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A.

B.

INTRO TO GENETICS
Intro
1. Types of genetic disease
a. Chromosomal (Trisomy 21, Klinefelter syndrome)
b. Single-gene, dominant (Noonan syndrome, Marfan syndrome)
c. Single-gene, recessive (CF, ataxia telangiectasia)
d. Single-gene, X-linked (Fragile X syndrome, hemophilia)
e. Mitochondrial (progressive external ophthalmoplegia)
f. Complex/multifactorial (cleft lip/palate, diabetes)
g. Somatic mosaic (proteus syndrome)
2. History taking and pedigrees
a. Red flags
Multiple, closely related individuals
Bilateral disease in paired organs
Sudden death of a seemingly healthy person
>3 miscarriages
Age of onset earlier than expected
Breast cancer <45-50 years
Colon cancer <50 years
Prostate cancer <60 years
Alzheimers <70 years
Vision loss <55 years
Hearing loss <55-60 years
Dementia <60 years
Heart disease <45-50 years
b. Autosomal dominant disorders
Affect 1 in 200 individuals, but each order is individually rare
Occurs with loss or alteration of 1 of 2 copies of a gene
On pedigree: vertical transmission, no skipped generations, males and females affected equally, father-to-son transmission
Recurrence risk: 50%
c. Autosomal recessive disorders
Loss/mutation of BOTH copies of a gene
One mutation inherited from each parent
Carrier parents are unaffected
On pedigree: unaffected parents, multiple affected siblings, males and females affected equally,
Recurrence risk: 25% - consanguinity may be present (and increases risk of recurrence)
d. X-linked recessive disorders
Mutations on X chromosome
On pedigree: males > females, daughters of an affected male are all carriers, no father-to-son transmission
Recurrence risk: 50% for sons of carrier female
Genomes and Mutation
1. General
a. Haploid genome = 3 billion bases (23X or 23Y); diploid genome = 6 billion bases (46XX or 46XY)
b. 20,000 genes, 1% protein coding, 5% regulatory DNA, 55% repetitive DNA
2. Epigenetics: histones rule the world, histones are modified and DNA is methylated preferentially based on the cell state and type of cell
a. Chromatid: one of two identical parallel DNA strands in a mitotic cell following DNA replication
3. Mitosis we use metaphase of mitosis to identify aneuploidies, count chromosomes
4. Meiosis recombination: 1-2 crossovers per chromosome per meiosis (between sister chromatids)
a. Female: oogenesis
1 gamete, 3 polar bodies
In embryo, begins and arrests mid-prophase I => Resumes at menarche, terminates at menopause
More recombination than male meiosis
More chromosomal non-disjunction with increasing age

INTRO TO GENETICS


b.

C.

Male: spermatogenesis
4 gametes
Occurs continuously from puberty until death
More DNA mutation with increasing age
5. Types of mutations: gain of function, loss of function, dominant negative (abnormal product interferes with normal product)
a. Single base change
Silent (synonymous) same amino acid is coded (wobble)
Missense (non-synonymous) different amino acid is coded (most common mutation underlying disease)
Nonsense (protein truncating) changes triplet to a stop codon
Splice site mutation: single sequences at exon-intron junctions are VIP to transcript splicing; esp first two bases of intron
Donor: GT
Acceptor: AG
b. Small insertions/deletions (indels)
3N indels gain/loss of amino acid
Non-3N indels frameshift
c. Microdeletions/duplications
d. Chromosomal abnormalities
e. Aneuploidy
6. When mutations occur
a. Replication errors
-8
1.5x10 mutations per nucleotide site
Errors cause de novo mutations (not in parents/inherited)
100 mutations per diploid genome per familial generation; 1 de novo coding mutation per familial generation
If in germline inherited
If in other cells somatic
7. Factors affecting mutation rates
a. Genomic context (e.g. CG dinucleotides mutate at elevated rate with deamination of methylated cytosines)
b. Parental age (e.g. increased non-disjunction in older females; more point mutations in older males)
c. Environmental exposures (e.g. chemical mutagens, radiation, UV sunlight)
8. Detection of mutations
a. PCR small chunks of DNA
b. Sanger Sequencing
c. Differences between individuals: 1 SNP per 1,000 bp
3-4 million SNPs per diploid genome (this number does not include large chunks of DNA that are missing or different)
Population genetics
1. Allele frequency fraction of chromosomes in the human population with a given allele
a. Common variants >1% (differences among individuals)
b. Rare variants <1% (more likely to cause disease)
c. De novo mutations -> AF = 1/14,000,000,000 (these are the variants that are occurring for the first time in a generation)
d. Positive and negative selection act to increase and decrease the reproductive fitness of an individual have influence on allele frequency
2. Hardy Weinberg Equilibrium
a. p = frequency of one allele; q = frequency of other allele; p+q = 1
2
2
b. In a randomly mating population: p +2pq+q = 1
2
P = fraction of p/p homozygotes
2pq = fraction of p/q heterozygotes
2
q = fraction of q/q heterozygotes

Sickle Cell Anemia


1 in 5,000 births; 1 in 500 African-American births
Glu6Val in beta-globin
Autosomal recessive (heterozygous carriers = sickle cell trait)
o Do NOT reflect HW equilibrium because of selective pressures heterozygote advantage - there is malaria resistance in heterozygotes)
Life expectancy 50-60 years

INTRO TO GENETICS


3.

D.

Probability in genetics
a. For independent events multiply probabilities
b. For mutually exclusive events add probabilities
c. The total probability of all possible outcomes must sum to 1
Mendelian inheritance
1. Autosomal dominant
Marfan Syndrome
Autosomal dominant (25% of cases are new mutations)
Prevalence: 1:10,000
Skeletal features: dolichostenomelia (long, slender limbs), arachnodactyly (spider-like long fingers), pectus excavatum, scoliosis
Cardiovascular features: ascending aortic dilatation, aneurysm, dissection; mitral valve prolapse
Ocular features: ectopia lentis (dislocation or subluxation of the lens)
Mutation: fibrillin-1 gene (FBN1)
o Extracellular matrix protein that is important for formation and maintenance of elastic fibers; acts through sequestration of TGF-B
Clinical overlap with Loeys-Dietz syndrome (TGF-B1, TGF-B2 mutations)
Losartan: anti-hypertensive, angiotensin II receptor antagonist
o Also down-regulates TGF-B types I and II in animal models
a.

