Describe Penetrance
Descripte expressivity
Basic concepts for Mendelian genetics
Penetrance = you either have the gene and express the trait or you dont
Expressivity = phenotype varies from slight to severe
Mendelian genetics: Patterns are predictable, random/independent assortment of alleles, no new mutations or natural selection
How to describe a pedigree
3 P’s
People
Position
Patterns
General rule for autosomal dominant disorders
All affected children will have at least one parent with disorder
Heterozygotes are affected
Two affected parents can produce an unaffected child and two unaffected will not have an affected child
M=F
Rule breakers:
- reduced penetrance
- Variable expressivity
- Late-onset trait
- Pleiotropy = Multiple different changes for 1 genetic mutation; single gene locus responsible for a number of distinct and seemingly unrelated phenotypes
Examples: Extrodactyly (split hand), NF1/2, Marfan, Achondroplasia (80% denovo from APA, double dominant is lethal)
ADPKD
Tuberous Sclerosis
22w11 depetion
Huntington
Genetic rules for autosomal recessive disorders
Affected children can have normal parents
Heterozygotes are normal
Two affected parents always have an affected child
Close unaffected relatives who reproduce are most likely to have affected children if they have joint affected relatives
M=F
Rule breakers:
- consanguinity –> can look like AD in a family tree
PARENTS OF AFFECTED = OBLIGATE CARRIERS
2/3 rule for siblings - siblings of affected person have 2/3 chance of being a carrier
Examples: CF, SSD, Tay-Sachs, SMA, Hemochromatosis, Lyosomal storage conditions, CAH
General rules for X-linked recessive disorders
M>F incidence of trait
Heterozygous XX generally not affected but can be with skewed X inactivation
M transmits to all his daughters
F transmits to 50% of sons
NO MALE TO MALE TRANSMISSION
Example: Hemophilia A
Fragile X
General rules for X-linked dominant disorders
Affected males with normal partners have NO affects sons but NO NORMAL daughters
Female heterozygotes have 50% chance of passing on to son and daughter
Pedigree looks like AD
Affected females are twice as common but usually milder
Some are lethal in males (REtt syndrome so only seen in females in pedigree)
No male to male
Example: incontinentia pigmenti (male lethal)
General rules for Y-linked disorders
ONLY males affected and pass disease to ALL of their sons and none of their daughters
Examples: Color blindness, Azospermia
Carrier frequencies to know:
Sickle Cell
Cystic Fibrosis
SSD: 1/10
CF: 1/25
Beckwidth Wiedeman
Overgorwth condition associated with omphalocele, macroglassia, large liver/kidney
Occurs in 4-5% of IVF pregnancies vs <1% in general pop due to epigenetic changes related to methylation pattern in Chromosome 11 modifying histones
Methylation can change during blastocyst period in IVF
20% UPD with 2 active paternal copies
Uniparental Disomy concepts and chromosomes to know
Can be seen with IVF, trisomy rescue and matters with imprinted genes on chromosomes 6, 7, 11, 14, 15 where epigentic markers from dad/mom exist
Prader Willi syndrome
Results from 3 scenarios
- Paternal deletion of PWCR chrom 15
- Maternal UPD Chrom 15
- Imprinting defect Chrom 15
Dx: DNA methylation analysis with abnormal parental specific imprinting
Absent paternal genes “Prader no father”
Clinical: Hypotonia, weak reflexes, weak cry, FTT, motor/developmental delay, small penis/hypoplastic scrotum, almond eyes, triangular mouth, small hands feet, obesity hyperphagia
Angelman syndrome
Angelman has “MAN” so absence of maternal copy
Results from:
- Deletion of maternal locus on chrom 15 UBE3A allele
- Paternal UPD chrom 15
- Imprinting defect
Mechanism important because risk of recurrence is low except with imprinting defect
DX: Parent-specific DNA methylation studies
ClinicaL : developmental delay, gait ataxia, tremors, happy demeanor, microcephaly, seizures, course facial feathres, delays start at 6month to 1 year
Principles and examples of multifactorial inheritance
Cluster in families but no specific genes identified
Certain isolated birth defects: NTD, CL/CP, CHD, Club foot
Risk to 1st degree relative is approx population risk squared (2-5%) but risk is sharply lower for 2nd degree relatives and declines further out
Germ Line Mosaicism - IMPORTANT TOPIC
Normal parent may have cell line of abnormal germ cells causing recurrence of dominant disorder
Ex: in 15% of cases with DMD asymptomatic mothers carry germ cell lines so recurrence risk is 15%x50%
Important for X-linked recessive –> mom’s blood test comes back negative but if there is a germline defect the recurrence risk is higher and so children will be heterozygous
Principles of Mitochondrial inheritance
All children affected through mother
variable proportions of mutant DNA received and variability in expression = Heteroplasmy bc difference # mitochondria can be affected
Affect Heart, Skeletal muscle, CNS
Examples: MELAS, Leber’s hereditaroy optic neuropathy, MERRF
Random terms to know:
Locus Heterogeneity
Polygenic Inheritance
Locus = Different genes can cause similar phenotype
Examples: Retinitis pigmentosa has 60 genets that can cause or TSC with TSC1 or 2 or Noonan with PTPN1/KRAS etc
Polygenic: Quantitiative, several different genes determine the phenotype and produce a bell-shaped curve
Ex: skin color, height, schizophrenia, diabetes, cancer ,cHTN
Aneuploidy Principles
Monosomy is more deleterious than trisomy
Only viable monosomy is X and anueploidies 21, 13, 18, x and y bc those have the lowest numbers of genes
Most common mechanism is meiotic nondisjunction in Meosis I
For T21 - NEED KARYOTYPE to know recurrence risk
Clinical features of
T21
T13
T18
Monosomy X
47XXY Kinefelter
T21: upward eyes, small ears/mouth, simean crease, white spots in eye, decreased muscle tone excess skin etc
T13 - Patau: VSD, Holoprosencephaly, overlapping fingers, proboscus, small head, absent eyebrowsk CL/CP, weird ears clenched hands polydactyly
T18 - Edwards: CPCs, RockerBottom, prominent occiput, clench fists with overlapping digits, stawberry shaped head, small low ears, shortened limbs, clubbed feet, SUA, Omphalocele, Cardiac defects, Spina Bifida, esophageal atresia, shield chest
Turner - Not assoc with AMA, most end with SAB, cystic hygroma, NIH, Coarc, HLHS, Horseshoe kidneys, edema hands/feet, FGR
Klinefelter - Tall, reduced facial hair, gynecomastia, osteoporisos, feminine fat, small testes
Principles of Trinucleotide Expansion Conditions
What is anticipation?
