalities Y-based
Absence of dominance/recessivity
mutated gene always expressed
Only men/boys affected
Protein sicknesses
Enz
Metab enz
Anti-enz disease (A1T1 deficit)
Loss of fx
alpha-1-antitrypsine protects lungs
mutation = deficit = 🚫 protection
mutation via enz mal repliée
liver?
try to figure out what's happening here
m.e.:
deposits
R.E.
= electron-dense stuff + flakey material sometimes
Malformations
Immunopatho
Proteopathy (e.g. amylose)
Neurodegen
Predisp to cancer
(@signaling
pathways)
Canalopathy (e.g. mucovicidose)
Genetic imprint (parental)
50 ish genes
imprint
= epigenetic process
intervening methylation/histone acet/deacetylation of genes
according to paternal/maternal origin, expression as if haploid
Imprint box: on flanks of gene, helps regulate expression
Selective advantage: mutation that helps you survive
Monogenic anomaly
e.g. Sickle cell anemia (falciforme)
Glu -> Val
via Hb S
Only in Black ppl
Protection from malaria (when heterozygote)
Africa
1 gene nucleotide replacement = change in gene
Cytogenetics:
chromosomes
Chrom. anomaly = large amount of genes -> ++malformations/malfx
chrom. anomalies = large reason for reprod. fails (50%) + congen. anom.-> ++ freq.
cancers
Cytogenetics = part of genetics focusing on heredity based on chromosomes
Caryotype = charac. chrom. formulation via # + morphology
Limits:
Resolution = 5million bp
needs mitoses
anomaly caracterizing is hard: bands can look alike
Gonosome: XX or XY
normal male: 46,XY
normal female: 46,XX
Anomaly indication: +21
Naming a chromosome:
Bande 17p13.1
17: #chrom
p: p/q (short/long arm)
13.1: int'l classif
gene
position
Aneuploidy: +/-
homol
pair chrom
Monosomy
incompatible w life other Xmonosomy
Trisomy
Caryotypes
1956 classic caryotype
Les paires sont placées par ordre de grandeur (les plus
grandes d'abord), selon la position des centromères (index
centromérique) et selon leur forme**
Molecular caryotype (more used): easier, used to find anomalies where mitosis can cause innacuracies/be infra-microscopic
FISH (in-situ fluo hyb)
based on denat/renat of DNA
molec radar hybridizes with genome sequence (compl)
mitosis
chromosomes or interphase chrom. Reading via radar fluorescence
Fluorochrome marking:
Specific to loci (Microdel, insertion, ++precise)
Painting: collection of several sondes to paint entire genome, use
translocations
Break-apart/disjx sonde:
translocs
Centromeric sondes: hybridize
centromeres,
denombrement
example
trisomy
21, slide 80
Limits:
Specific sondes - break-apart = targeted study
Paintings = 1.5Mb resolution @ telomeric translations
Insertion:
impossible to know which region implicated
CGH (Comparative genomic hybridation
metaphase)
Study global content
DNA
Compare # DNA molecs of pt w/ control => establish ratio
0.5 ratio = deletion
1.5 ratio = trisomy
on m. slides fixated w DNA/genomic seqs or sondes
resolution depends on # + localization of sondee
Limits:
Genetic mutations
Does not detect balanced anomalies
translocs
balanced inversions
Does not detect UNbalanced anoms
<10-20%
of c. (e.g. weak mosaic)
SNP array
Fixate on oligonucl. m. slide an SNP
Advantages:
lets you detect uniparental disomies (OR loss of heterozyg. w/ allele duplication)
Gives variation of #copies
allelic
profile
When to do cytogenetics?
Genetic council + prenatal diagnostic
carrier parents
balanced
transloc
already abnormal child in family
Familial mental challenges
Product of repeated abortions
50% due to chrom anomaly
Infertility problems
XX/XY issues
Cancers:
Helps in:
Confirmation of diagnostic
Classif
type
of tumor
Prognostic
Orientation
therapy
Clinical applications:
FISH: used to detect microdels (compl to caryotype)
frag
losses of 500000 to 4Mb
Interphasic FISH:
no cell culture req'd, emph.
nuclei
e.g. diagnostics
trisomy
13/18/21
amniotic
c.
e.g. oncology translocs via imprints/c. cuts
CGH array:
acquired
pathologies (e.g. onco): usually not first method
Ref tech
constit.
anomalies (genomic diseq. type)
EXAMPLES (w/ symptoms)
Trisomy 21 (47,XX,+21 ou 47,XY,+21)
Fentes palpébrales obliques = mongoloïdes (up and outward)
Very large tongue
Pli palmaire médian unique (only one palm fold)
General (mscl.) hypotonia
Phys/ment dev. retardation
Heart malformations (freq.)
Trisomy 18 (Edward's Syndrome): 1/6000 to 1/8000 births
Small weight
birth
(RICU)
Mental retardation
Hypertonia
Craniofacial dysmorphia: microretrognathism
stub hands (mains botes)
omphalocele
birth defect of the abdominal (belly) wall. The infant's intestines, liver, or other organs stick outside of the belly through the belly button. The organs are covered in a thin, nearly transparent sac that hardly ever is open or broken.
precocious death
Turner Syndrome :
45,X (1/2500 naissances)
Fem phenotype
IQ normal or slightly less
Shorter stature than average
Infertile
Palmed neck (slouched over + droopy)
V little secondary sexual carac dev
Aorta coarctation
part of the aorta, the tube that carries oxygen-rich blood to the body, is narrower than usual.
Klinefelter Syndrome) :
47,XXY (1/500 garçons)
Masc phenotype
Tall height
Less-than-average sec sx carac dev
Gynecomastia (30%)
Hypogonadism (+/-):
No germinal line
Very small testicles
mosaic
prolif including normal => discrete germinal prolif
Osteoporosis
