Genetics 2

Fragile X syndrome: inheritance pattern and why females are less affected

X-linked dominant (XLD); females are usually less affected due to X inactivation

Fragile X syndrome: mutation, gene, and carrier frequency

CGG trinucleotide repeat expansion in the FMR1 gene; 1 in 150 women are carriers

Fragile X syndrome: clinical features

Intellectual disability, joint laxity, macroorchidism (large testes), macrocephaly, long face, large ears, prominent jaw

Fragile X: 5-44 repeats vs 45-54 repeats

5-44: normal allele, not affected.

45-54: intermediate allele, not affected but possible risk for grandchildren

Fragile X: 55-200 repeats vs more than 200 repeats

55-200: premutation; carrier, can be affected with FXTAS (males and females) or FXPOI (females).

More than 200: full mutation; Fragile X syndrome

Huntington's disease: inheritance pattern and type of disorder

Autosomal dominant; late-onset neurological disorder

Huntington's disease: psychiatric, cognitive, and motor features

Psychiatric: personality changes, depression, irritability, apathy.

Cognitive: progressive decline in memory and thought process.

Motor: chorea, bradykinesia, dystonia (abnormal involuntary movements)

Huntington's disease: mutation and mechanism

CAG triplet repeat expansion in the HTT gene; gain-of-function, where mutant huntingtin protein misfolds and forms amyloid-like aggregates that cause disease

Huntington's disease: which parent's transmission usually causes the repeat to expand?

Paternal (from dad); usually expands by more than 7 CAG repeats in 1 generation

Huntington's disease: fewer than 26, 27-35, and 36-39 CAG repeats

Fewer than 26: normal, unaffected.

27-35: intermediate allele, unaffected but grandchildren at risk.

36-39: reduced penetrance, sometimes affected

Huntington's disease: 40+ and more than 55 CAG repeats

40+: classic adult-onset, affected around 35-44 years old.

More than 55: juvenile-onset, affected before age 20

Multifactorial inheritance

Trait caused by multiple genes interacting with environmental factors like lifestyle, diet, and exposure.

Aneuploidy and trisomy

Aneuploidy: not having the correct number of chromosomes, usually causes miscarriage.

Trisomy: 3 copies of 1 chromosome

Most common cause of aneuploidy?

Nondisjunction error in meiosis (example: egg gets 2 copies of chromosome 21 instead of 1)

Conditions NIPT screens for?

Trisomy 21, 18, 13, triploidy (3 copies of all chromosomes), Turner syndrome (45,X), Klinefelter syndrome (47,XXY), and (sometimes) 22q11.2 deletion

NIPT: screening or diagnostic, and why?

Screening (NOT diagnostic), because placental DNA doesn't always match fetal DNA

NIPT: DNA source, sample type, and earliest timing

Cell-free DNA (cfDNA) from the PLACENTA circulating in the mother's blood; maternal blood sample only, from 10 weeks gestation onward

NIPT positive: what value do you check and what does it mean?

Positive predictive value (PPV); the percentage of high-risk screening results that are a true diagnosis (affected pregnancy)

Trisomy 13: prognosis, and heart defect rate

severe, 70% result in miscarriage, a minority may live shortly after birth; 85% have congenital heart defects

Trisomy 13: clinical features

Microcephaly, cleft lip/palate, small eyes, low-set malformed ears, polydactyly and syndactyly, polycystic kidneys, rocker-bottom feet

Trisomy 18: name, prognosis, and heart defects

Edwards syndrome; severe, 95% result in miscarriage, a minority may live shortly after birth; congenital heart defects in 95% (the cause of death)

Trisomy 18: clinical features

IUGR, hypertonia, microcephaly, micrognathia (small jaw), cleft lip/palate, clenched fists, rocker-bottom feet, omphalocele (organs protruding through navel), horseshoe kidney

Trisomy 21: chromosomal basis and main clinical features

3 copies of chromosome 21; intellectual disability, congenital heart defects (30-50%), hypotonia, feeding difficulties, failure to thrive (underweight)

Trisomy 21: facial features

Low nasal bridge, up-slanting palpebral fissures, small low-set ears, epicanthal folds

Trisomy 21: cancer risk, lifespan, and later-life risk

15-fold increased risk for leukemia; lifespan about 60 years; increased risk for Alzheimer's

Amniocentesis: what it is, whether it is diagnostic?