Penetrance: probability that a genotype will have any phenotypic expression at all (all or none)
Incomplete penetrance: some individuals may inherit the mutation but fail to express the trait (aka reduced penetrance)
New (de novo) mutation: new mutations can account for large fraction of cases of a dominant disorder depending on fitness of
syndrome (more severe disease => more likely to be de novo)
Bayes Theorem offers formal means to change probability estimate to take into account new information

Inherited Thrombophilia (penetrance)


Hypercoagulable state -> DVT, PE
Types:
o Factor V Leiden 40-50% of cases
o Prothrombin mutation
o Protein S deficiency, Protein C deficiency
o Antithrombin deficiency
o Dysfibrinogenemia
b.
c.

Familial breast cancer (penetrance)


BRCA1, BRCA2 mutations high risk of early onset breast
cancer; both genes involved in DNA repair and genome integrity
Usually clear loss-of-function mutations
Prophylactic bilateral mastectomy

Variable expressivity: degree of expression of the phenotype; the same genotype can produce phenotypes of varying severity
Pleiotropy: the variety of effects that a genotype can have on multiple traits or organ systems

Neurofibromatosis Type 1 (NF-1)


Autosomal dominant, 1:3,500
Clinical presentation: caf-au-lait spots, neurofibromas
o Variable expressivity: NF1 skin phenotypes => some have few spots, some have disfiguring plexiform neurofibromas, MPNST
o Pleiotrophy: one disease affecting one protein, but you can have affects on many different systems
Gene: neurofibromin (tumor suppressor gene, negative regulator of Ras oncogene)
50% mutations inherited, 50% de novo
Molecular diagnosis: PCR and Sanger sequencing of all 57 exons
2.

Autosomal recessive

Cystic Fibrosis
Autosomal recessive: 1:2,500
Mutations in cystic fibrosis transmembrane receptor (CFTR) - F508 is most common mutation
Heterozygote advantage: diarrheal illnesses
Clinical presentation: poor growth, poor weight gain, accumulation of thick mucus in lungs, chronic respiratory infection with Psuedomonas
aeruginosa (among others) => bronchiectasis

INTRO TO GENETICS


a.

3.

Consanguinity
Autosomal recessive conditions are much more common when parents are related child
will be homozygous for mutation, rather than a compound heterozygote
10% of marriages world-wide are between second cousins or closer, some countries it is 30%
X-Linked recessive
a. Lyonization: a term describing the random inactivation of one X chromosome in each cell of a
female => a female may be at least partly affected for an X-linked recessive disorder

Hemophilia A
X-linked recessive, 1:5,000
30% of cases are new mutations
Clotting factor VIII (F8) deficiency prophylactic F8 replacement therapy; risk of development of inhibitor
antibodies
Clinical presentation: hemarthrosis, ecchymosis and purpura

--------

CHROMOSOME STRUCTURE AND CYTOGENETICS


A.

Cytogenetics: techniques in chromosome analysis


1. Karyotype
a. 23 pairs of chromosomes; autosomes 1-22; sex chromosomes X and Y
b. Chromosome classification (shape, size, and positions of centromere)
Metacentric centromere occurs near the middle of the chromosome
Submetacentric centromere occurs somewhere in between the middle and the tip
Acrocentric centromere occurs near the tip
P-arms are virtually not existent in this type of chromosome, contain stalk and satellite portion
c. Metaphase cell
d. If you want to visualize WHERE on the chromosome the problem is use karyotype
e. Giemsa banding (G-Banding) is technique most often used; more A-T rich regions stain darker & have fewer genes; more G-C rich
regions stain lighter & have more genes
f. Good screen for aneuploidy or large rearrangements most of these are pathogenic
g. Resolution: 3-5Mb
h. Results:

2.

3.

B.

der is derivative chromosome


Fluorescent In-Situ Hybridization (FISH)
a. Targeted assay (200bp) used to confirm a suspicion or karyotype finding not exploratory (you must know what you are looking for);
assesses how many copies of a given sequence are in the cell
b. Metaphase FISH: slow, traditional microscopy procedures
c. Interphase FISH: very rapid, used to look for aneuploidy, can be used in prenatal dx (this can be done in amniocytes), tumor cells
d. Resolution: 50-100 kb
Comparative Genomic Hybridization/Chromosome microarray
a. Comparative assay detects difference between 2 individuals; requires reference DNA sample (control); only gives RELATIVE copy
number
Looking for small deletions across entire genome on one microscope slide
b. Probes are oligonucleotides (60-80bp)
c. Resolution is dependent on array design usually 50 kb
d. Fluorescently labeled probes on both control and patient DNA areas of duplication or deletion will show a corresponding color
e. Now recommended (over karyotype) for autism, mental disabilities, heart defects

Chromosomal abnormalities and disorders


1. Types of numerical abnormalities
a. Diploid = normal (23 pairs of chromosomes 46 total)
b. Haploid = half of diploid
c. Polyploidy = multiple of the haploid number (triploidy is 3 sets69 chromosomes)
d. Aneuploidy = not an exact multiple of haploid
Usually one extra (trisomy) or one missing (monosomy)
Non-disjunction: failure of chromosomes to disjoin normally during meiosis

CHROMOSOME STRUCTURE AND CYTOGENETICS

Non-disjunction during meiosis I: failure of separation of homologs of chromosome end up with two different homologs of the
same chromosome (majority of non-disjunction is this during female gametogenesis)
Non-disjunction during Meiosis II: failure of separation of sister chromatids end up with two copies of the same homolog
Pregnancy losses
Chromosome abnormalities are seen in 40-50% of spontaneous pregnancy losses
45,XO (Turner syndrome) is the most common, accounts for 20% of chromosomally abnormal losses
Trisomy 16 is seen in 30% of abortuses and is never live born
Autosomal Abnormalities

2.

Trisomy 21 (Down Syndrome)


Incidence: 1/700-1/1000
Pregnancies lost: 80%
Phenotype: hypotonia, upslanting palpebral fissures and
epicanthal folds, low set ears, single palmar crease, congenital
hear defects, moderate to severe intellectual disability,
increased risk of leukemia, hypothyroidism, early onset
Alzheimers in adults
Cause of abnormality: most often is nondisjunction event, 25% of cases are due to presence of unbalanced Robertsonian
translocation
Recurrence risk is 1% for free-lying trisomy 21; 10-15% if
mother has balanced Robertsonian translocation; 1-2% if
father has balanced Robertsonian translocation
Risk increases with increasing maternal age: karyotype is
recommended after age 35
3.

Trisomy 13 (Pataus Syndrome)


Incidence: 1/10,000
Phenotype: cleft lip, small palpebral fissures, postaxial polydactyly (too
many fingers, usually on hypothenar side), cutis aplasia, microcephaly,
CNS/heart/renal abnormalities
5% survive the first year

Sex Chromosome Abnormalities (less severe than


autosomal)
a. 1/500 live births have sex chromosome aneuploidy very subtle or no recognizable facial defects
b. Less common: 47,XXX; 48,XXXX (with increasing # of X chromosomes, increasing likelihood of learning difficulties)

45,X (Turner Syndrome)


Incidence: 1/2000-1/5000 females
99% result in spontaneous miscarriage
Phenotype: short stature, webbed neck, heart and renal
abnormalities (coarctation of the aorta), lymphedema
(present at birth), ovarian dysgenesis, normal intelligence
4.

