Genetics Mid-Term

clinical genetics

family tree - pedigrees + patterns, risky business

genetic counseling

understand ?s - educate, interpret, counsel

components of genetic couseling

set expectation

gather info

what is risk

talk + educate

testing? - consent

result + plan - emotions of pxt and testing family

genetic terms small to big

nucleotide - gene - DNA - chromosome - genome

central dogma of life

DNA - RNA - protein (doers)

different forms of proteins

enzymes

receptors

cell structures

cell function

indications for genetic counseling

unexplained chronic sxs

child w/ developmental delays

child w/ birth defect

family hx of genetic disease/cancer

abnormality on U/S

progressive vision issues

new cardiomyopathy

AA

coiled and structured proteins

folding pattern determined by polarity/charges of AAs

missense mutation disease example

sickle cell disease

Glutamate (-) to Valine (+) = change in charge, change in shape

mutation in hemoglobin

nonsense mutation disease example

CF

premature stop codon

truncated CTFR protein - can’t reach surface of cell

deletion and duplications

genes or chromosomes - big boys

extra or missing

point mutations

nonsense

missense

frameshift

silence

nonsense mutation

nucleotide change = premature stop codon = truncated protein

Ex: CF

missense mutation

nucleotide change = new AA

Ex: sickle cell

frameshift mutation

insertion or deletion of nucleotide that affects 3-AA reading frame

silent mutation

base substitution w/o AA change or functionality change

normal variability from person to person

germline mutation

occurring during formation of egg or sperm

most genetic disease

somatic mutation

genetic change post-conception (~3 weeks)

Ex: cancer

mosaicism

some cells have genetic variant, some don’t

mild or asxs

5 categories of genetic variants

pathogenic

likely pathogenic

variant of uncertain significance (VUS)

likely benign

benign

autosomal

non sex-linked chromosomes

de novo

spontaneous genetic mutations

not inherited

autosomal dominant

no carriers - affected or don’t have

50% chance of passing it down

heavy prevalence in each generation - family hx

autosomal recessive

less likely to have family hx

carriers exist

if both carriers - 25% unaffected, 50% carriers, 25% affected

X-linked

exist only on X-chromosome

no male-to-male transmission

women tend to have more mild version d/t 1 affected X and 1 unaffected X

mitochondrial pattern

inherited through maternal line - if mom has, all kids have

heteroplasmy common (mosaicism) - impact how severe disease presents

non-mendelian inheritance patterns

more complex

multifactorial - environmental AND genetic

co-dominant - 2 alleles both getting expressed (AB blood type)

polygenic - more than 1 gene controlling it

red flags in family hx

dx in young age

multiple family members w/ same

rare genetic

very severe versions of disease

key elements of pedigrees

keys for relevant dx

ancestry

arrow pointing to proband (pxt)

who provided info - historian

approx age at dx

3 generation = good

date obtained and by who

chromosome testing

karyotype

chromosome microarray

FISH

DNA sequencing

family variant

single gene

single site

panels

WES

WGS

chromosome non-disjunction

entire chromosome missing or added

chromosomal translocation

still have all genetic data

balanced or unbalanced

karyotype

picture of all chromosomes

can only see large anomalies

commonly dx trisomys and uneven sex chromosomes

chromosome microarray

1st line

analyzes chromosome length - detect extra or missing pieces

more detailed than karyotype

cannot detect translocations or single gene disorders (too small)

common dx insertion/deletions - Williams, DiGeorge

common reason for chromosome genetic testing

developmental delays/intellectual disability

growth delays

birth defects/congenital anomalies

dysmorphic facial features

suspect specific disorder

FISH

fluorescence in situ hybridization - probes attach to specific points of chromosomes

count how many probes can see vs normal

detects deletions and duplications

targeted at 1 chromosome - order specific 1 based on suspected dx

can detect translocations + mosaicism

single site testing

super targeted at 1 genetic mutation

FHx of known mutation

undx pxt w/ dx family member

test for carriers of recessive conditions

chromosome 10q deletion syndrome

PARK2 gene disruption - autosomal recessive Juvenile Parkinsons’s

growth delay

feeding difficulties

hypotonia

variable abilities in learning, speech, motor

eye abnormalities

kidney/UT anomalies

microcephaly

genital anomalies

seizures

ADHD, impulsivity, or autism/autistic traits

single gene testing

single gene

only common variants

pxt presents w/ specific sxs and you have suspected dx

panel testing

list of genes that present w/ similar sxs

only common variants

examples - hearing loss, cardiomyopathy, epilepsy, cancer, hematological

exomes vs genome

exome = coding DNA only

genome = coding and filler

WES

read just exons of ALL genes for common sequence variants

cannot detect deletions/duplications reliably - need chromosome microarray

WGS

read both exons and introns - ALL of genes for common variants

more extensive than WES

can detect deletions/duplications

WES/WGS indications

not have 1 specific dx in mind - lots of conditions associated w/ sxs

previous testing negative but suspect genetic

multiple organ systems affected

bioinformatic filters - related to any of pxt’s sxs, parent/family member samples