Basics:
- Expansion of trinucleotide repeats that reach a threshold and become unstable and cause disease. Unstable repeat stops transcription to cause disease. Increasing # increases disease severity and onset.
Anticipation:
- Next generation has further expansion with condition coming earlier and more severe
- Mechanism of expansion = slipped mispairing mismatch and expansion of a stable segment of DNA with repeat units to make it unstable
- Repeat randomly and exponentially expand in the next generation
All of these disorders have neurologic / cognitive symptoms
Inheritance patterns vary
Presentation can be at middle or later in life
Anticipation occurs
Trinucleotide Table to KNOW;
HD - inheritance, repeat, Gene, Normal #, Affected #
Fragile X
Myotonic dystrophy
Friedrich Ataxia
HD = AD, repeat is CAG with HD gene, Normal <36, Affected >40
Frag X = X-linked CGG, FMR1 gene, Normal <60, Affected >200
MD = AD, CTG repeat in DMPK gene, normal <30, Affected 80-2000
FA = AR, AAG gene, FRDA, normal <34, Affected 36-1000
Myotonic dystrophy:
Clinical
Genetic
Autosomal dominant CTG repeat in DMPK gene
Causes adult onset muscular dystrophy
5-37 normal
50-90 mild - cataract, balding, limited muscle involvement, starts >50 yo
90-1000 - muscle weakness, gynecomastia, myotonia, cataracts in 20s
>1000 - CONGENITAL - polyhydramnios, hypotonia, develop delay
Congenital DM ALWAYS due to maternal expansion
*Difficulty releasing grip
Fragile X Syndrome
Clinical
Genetic
IMPORTANT STUFF
Most common form of MR on FMR1 gene
CGG repeats associated with ribosomal proteins
>200 = disease
50-200 = premutation (can have FA and POI)
X-linked Dominant with REDUCED PENETRANCE - males will have but females may or may not depending on x-inactivation so skewed X-inactivation can have disease
Incidence 1/4000 males and 1/8000 females
Clinical: MR, ADHD, Autism, long think face, prominent forehead and ears, hypotonia, flexible joints, enlarged testicles
**ANTICIPATION MOSTLY FROM MATERNAL GENES - male with premutation carrier will pass on premutation to all daughters but unlikely to expand
Can assess FMR protein level in neurons
Normal - widely expressed, premutation - increased mRNA, full mutation –> no protein and methylation
Risk of expansion varies by pre-mutation size and # of AGG triplets:
- Number of maternal CGG repeats in premutation carrier changes affected risk of child and number of AGG repeats increases stability and reduces expansion
PREMUTATION CARRIERS CAN HAVE DISEASE:
- Fragile X associated tremore/ataxia = late-onset progressive cerebellar ataxia, memory loss, cognitive decline, proximal muscle weakness and autonomic dysfunction and PENETRANCE RELATED TO AGE
- POI = cessation of menses before age 40, occurs in women with premutation in FMR1 (carriers for Frag X) and occurs in 21% of females. All women with >200 repeats will have.
Huntington
clinical
Genetic
Testing
AD HD gene with CAG repeat targets protease for neural apoptosis. Affects basal ganglia in caudate nucleus.
Progressive neurodegen condition
Increased meiotic instability in males and so paternal transmisiosn sees greater expansion and contributes to 3/4 juvenile cases
10-28 normal
29-35 paternal meiotic instability
36-39 reduced penetrance
40-100 HD
Options for PGT if you want to figure out the risk without knowing your specific status then can do genetic linkage analysis where you test grandparents, parents to understand which alleles are coming from where to determine if baby has potential for allele or not but not necessarily if baby affected
Differential diagnosis of msAFP elevation
Fetal - NTD, Abd wall, Teratoma, cystic hygroma, congenital nephrosis, skin defects, OI
Placental - FGR, oligo, HDP, PTB, abruption, SB
Maternal - cirrhosis, Germ cell or YS tumor, HCC
Amnio distinguishes between maternal and fetal sources