Trisomy 18 (Edwards Syndrome)


Incidence: 1/6000 live births
Experience intrauterine growth restrictions therefore are born
quite small
Phenotype: Small, simple ears, short palpebral fissures, overlapping
fingers, rocker bottom feet, congenital heart defects, severe
intellectual disability
50% die within the first year

47,XXY (Klinefelter Syndrome)


Incidence: 1/1000 male births (1/10 azoospermic infertile males)
Phenotype: tall, long limbs (height gene is on X chromosome),
hypogonadism, gynecomastia (increased risk for breast cancer), learning
difficulties, mean IQ 85-90

Structural Chromosome Abnormalities


a. Terminal vs. Interstitial deletion
Terminal rearrangements deletion or duplication

Wolf-Hirschhorn Syndrome
Abnormality: 4p terminal deletion
Phenotype: epicanthal folds, hypertelorism, Greek Warrior Helmet (look at shape of forehead and nose), microcephaly, downturned mouth,
developmental delays, intellectual delays, seizures

CHROMOSOME STRUCTURE AND CYTOGENETICS

Interstitial rearrangements: two breaks are required, does NOT include the end; deletion or duplication
Some are due to random breaks, some of these are recurrent (Prader-Willi/Angelman, Williams Syndrome, Smith-Magenis
Syndrome, 22q11 deletion syndrome)
Non-allelic homologous recombination structure of chromosome is set up such that it is paired incorrectly during
recombination ends up with one gamete with a duplication and one with a deletion
22q11 Deletion Syndrome (highly variable expression)
Velocardial Facial Syndrome (VDFS) palate, facial, and cardiac defects
DiGeorge thymic, parathyroid, and cardiac defects, deletion of 22q11.2
b.

C.

7q11.23 deletion (Williams Syndrome)


Phenotype: Periorbital fullness, full lips, wide mouth,
supravalvular aortic stenosis (75%), overly friendly,
visuospacial difficulties, strong language memory

Inversions
Carrier frequency: 1/1000
No missing or extra DNA, usually benign, no phenotype associated with this
Can have higher chance of chromosomal abnormalities in offspring
Microarray would NOT show this; would see changes in banding pattern on karyotype
c. Ring Chromosomes
Two breaks required ends rejoin, telomeres are lost, may or may not have centromere
Trouble with mitosis often mosaic phenotype
Very unstable, can be lost completely in some cells
d. Translocations
Robertsonian Translocation: balanced translocation between
long arms of two acrocentric chromosomes
P arms are very small in acrocentric chromosomes
Fused at centromere, loss of P arm
NOT detectable on array, use karyotype
Possible offspring of balanced translocation carrier
inheriting trisomy 21 (see Downs Syndrome box above)
Next-Generation Sequencing Techniques
1. Sequence millions of fragments simultaneously massively parallel sequencing
2. Exome sequencing
a. Pull out just the exomes (1% of genome)
b. Only 20,000 variants between individuals (instead of 3 million)
3. Gene discovery techniques in clinic
a. Trio analysis: sequence mom, dad, and child look for de novo changes in child
Severe, de novo disorder discovery
Most commonly used
b. Family based analysis: sequence selected individuals, inspect inheritance pattern
Used in families with multiple affected individuals, recessive diseases
c. Multiple unrelated affected
Sequence multiple individuals with disease
Looks for same gene abnormality across multiple affected
4. Gene panels: sequencing multiple genes that could be causing the syndrome
5. Copy Number Variation (CNV) can be identified from sequence data now
a. Based on number of times a given genome region is sequenced compared to the rest of the genome (depth of coverage)


A.

B.

C.

CANCER GENETICS
Overview
1. 3 types of cancer genes: oncogenes, tumor suppressor genes, DNA repair/cell cycle genes
a. These are not exclusive for example, BRCA1 and BRCA2 and the various Lynch syndrome genes are involved in DNA repair AND have
properties consistent with tumor suppressor genes
Oncogenes
1. Retroviruses (study of these lead to discovery of oncogenes, extensive history lessonTMI)
a. Genome structure
Gag => glycosaminoglycan portion, forms the core of the virus
Pol => reverse transcriptase that also functions as an integrase
Env => envelope protein responsible for host tropism
LTRs => act as promoter sequence
b. Viruses can be horizontally or vertically spread through an animal population
c. Can cause cancer in animals, but not usually in humans
st
d. 1 Discovery: occasionally, RNA transcript picks up a host gene adjacent to
the site of integration of the RT viral genome
Sometimes host gene is oncogenic when mutated (remember that
RTase has a very low fidelity rate)
Therefore an oncogene is an activated form of a cellular gene
2. Proto-oncogene is mutated to oncogene - ACQUIRED
a. Point mutation (RAS missense mutation)
b. Chromosomal translocation (9:22 CML Ph chromosomes; BCR-ABL fusion
protein)
c. Gene amplification (breast cancer HER2)
d. MEN2 IS AN EXCEPTION => HEREDITARY
RET proto-oncogene is a germline mutation
Medullary thyroid carcinoma, parathyroid tumors, and pheochromocytoma
e. Dominant at cellular level only need one allele mutated
3. Oncogenes regulate cell growth as
a. Growth factor receptors
b. Part of the cytoplasmic-to-nucleus transduction cascade
Most familial forms of cancer
c. Transcription factor regulating other genes contributing to cell growth
caused by mutations in tumor
Tumor Suppressor Genes
1. Retinoblastoma
suppressor genes do not have
a. Fetal retinoblasts that normally differentiate into post-mitotic retinal photoreceptors and neurons
complete penetrance
b. Clinical presentation: leukocoria loss of red reflex
Bilateral: hereditary (50% offspring will have autosomal dominant trait)
40% of all cases of retinoblastoma have a germline inheritance of RB mutations
80% of germline cases are de novo mutations (this disease has reduced genetic fitness, so this is expected)
Earlier age of onset
Unilateral: sporadic, not germline mutation (15-20% have family history)
Two hit hypothesis (loss of heterozygosity): the locus of the unaffected parent is lost/replaced
Inherited in a dominant manner, but act recessively at the cellular level
Some cases with a family history can be unilateral because remember that the second hit is a random occurrence
c. RB gene and protein
DNA binding transcriptional repressor inhibits cell-cycle progression at the G1/S boundary
Interacts with other cell cycle regulators
Deactivated by phosphorylation allowing progression through the checkpoint
Somatically mutated in other types of cancer (breast, prostate, CML) that are not associated with retinoblastoma
2. p53
a. General
Protein: p53
Gene: TP53 (chromosomes 17p13)
Target of SV40 T-antigen

CANCER GENETICS

D.