WES/WGS limitations

20,000 genes to analyze - only know 7,000

expensive - difficult insurance approval

incidental findings - opt in/out of seeing - could have future actions (screenings)

unexpected findings - non-paternity/maternity, consanguinity

takes 3 months - long

why genome testing needed prior to surgery

if given blood transfusion, test can detect donor’s DNA

G6PD deficiency

RBCs break down prematurely (hemolysis)

sxs - paleness, jaundice, dark urine, fatigue, SOB, tachycardia

episodic

X-linked recessive

NBS - low levels = high risk, high levels = nothing

Hemophilia

clotting disorder caused by mutations in F8 or F9 gene - missense = mild, deletions = severe

factor VIII = A

factor IX = B

X-linked recessive

hemarthrosis

coag labs - prolonged APTT, normal PT, normal bleed time, normal fibrinogen

txt = factor replacement

dysmorphology

structural defects

congenital malformations

Noonan syndrome

downward slanting eyes

triangular shaped face

prominent forehead

hypertelorism

eyes far apart

hypotelorism

eyes close together

epicanthal fold

little bit of skin covering medal part of eye

synophrys

unibrow

trisomy 13 (Patau syndrome)

heart defect - VSD, ASD, PDA

cleft lip and palate

microcephaly

polydactyly

small growth in-utero

scalp lesions

not live past 1st days/weeks (10% past 1st yr)

dx prenatally d/t U/S or maternal serum

trisomy 18 (Edwards syndrome)

clenched hands w/ overlapping fingers

club feet

SMOL

heart defect - VSD, ASD, PDA

increased risk w/ increased maternal age

not live past 1st days/weeks (10% past 1st yr)

dx prenatally d/t U/S or maternal serum

trisomy 21 (Down syndrome)

facial - upwards eyes, small folded ears, macroglossia, flat nose

short

singular palmar crease

heart defect - VSD, ASD, PDA

GI, hearing/vision, thyroid problems

comorbidities - hematological disorders, alzheimer’s

most often sporadic event

variable range

increased risk w/ increased maternal age

Klinefelter syndrome (47XXY)

extra X

only in males

psych - ADHD, anxiety, depression, learning disabilities

long arms

gynecomastia

delayed puberty - hypogonadism, often infertile

increased risk for - T2DM, autoimmune, osteoporosis (low bone density), blood clots

txt - HRT testosterone, therapies, breast tissue removal, fertility txt, screenings

dx during puberty/adolescence

Turner syndrome (45X)

most common sex anomaly in females

webbed neck

low bone density

heart defect - coarctation of aorta, bicuspid aortic valve

renal - horseshoe kidney

delayed puberty/amenorrhea - fertility issues

lymphedema

drooping eyelids

increased risk for metabolic - obesity, insulin resistance, T2DM, dyslipidemia

higher percent mosaic

many pregnancies do not survive to birth

sporadic/not inherited

txt - HRT estrogen, therapies, fertility txt, bone health, screenings

22q11.2 deletion (DiGeorge syndrome/Velocardiofacial)

most common microdeletion

90% de novo

heart - VSD, TOF, interrupted aortic arch

palate - vp incompetence, cleft palate, bifid uvula

immune deficiency

facial - hooded eyelids, ear anomalies, bulbous nose, micrognathia, asymmetric crying facies

hearing/vision, thyroid, calcium regulation issues

psychiatric illness - schizophrenia, autism

Williams syndrome (7q11.23 syndrome)

de novo - autosomal dominant

heart - stenosis, HTN

facial - wide mouth, upturned nose, small chin, full cheeks, big ears

endocrine - hypothyroid, hypercalcemia, early puberty

feeding issues/poor weight gain

“friendly” personality trait - anxiety, ADHD

hearing/vision

txt - therapies, surgical repair, manage sxs

Prader-willi syndrome (15q11.2-q13 deletion)

paternal chromosome

infancy - hypotonia, feeding issues

endocrine - delayed puberty, hypogonadism, DM, hypothyroid

facial - almond-shaped eyes, narrow forehead, downturned corners of mouth

voracious appetite - obesity

microarray then methylation to ddx from AS

Angelman syndrome - AS (15q11.2-q13 deletion)

maternal chromosome

speech issues

seizures

require less sleep (polyphasic)

fascination w/ water

hyperactive/happy, aggression, anxiety

microarray then methylation

newborn screening

required for all

diseases benefit from early intervention

3 parts - hearing test, cardio (pulse ox), blood (heel stick)

24-36 hrs postpartum - timing important

screening, not dx

inborn errors of metabolism

body cannot properly turn food into energy

often as infant, may present at any age

disrupt carb, protein, FFA metabolism, or glycogen storage

urea cycle disorders

cannot remove urea toxic waste d/t missing enzyme

build up of ammonia (neurotoxic)

sxs - lethargy, N/V, fussiness, unable to eat, seizures, coma, death

citrullinemia, OTC deficiency

citrullinemia

urea cycle disorder sxs

autosomal recessive (type 1) - mutations in ASS1 gene

lysosomal storage disorders

lysosome cannot destroy things so buildup and organs no work

progressive

multisystemic

tay sachs, fabry, sanfilippo

fabry disease

X-linked recessive - GLA gene

alpha-galct A - build up of globotri-ceramide

episodic pain, N/V

txt - enzyme replacement

mitochondrial disorders

body make no energy

multisystem

mDNA or DNA

sxs - neuro sxs, muscle weakness

MCAD

autosomal recessive - ACADM gene

hypoketotic hypoglycemia

healthy → N/V, seizures, coma

triggered by illness

txt - eat carb

fatty acid oxidation defects

no fat breakdown

rhabdo + cardiomyopathy

MCAD, VLCAD, LCHAD

amino acid disorders

proteins cannot use

build up of AA = sxs - neuro, odors, hypoglycemia

PKU

PKU

autosomal recessive - PAH

phe breakdown not happen

toxic phe levels - irreversible intellectual disability

txt - limit protein in diet, formula

BH4 meds - convert phe to tyr