Needle inserted into the amniotic sac that can diagnose any genetic condition; fluid contains fetal DNA, so it is DIAGNOSTIC

Amniocentesis: typical timing?

15-22 weeks gestation

FISH: turnaround time and how it works

24-48 hours; fluorescently labeled DNA probes light up specific chromosome areas to count chromosomes (usually tags for 13, 18, 21, X, and Y)

FISH: role in testing and limitations

Rapid preliminary test that must reflex to more comprehensive testing; cannot rule out partial deletions/duplications, cannot tell anything at the gene level, NOT diagnostic

Karyotype: what it detects and main drawback

Diagnostic; detects extra chromosomes and large missing/extra pieces (not exact breakpoints or genes), a "bird's eye view" of chromosome number, order, size; takes 2-3 weeks for results

The only genetic test that can detect balanced translocations

Karyotype

Turner syndrome (45,X): clinical features

X missing , Short stature, webbed neck, widely spaced nipples, elbow deformity, rudimentary ovaries, no menstruation

Turner syndrome: pregnancy outcome and mosaicism

Majority result in miscarriage (only 1-3% survive to live birth); up to 40% of live-born cases are mosaic

Klinefelter syndrome: karyotype and clinical features

47,XXY; tall stature, hypogonadism/undescended testes, gynecomastia, sparse pubic hair, poor beard growth, infertility

Balanced translocation

Only type of down syndrome thats hereditary 3-4% / this is when 2 diff chromes swap pieces / only found on karyotypes from mom

22q11.2 deletion syndrome: other name, frequency, and heart defect rate

DiGeorge syndrome; one of the most common microdeletions (can be added on to NIPT); 75% have congenital heart defects, a major cause of mortality

22q11.2 deletion: non-cardiac and facial features

Hypocalcemia, thymus abnormality/immune disorders, hypernasal speech; long face, hooded eyes, short philtrum, cleft palate

22q11.2 deletion: psychiatric concerns

20-30% develop schizophrenia or bipolar disorder

22q11.2 deletion: What test?

Chromosomal micro array (detetcts smaller missing pieces of chromes)

Genomic imprinting (definition, main idea, first human examples)

Modification of genetic material (and phenotype) depending on whether it came from the mother or father

An imprinting disorder means all gene expression comes from ONE parent

First examples were Prader-Willi and Angelman syndrome

3 ways an imprinting disorder can happen

(1) Deletion of one copy of 15q11-q13

(2) uniparental disomy - Child inherits 2 copies of a chromosome from ONE parent instead of 1 from each

(3) imprinting center defect (very rare)

15q11-q13 deletion: which parent's deletion causes which syndrome?

Maternal deletion causes Angelman (only paternal copy expressed)

Paternal deletion causes Prader-Willi (only maternal copy expressed)

Prader-Willi syndrome: neonatal features

Low birth weight, hypotonia, poor suck

Prader-Willi syndrome: features after infancy

Polyphagia (enormous appetite) and obesity from about 6-12 years and beyond, small hands and feet, hypogonadism in males, short stature, developmental delay

Angelman syndrome: clinical features

Episodes of inappropriate laughter (very happy), growth deficiency, large mouth with tongue protrusion, developmental delay, puppet-like gait with ataxia and jerky arm movements, speech problems

Mnemonic for Angelman vs Prader-Willi

AngelMAN: absent/silenced maternal copy;

Prader-Willi: absent/silenced Paternal copy (same locus, different parent)

WES test and microarray

Whole exome sequencing best test that sees everything but doesn’t see balanced translocations

Detects extra and missing pieces of chromosomes

What are acrocentric chromosomes

13,14,14,21,22 higher risk of recombining or translocation

Whole genome vs exome

Genome can detect repeat disorders / protein coding and everything

Exome is only protein coding

Panles

Only test certain genes

Exp: testing for breast cancer due to family history of it