Guardian of the genome p53 detects DNA damage and either temporarily halts cell cycle so that DNA repair can proceed or
initiates apoptotic cell death
Loss of p53 leads to somatic chromosomal abnormalities
b. Li-Fraumeni Syndrome (germline mutation in TP53)
Two hit hypothesis - autosomal dominant inheritance, very rare
Multiple malignancies: breast cancer, sarcoma, brain tumors, leukemia, adrenocortical carcinoma, other tumors
Genetic heterogeneity mutations in CHEK2 cause similar phenotype
CHEK2 is gene that codes for checkpoint 2 (CHK2) protein
CHK2 regulates p53 action
3. Neurofibromatosis (NF1) see intro lecture on variable expressivity and pleiotropy
a. Autosomal dominant
b. Incidence: 1/3000
c. NF1 encodes Neurofibromin (17q11), a GTPase-activating protein that down regulates RAS
Enormous gene size (350kb)
d. Benign neurofibroma, occasional malignant neurofibrosarcoma, schwanoma, glioma, pheochromocytoma, some leukemia
e. Clinical presentation: cafe-au-lait spots; axillary/inguinal freckling
4. Familial Adenomatous Polyposis
a. 1% of all colon cancers
b. Polyps begin in first decade of life
c. APC (5q21) cytoplasmic protein that interacts with B-catenin in Wnt signaling pathway => somatic chromosomal instability
d. Loss of APC causes adenoma formation, additional mutations (RAS, TP53, SMAD4) transform into full-blown malignancy
APC is also mutated in sporadic colon adenocarcinoma
DNA repair genes
1. Hereditary Nonpolyposis Colon Cancer (HNPCC) Lynch Syndrome
a. Autosomal dominant
b. Predisposes to numerous types of carcinomas esp of the colon
Mutation in DNA repair gene could lead to cascade of mutations in many other genes
(tumor suppressor, proto-oncogenes, etc.)
c. Genomic instability of repeat sequences
d. Warning: these patients still have polyps, but just not quite to the same degree as FAP
e. Diagnosis: analysis of repetitive DNA sequences (micro-satellites) on gel electrophoresis;
immunostaining on tumor specimen
Mismatch repair genes

2.

Fanconi Anemia
a. Autosomal recessive (very rarely sex-linked)
b. 13 genes involved
Extreme locus heterogeneity
12 genes are autosomal
Chromosomal breakage in Fanconi Anemia
One is X-chromosome
c. Does not follow 2-hit hypothesis recessive!!
d. Clinical presentation: short stature, radial ray limb defects, abnormal pigmentation, developmental delay, bone marrow failure
e. Increased risk of leukemia and solid tumors (average age of 23 y/o)
f. Diagnosis: formation of chromosomal aberrations in cultured cells after treatment with a DNA interstrand crosslinking agent
FANCD2 (aka BRCA2) monoubiquitination of FANCD2 is an important step on the repair pathway new clinical test for diagnosis
uses this

CANCER GENETICS


3.

E.

Hereditary Breast-Ovarian Cancer Syndrome


a. Autosomal dominant
b. 2 genes involved: BRCA1 and BRCA2 (both behave as tumor suppressor genes for the most part)
c. Lifetime penetrance for breast cancer is 80%, for ovarian cancer is 25-50%
d. Breast/ovarian cancer tend to occur earlier and often recur or are bilateral
e. Also associated with male breast cancer, prostate cancer, and pancreatic cancer
f. Note: homozygous BRCA2 mutations cause Fanconi anemia#
Summary notes
1. Differences between cancer predisposition resulting from a so-called common variant and a mendelian-form of cancer
a. Common variant:
Common in general population
Not as harmful (usually)
Low penetrance
Outside of coding region of a gene (influence gene expression)
No specific phenotype (usually) and therefore difficult to show generational inheritance
b. Single gene mutations:
Rare and unique to a family/particular population
High penetrance
Mutation within coding sequences (disruption of function of an encoded protein),
Characteristic phenotype therefore inheritance can be tracked based on causative gene

NONTRADITIONAL MODES OF INHERITANCE

A.

Mitochondrial inheritance
1. Mitochondria maternally inherited, have their own unique genome
a. 16,569bp in size, circular genome
b. Single exon genes encode for 22 tRNAs, 2 rRNAs, 13 oxphos proteins
c. 10x higher mutation rate than nuclear genome
d. Some nuclear genes function in mitochondria
2. Heteroplasmy
a. 100-1000s of mitochondria per cell
b. Since each mitochondrial genome is unique, if there is a mutation present in
one, it wont necessarily be in all of the mitochondria
Distribution of mutations will affect inheritance pattern & disease expression
This may mimic autosomal dominant inheritance pattern with incomplete penetrance
3. Mitochondrial inherited disorders

B.

Imprinting
1. Transcriptional silencing of one allele of a gene depending on the parent of origin happens at gametogenesis (epigenetic phenomenon)
2. Methylation is primary mechanism of silencing
3. Pedigrees
a. If the inherited gene is from the father, those children who inherited the gene will be affected (maternal genes will be silenced)
b. If this affected father has a daughter, then the gene will be silenced when it is passed on to her child (because only paternally allele is
expressed)

Prader-Willi Syndrome
Mutation occurs on paternal chromosome in the SNRPN gene
which is paternally expressed (maternal imprinting)
o 70% due to paternal deletion
o 29% due to uniparental disomy
o <1% due to imprinting center defect (this is where
methylation occurs)
Clinical presentation: hypotonia at birth with feeding difficulty,
failure to thrive; small hands, feet; hypogonadism (more
apparent in boys), moderate developmental disability
o Later in childhood: food obsession and obesity

Angelman syndrome
Mutation occurs on maternal chromosome in the UBE3A gene which is
maternally expressed (paternal imprinting)
o 68% maternal deletion
o 11% point mutation of UBE3A
o 7% uniparental disomy
o 3% imprinting center defect
o 10% unknown cause
Clinical presentation: severe intellectual disability, absent speech, acquired
microcephaly (born with adequate sized skull as they age their skull does
not grow adequately), seizures, ataxic gait, happy personality/inappropriate
laughter

NONTRADITIONAL MODES OF INHERITANCE


C.

D.

Uniparental disomy
1. Inheritance of both alleles from one parent
a. Trisomy rescue: nondisjunction occurs, cell kicks out one of the extra chromosomes
b. Monosomy rescue: nondisjunction occurs, cell creates a copy of the existing chromosome
c. Isodisomy: inheritance of two copies of the same homolog (identical)
d. Heterodisomy: inheritance of both homologous chromosomes from one parent (not identical)
2. This is one mechanism by which Prader-Willi and Angelman syndromes can occur
3. If there is consanguinuity, there will be homozygosity in stretches of UPDs
4. Other UPD syndromes
a. Russell-Silver Syndrome (maternal UPD11, maternal UPD7)
Short stature, limb asymmetry, triangular face
b. Beckwith-Wiedemann Syndrome (paternal UPD11)
Neonatal hypoglycemia, omphalocele (protrusion of gut contents outside of abdominal cavity), macroglossia, cancer predisposition
(Wilms tumor, hepatoblastoma)
5. ALL paternal input: hydatidiform mole (molar pregnancy)
6. ALL maternal input: ovarian teratoma
Trinucleotide repeat expansion
1. Trinucleotide repeats are common in the human genome
polymerases slip on these leads to repeat expansion
a. Expansion past a certain threshold = disease (what is the magic
number? Mystery)
2. Can affect different parts of a gene (upstream, downstream, intron,
or exon)
3. Anticipation
a. The more expanded a repeat becomes, the more likely it is to expand further in subsequent generations
b. Larger expansion => more disease
c. Large expansions tend to occur in either the paternal or maternal germline, depending on the disorder
Huntington disease (Incidence: 1 in 5,000 to 10,000)
Autosomal dominant, usually adult onset
Gain of function mutation
o (CAG)n => polyglutamine stretch in protein
o Expansion leads to protein misfolding, aggregation, and nuclear inclusions
Progressive movement (chorea) and neurodegenerative disorder
o Intellectual decline may be the first sign of disease onset, psychosis
o Death 10-20 years after onset
Basal ganglia degeneration
4.

Other polyglutamine repeat disorders: spinocerebellar ataxias (SCA1, 2, 3, 6, 7, 17), spinobulbar muscular atrophy (SBMA), Dentatorubralpallidoluysian atrophy (DRPLA)
a. All neurological diseases, slowly progressive, similar median age onset, all exhibit anticipation
b. Fragile X premutations (55-200 repeats)

Fragile X Syndrome (Incidence: 1 in 5,000)


Loss of function mutation in FMR1 gene
o CGG repeat expansion in 5 untranslated region
o Expansion => increase in methylation => FMR1 gene is shut off
o Large expansions are maternal in origin
Clinical presentation: tall forehead, large ears, prominent chin, autistic behaviors
o Most common genetic cause of intellectual disability in males
Fragile X-associated Tremor Ataxia Syndrome (FXTAS) in males with permutation
Tremor, ataxia, cognitive impairment (brain atrophy)
Penetrance is about 1 in 3 male carriers by 80 y/o
Mechanism = RNA toxicity
Females with permutation are at risk for premature ovarian failure

NONTRADITIONAL MODES OF INHERITANCE

Myotonic Dystrophy Type 1


Incidence: 1 in 8,000 adults most common muscular dystrophy in adults
Autosomal dominant inheritance with anticipation
Gain of function mutation in DMPK gene
o CTG repeat expansion in 3 untranslated region
o mRNA remains in nucleus -> interferes with splicing -> abnormal gene expression
Clinical presentation: progressive muscle weakness, myotonia, facial hypotonia, cardiac arrhythmias, cataracts, diabetes
5.

Triplet repeat disease summary


a. Primarily neurological disease
b. Repeats can be located anywhere in the gene
c. Anticipation can occur
d. Large expansions happen preferentially in maternal OR paternal germline (unique to disorder)
e. Effect of repeat expansion varies


A.

B.

C.

PRENATAL DIAGNOSIS
Rationale for prenatal diagnosis
1. Reassurance of family
2. Maximize management options for affected pregnancy (termination vs. continuation)
3. Prenatal therapy (surgical or medical)
4. Anticipate neonatal support able to deliver in tertiary care center
5. Education (family AND frontier of science)
a. Understanding disease process
b. Molecular testing still at discovery phase, lack of definitive molecular clinical correlation
6. Recurrence risk
Procedures for prenatal diagnosis
1. Amniocentesis (invasive)
a. 15-20 weeks gestation
b. Ultrasound guided
c. Cytogenetic techniques are standardized
d. Readily available
e. Pregnancy loss rate 1/200 to 1/400 (likely because now there are fewer people well trained in amniocentesis due to introduction of better
technology)
f. Disadvantages
Legal limit for termination in
Delay of performing procedure until midtrimester
Washington is 26 weeks and 6 days
Time-interval from procedure to diagnosis (not rapid)
Realtime ultrasound vividly demonstrates fetal viability
Midtrimester abortion required for termination of pregnancy
2. Chorionic Villus Sampling (invasive)
a. Placental biopsy completed 10-12 weeks gestations
b. Ultrasound guidance
c. Transabdominal and transvaginal approach
d. Complications
Pregnancy loss rate: 1%
Ambiguous results/maternal cell contamination: 1-2%
Culture failure: 1-2%
e. Benefits earlier diagnosis
Confidentiality protects
Complex DNA testing may require long time (plenty of time to decide termination/continuation)
st
1 trimester termination is possible
f. Disadvantages
Safety depends on operator experience
Not readily available (not very many physicians trained in this)
3. Percutaneous Umbilical Cord Blood Sampling (PUBS)
a. Applications: diagnosis and treatment of fetal anemia, can do a transfusion through this
b. Ultrasound guidance
c. Complications: pregnancy loss = 1%
4. Fetoscopy
a. Visualization of fetus directly
b. Tissue biopsy
c. Used to place shunts for fetuses with bladder outlet obstruction
Genetic evaluation of fetus done if known diagnosis
1. Condition must be associated with detectable abnormality in fetus and/or fetal tissues (structural abnormality on ultrasound, biochemical
abnormality in amniotic fluid, cytogenetic abnormality, molecular diagnosis)
2. Fetal Karyotyping
a. Obtained from: CVS, amniocytes, blood draw
b. Traditional banded karyotype
c. Fluorescent in situ hybridization (FISH)
Interphase FISH is fast and can test for the common trisomy disorders
Identification of origin of extra chromosomal material

PRENATAL DIAGNOSIS

Specific microdeletion syndromes


DNA
a. Molecular testing: chromosomal microarray and SNP arrays
4. Biochemistry
a. Blood routine CBCs, electrolytes
b. Amniotic fluid AFP levels, acetylcholinesterase in Neural Tube Defects)
c. Amniocytes (evaluation of enzymatic function metabolic diseases)
Noninvasive testing and screening
nd
1. Maternal serum screening 2 trimester biochemical markers
AFP
uE3
Down
a. Know this table!

b. Alpha fetoprotein (AFP)


Syndrome
Trisomy 18
Elevation associated with multiple gestation, impending

pregnancy loss, neural tube defect, abdominal wall defects,


Neural Tube
obstetrical complication
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Defect
c. Unconjugated Estriol (UE3)
d. Human Chorionic Gonadotrophin (hCG)
e. Inhibin A (INH)
2. Ultrasound
st
a. 1 trimester screening (11-14 weeks)
Nuchal translucency => marker for fetal chromosome abnormalities like Down syndrome
(sonographic appearance of subcutaneous collection of fluid behind the fetal neck in the first
trimester of pregnancy)
Presence of AV canal is Down syndrome until proven otherwise
nd
b. 2 trimester screening
rd
c. 3 trimester
Fetal micrognathia & other defects that may disrupt airway and cause shitty time for intubation
Risk Calculation: takes into account maternal age risk and likelihood ratios of nuchal translucency, biochemical markers,
and quad screen
Preimplantation Genetic Diagnosis (PGD)
1. Requires IVF technology
a. Expensive
b. Intracytoplasmic sperm injection
2. Approaches
a. First polar body examination
b. Blastomere biopsy (can disrupt implantation)
Day 3-4 after fertilization
1-2 cell biopsy, single gene, cannot study full complement of chromosomes
Embryo is mosaic
c. Blastocyst biopsy
Day 5-6 after fertilization
2 sets of cells: Trophoectoderm (begets placenta) and Inner Cell Mass (begets fetus proper)
More cells allow for chromosome evaluation
Biopsy trophoectoderm
Limitations and discovery: mosaicism
Discordance between trophoectoderm and fetus and within trophoectoderm itself
3. Embryo selection
4. Molecular diagnosis for single gene mutations
5. Aneuploidy evaluation
6. aCGH
7. ICSI (imprinting issues unknown)
Cell-free DNA
1. General
a. Short fragments of DNA in peripheral circulation
b. During pregnancy ~10% originate from placenta (apoptosis)
3.

D.

E.
F.

G.

hCG

INH

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Nuchal translucency

PRENATAL DIAGNOSIS

2.

3.

4.

c. Clear maternal circulation ~48 hours after delivery


d. Performance of test in high risk pregnancies only
Test results
a. Sensitive screening for trisomy 21, 13, 18, sex chromosomes
b. Interpretation of test results based on quantitative analysis of DNA for each chromosome in maternal serum
c. Sensitivity depends on quantity of cfDNA fragments in maternal serum
Limitations
a. Only for trisomy 13, 18, 21
b. Not for use in twin gestations
c. Unknown performance in low-risk population (impending fetal demise and vanishing twin syndrome)
d. Placental mosacism
Indications
a. Late pregnancy with birth defects
b. Avoidance of invasive procedures and risks
c. Acceptance of limitations of results


A.

B.

C.

D.

DNA SEQUENCING GENE PANELS


Next-Generation Sequencing in Clinical Genetics
1. Background
a. First Generation is Sanger Sequencing (can sequence a single gene)
b. Next generation refers universally to techniques used to sequence an entire genome in one shot (7+ ways to do this)
Can detect copy number, translocations, small insertions/deletions, single nucleotide variants
2. Copy number analysis by depth of coverage sequence short sequences over and over again
a. Allows for detection of mosaic mutations
b. Gives quantitative data, not just qualitative
3. Advantages
a. Can analyze up to whole genome in a single run
b. High sensitivity for rare subpopulations of cells/mosacism
c. Efficient 1-step testing
4. Disadvantages
a. Information overload, incidental findings
b. Longer turnaround time
Clinical Applications of Targeted Gene Panels
1. Genetic hereogeneity
a. Multiple genes often considered in suspected hereditary syndromes (Lynch Syndrome, cardiomyopathy, hearing loss, epilepsy, etc.)
b. Current testing is stepwise high cost to patient, genetic testing fatigue
2. Multiplex testing
a. Tumor sequencing to guide therapy multiple genetic tests are indicated for a single disease
b. Multiplex panel testing is more efficient, cost effective, and can help preserve a limited tissue sample
3. Examples
a. Cancer Risk Panel: 7-50 genes, colon cancer, breast cancer, comprehensive
b. Tumor sequencing Panels: 20-400 genes, tumor-based testing to guide therapy, hot-spot vs. all exons
c. Syndromes with genetic herterogeneity: inherited cardiomyopathies, epilepsy, Noonan syndrome, hereditary hearing loss panels
4. What makes up a panel is based on clinical need
Common hereditary cancer syndromes have overlapping clinical features
Lynch syndrome
Familial Adenomatous Polyposis (FAP)/(AFAP)
MUTYH-associated polyposis (MAP)
Once you know the specific mutation, you can screen family members
Variant Interpretation
1. Germline autosomal dominant/recessive;
a. Generally looking for loss of function mutations
b. In order of strength of evidence: segregation in families > de novo mutations described > functional evidence > population specific
frequency > evolutionary conservation > computer prediction
2. Tumor somatic (tumor-acquired)
a. Generally looking for gain-of-function mutations
b. Valuable in looking for mutations associated with response to cancer therapies
Clinical Reporting
1. Does the panel detect deletions and duplications in addition to single nucleotide insertions and deletions?
a. If not, is that important? Do you need that?
2. Analytical validity
a. Types of mutations validated
b. Limits of detection
c. Pseudogenes
d. Sequencing artifacts
3. Clinical validity
a. Clinical context
b. Strategy for poorly characterized variatns
c. Decision support, clinical support
d. Incidental findings


A.

GENETIC DISORDERS OF METABOLISM


Inborn Errors of Metabolism
1. General classification
a. Intoxication (block in enzyme, leading to buildup of precursor)
Acute, progressive (may be symptom free or have intermittent presentation)
Commonly: organic acids, ammonia, lactate
Examples: MSUD, PKU, OTC, UCDs, galactosemia
b. Energy deficiency (block in enzyme leads to deficient amounts of product leading to an energy deficiency)
Clinical presentation: Failure to thrive, shock, SIDS, hypoglycemia
Examples: Mitochondria respiratory chain disorders, lactic acidemias, fatty acid oxidation disorders
c. Accumulation of complex molecules (deficiency of enzyme results in an unstable precursor spontaneously converting to a harmful product)
Permanent, progressive
Examples: Lysosomal storage diseases, perioxsmal disorders, Smith-Lemi-Optiz (cholesterol)
2. Urea cycle disorders
a. General
Clinical presentation:
Hyperammonemia (this can be very difficult to distinguish clinically from sepsis/infection)
Loss of appetite, vomiting => metabolic acidosis
Aversion of high protein containing food
Lethargy, somnolence, coma => terminal cerebral edema
Hyperpnea => respiratory alkalosis
Hypo/hyperthermia (newborns)
Hepatomegaly, liver dysfunction, AST, ALT, coagulation defect
Diagnosis: plasma amino acid measurements, ammonia, urine organic acids (orotic acid)
Treatment: avoidance of protein (high fat/carb diet), hemodialysis if NH3 levels > 500, glucose + insulin, liver transplant, gene therapy
Sodium phenylacetate and sodium benzoate BIND ammonia and remove from body
b. Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) Syndrome
Defective mitochondrial ornithine transporter 1 (ORNT-1)
c. Ornithine transcarbamylase (OTC) deficiency
Most common urea cycle defect, one of the most common metabolic disorders
Hyperammonemia
Classic presentation of severe OTC deficiency: male newborn begins vomiting with feeding (day 1-2), becomes lethargic, progresses
to coma, death over hours to days
X-linked recessive disorder: just as severe, possible associated with migraines
~15% of female carriers can manifest symptoms
Adults: onset after Atkins diet, post-partum, bariatric surgery (disturbs metabolism, fasting, poor nutrition)
Liver failure, hepatocellular carcinoma
d. Phenylketonuria (PKU)
Liver phenylalanine hydroxylase (PAH) deficiency
Autosomal recessive inheritance
1:16,000 live births in the US (part of newborn screening)
Elevated total body phenylalanine => excessive phenylalanine in brain => toxicity
Reduced large neutral amino acid transport into the brain (including tyrosine and tryptophan) => reduced synthesis of key
neurotransmitters (dopamine, serotonin) also melatonin
Part of newborn screening
Classical Phenylketonuria:
Without treatment: epilepsy, severe intellectual disability, microcephaly, fair complexion/hair, hypomyelination, hyperactivity,
autistic-like behavior, eczema rash, mousy urine odor, schizophrenia
With treatment: low protein diet is necessary, but otherwise individuals are healthy throughout lifetime
Maternal phenylketonuria: mothers with uncontrolled PKU expose the fetus to high phenylalanine levels (teratogenic)
Abnormalities in newborn: microcephaly and mental retardation, growth retardation, heart malformations, dysmorphic facies,
bowel malrotation, bladder extrophy, cataract, coloboma, cleft lip and palate

GENETIC DISORDERS OF METABOLISM


3.

4.

5.

6.

Sugar metabolism disorders


a. Galactosemia
Galactose-1-Phosphate uridyltransferase deficiency (GALT)
Can be caused by others galactokinase deficiency (GALK), uridine diphosphate galactose 4-epimerase (GALE)
Autosomal recessive inheritance
Incidence: 1 in 30,000 (part of newborn screening)
Clinical presentation: neonatal cataracts, liver failure, E. coli sepsis, hemolytic anemia, failure to thrive, mental retardation, speech
abnormality, ovarian failure
Elevated blood galactose; (+) urine screen
Treatment: dietary avoidance of galactose, lactose (be careful, these are everywhere, need extensive counseling from dietician)
Fatty acid metabolism disorders
a. Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD)
Diagnosis: Elevated C14:1 on blood test
Sudden death in children
Fatty liver
b. Medium chain acyl-CoA dehydrogenase deficiency (MCAD)
Prevalence: 1 in 6400
Clinical presentation: vomiting, lethargy, fatty liver, Reyes Syndrome, acute illness 3-15 months, failure to thrive, developmental
disability, ADD/ADHD
50% present with death, SIDS
Diagnosis: no ketones, hypoglycemia
Plasma acylcarnitine, urine acylglycines
DNA testing, FAO probe
Treatment: reduction of fat intake, carnitine supplementation, avoidance of fasting, IV glucose if necessary
Prognosis: near zero morbidity with newborn screening
Neurological disorders
a. X-Linked Adrenoleukodystrophy
Disorder of peroxismal beta-oxidation => accumulation of very long-chain fatty acids
Mutation in ABCD1 gene
Four phenotypes all from same mutation, no way to predict which phenotype will be present
Childhood cerebral onset form (4-8 y./o presentation, ADD, ADHD, progressive neurodegeneration)
Adult adrenomyeloneuropathy (onset in late 20s, progressive prarparesis, sphincter disturbances, sexual dysfunction, impaired
adrenocortical function)
Addison-only disease: adrenocortical insufficiency (onset after 2 y/o, no neurological abnormalities)
Middle-age/older women (carriers): mild presentation, 20% have symptoms like AMN
Lysosomal storage disorders
a. Tay Sachs Disease
Deficiency in Hexoaminidase-A
High carrier rate (1 in 250; much higher in Ashkenazi Jews)
Clinical presentation: muscle weakness, problems with coordination, rhythmic muscle contractions, stiff muscles, whole body wasting,
difficulty swallowing, hearing loss, seizures, vision loss, voice changes, cherry red spot on macula
Symptoms of slowed development usually appear around 6 months of age, progress to death around age 4
b. Gaucher Disease Type 1 (most prevalent type of Gaucher Disease 94%)
Non-neuronopathic
Incidence: 1 in 50,000 (higher in Ashkenazi jews)
Accumulation of glycosphingolipids
Clinical presentation: quality of life can be severely affected
Spleen: splenomegaly, bleeding, bruising, low energy
Skeletal: bone pain, thinning bones, fractures, erlenmyer flask deformity of the distal femur
Liver: hepatomegaly
Treatment: enzyme replacement therapy

GENETIC DISORDERS OF METABOLISM


c.

B.

Mucopolysaccharidosis
Type I: Hurler Syndrome
Alpha-L-iduronidase deficiency
Autosomal recessive
Hurler (youngest age onset), Hurler-Scheie (presents in adolescents), Scheie (mild form, presents in adults)
Treatment:
Supportive care; cardiac or respiratory complications
Bone marrow transplantation
Laronidase (enzyme replacement therapy cannot cross blood brain barrier), stem cell transplants
Can reverse many of the symptoms, but neurological impairment is permanent
Type II: Hunter Syndrome
Iduronate-2-sulfatase deficiency
X-Linked recessive
No corneal involvement
Common symptoms of Type I and Type II
Growth affected later in childhood (normal in early childhood)
Macrocephaly, coarse facies (macroglossia, full lips, hypertrichosis)
Dystosis multiplex (stiff joints, skeletal abnormalities)
Hepatosplenomegaly (=>hernia umbilical and inguinal)
Cardiomyopathy and valvular disease
Obstructive sleep apnea
Deteriorating course, hydrocephalus
Treatment of metabolic disease
1. Acute Therapy management of acidosis, hyperammonemia, infection
a. Rehydration
b. Glucose (bolus D10W 8-10 mg/kg) plus insulin
c. Bicarbonate correct acidosis
If plasma bicarb is <10 and respiratory status is adequate
d. Withhold intake of protein
e. IV intralipids increase caloric intake (NOT for fatty acid disorders
2. Nutrition removal of causative agent
3. Medications binding of nitrogen, alternative pathway
a. IV ammonul (sodium phenylacetate-sodium pneylbenzoate)
b. IV L-arginine
c. Sodium pnehylbutyrate, oral
d. Glycerol phenylbutyrate, oral
e. Citrulline supplementation
f. Arginine supplementation
g. L-Carnitine
4. Cofactors - supplementing remaining enzyme activity, replacing deficiency
a. Coenzyme Q10, pyridoxine, glycine, folate, vit C, vit E
5. Enzyme replacement therapy
a. Cerezyme, others, very expensive
6. Small molecule therapy
a. Chaperones: Fabry disease, Gaucher disease
b. Substrate reduction therapy: Gaucher Type 1, Niemann-Pick type C, Juvenile GM2, Tay-Sachs, Sandhoff
7. Gene therapy is on the horizon


A.

B.

GENETICS OF COMPLEX DISEASE & PHARMACOGENETICS


Genetics of Complex Disease
1. Heritability: fraction of variation in a trait that is attributable to additive genetic factors (rest if made up of environment, epistasis, random
chance)
a. Estimated best by twin concordance
Monozygotic twins are genetically identical
Dizygotic twins share ~50% of genetic material
High heritability is not equivalent
b. Concordant = same trait/phenotype (purely genetic trait will show 100% monozygotic concordance)
to a simple genetic architecture
c. Monozygotic >> dizygotic concordance => higher heritability
d. Controls for many environmental factors
2. Genetic architecture: number, allele frequencies, and effect sizes of genetic variants contributing to a given trait
3. Features of complex inheritance
a. Mendelian vs. Common Disease
Mendelian disorders & traits usually determined by a mutation of a single gene, individually rare
Common diseases & traits usually complex inheritance, involve many genes + environment + chance
b. Family aggregation, but no pattern, usually unable to map gene
c. Recurrence risk is proportional to the population incidence of the disease
d. Recurrence risk is higher when more than one family member is affected (termed multiplex or simplex)
e. Recurrence risk fades rapidly with distance of genetic relationship
f. Recurrence risk is greater when the affected are of less susceptible sex (observed in pyloric stenosis, congenital hip dysplasia, club foot,
rheumatoid arthritis, etc.)
g. Recurrence risk is increased by the presence of a more severe form or earlier onset of the disorder
h. Recurrence risk increased by consanguineous relationships
4. Discovery of complex disease genes
a. Vast majority of genetic variation is common nearly all SNPs in an individuals genome are in someone else too
b. Common variant hypothesis
Common genetic variants underlie the heritability of common diseases
Presence of each such genetic variant has a small effect on the probability of the disease phenotype
For some diseases/traits (diabetes, height): many common variants of very small effect - very small contribution of rare and
de novo variants compared to Mendelian forms
For other diseases/traits (autism, intellectual disability): much larger role for de novo mutations in any hundreds of genes,
sometimes common variants contribute
c. Gene association: enables one to look at probabilistic effects
Enables modeling multiple genetic variants, as well as non-genetic influences
d. Genome-wide association studies (GWAS) this was done with T2DM, showed about 40% heritability
e. Rare variants can sometimes contribute to common disease risk
24% of unselected subjects with primary ovarian, fallopian, and peritoneal carcinoma have germline, loss-of-function mutations in
known cancer gene
Pharmacogenetics
Adverse drug reactions are fourth
1. Genetic variants can influence drug response
leading cause of death in US
2. Carbamazepine: antiepileptic
a. Maculopapular rash (1 in 20)
b. Hypersensitivity reaction with eosinophila, fever, systemic involvement (1 in 5000 caucasians) 10% mortality
c. Stevens-Johnson Syndrome/toxic epidermal necrolysis (1 in 10,000 caucasians, more common in Asians) 30% mortality
3. Thiopurine methyltransferase deficiency (TPMT)
a. Normally inactivates 6-mercaptopurine and azathioprine (used in
leukemia therapy, immunosuppression after organ translplant)
b. Poor clearance of these drugs leads to bone marrow toxicity
c. Use LOW dose
4. VKORC1 and CYP2C9 and Warfarin dosing
a. VKORC1 vitamin K epoxide reductase complex subunit 1
b. CYP2C9 cytochrome P450 enzyme
c. Knowledge of these mutations can be used to minimize time to
stable therapeutic dose as well as risk of adverse events


A.

DYSMORPHOLOGY
Dysmorphology
1. Terminology
a. Congenital present at birth, does not imply genetic
b. Anomaly structural defect that deviates from normal (major: surgical, medical, or cosmetic importance)
c. Malformation results from intrinsically abnormal developmental process (can be genetic, but not always)
Cleft lip/palate, polydactyly, congenital heart defect
Minor no surgical or cosmetic consequence
3 or more minor malformations association with risk of occult major malformation
d. Deformation results from mechanical forces on an otherwise normally formed tissue
Club foot, overlapping toes, unusual head shape
e. Disruption destruction or interruption of normally developing tissue
Amniotic bands, intestinal atresia due to vascular disruption
Poland syndrome malformed arm and upper chest shape due to bands
Asymmetric
f. Syndrome pattern of multiple malformations (major and minor) with a single genetic
etiology
Physical exam is important for determining whether a child has an isolated anomaly or
multiple anomalies that may be part of a syndrome
2. Physical exam
a. Scalp: hair patterning, whorls, cutis aplasia congenital, color
b. Eyes
Spacing: distance between eyes, length of palpebral fissures, orientation of palpebral
fissures
Hypotelorism decreased distance (extreme form => cyclopia), may indicate
abnormal development of frontal lobes
Hypertelorism increased distance, often associated with widows peak
Up slanting palpebral fissures: trisomy 21
Down slanting palpebral fissures: Noonan syndrome
Epicanthal folds
c. Ears: placements, pits, tags
d. Hands: single palmar crease, hockey stick crease, polydactyly (postaxial, preaxial)
3. Disorders of sexual development (DSD)
a. Ambiguous genitalia (1 in 500-1000 live births); hypospadias, large clitoris, small penis
b. Common etiology
Congenital adrenal hyperplasia (CAH) MOST COMMON CAUSE of ambiguous genitalia
Recessive disorder
Partial to complete masculinization in XX female
Treatable
Androgen insensitivity syndrome (AIS)
XY females inability to respond to androgens
Androgen receptor gene, triplet repear expansion, X-linked
No uterus, ovaries, Fallopian tubes -> infertile
Can be partial or complete

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