HD018

Family Hx for Genetics Consult should ask...

Trsiomy 21

18

13

3 generation family tree (pedigree)
Names, dates of birth and death
NND, stillbirths, SA

Downs (21):

Single palmar crease, Brushfield spots (eyes)

Edwards (18):

Rocker bottom foot -> ankle bone is changed
Pataues (13):

Cutous aplasia (absence of part of scalp), Post-axial polydactyl

HD018

Autosomal Dominant:

Characteristics

Examples (4)

Characteristics of AD:

• Occurs through vertical transmission
• New mutations occur frequently
• The more severe the phenotype, the more likely that cases are due to new mutations
• Advanced paternal age is correlated with new mutations
• Mutations in AD conditions may be in structural proteins
• Incomplete penetrance (proportion of individuals carrying the gene that have phenotypic expression)
• Variable expression (individuals within the same family with the same mutation may have different phenotype- may include severity, S & S, age of onset)

Examples

1. Huntington disease

2. Myotonic dystrophy

3. Marfan syndrome

• Connective tissue disored where person is tall, flexible, joints can dislocate, early onset arthritis.
• Long fingers and arms
• Increased risk for heart attack -> dilated aortic root (4.4 cm) and ascending aorta (4.2 cm)

4. Neurofibromatosis

• Glioma behind eye
• Freckles in non-sun exposed areas such as axilla and groin

HD018

Genetic Heterogeneity

Autosomal Recessive and 1 example (HH)

Different mutations produce similar phenotypes

Allelic heterogeneity - different mutations at same disease gene
Locus - mutations on different genes

Characteristics

Horizontal inheritance

Ex:

Hereditary Hemochromatosis (HH)

• Inappropriately high absorption of iron by the gastrointestinal mucosa, resulting in excessive storage of iron particularly in the liver, skin, pancreas, heart, joints, and testes. Due to mutations in the HFE gene (C282Y- more symptomatic mutation, H63D- mild mutation)
• W/o therapy, males may develop symptoms between age 40 and 60 years and females after menopause.
• In untreated individuals may include progressive increase in skin pigmentation, diabetes mellitus, congestive heart failure and/or arrhythmias, arthritis, and hypogonadism.
• Treatment: regular phlebotomy until ferritin is lowered

HD018

 X Inactivation

X-linked Recessive

• X inactivation occurs early in development and involves the XIST gene in the X Inactivation Centre (XIC) on Xq
• Several regions of X chromosome remain active in all copies of the X chromosome.
• X inactivation is random, fixed and incomplete

• No male to male transmission (unless XXY which is very rare)
• All daughters of affected males inherit the gene mutation (obligate carriers)
• Female carriers transmit the mutant gene to half their offspring
• Males are more severely affected
• Female carriers can occasionally be symptomatic due to..
• skewed or unfavorable X inactivation which can cause variable expression (manifesting heterozygote)
• Females with one X chromosome –Turner syndrome
• Translocation or deletion of X chromosome
• Ex. – Hemophilia A, Red-green colour blindness
• Ex: Duchenne muscular dystrophy
• Progressive symmetrical muscular weakness,
  proximal greater than distal, often with calf hypertrophy
• Symptoms present before age five years
• Wheelchair dependency before age 13 years
• Caused by mutation in the dystrophin gene
  
  

HD018

X-Linked Dominant

Y-Linked Disorders

New Mutation

• Daughters of affected males always inherit the disorder
• Son of affected males never inherit the disorder
• Affected females can transmit the disorder to offspring of both sexes
• An excess of females exists in these pedigrees
• Females usually milder expression
• Example - X-linked Hypophosphatemic Rickets (nutrition due to poverty), Rett syndrome, Incontinentia Pigmenti

• Only males are affected
• Only male-male transmission
• Y chromosome has relatively few genes; genes encoding testis-specific spermatogenesis factors

• No family history
• Commonly seen in autosomal dominant disorders
• Recurrence risk for the parents may not be elevated above that of general population but may not be 0 because of gonadal mosaicism
• Risk of offspring of affected child is high (50%) for autosomal dominant condition

HD012

Common pedigree symbols, definitions and abbreviations

HD014

Teratogens Risk Period

Criteria (only nonobvious ones)

• Risk is greatest AFTER 2 weeks from conception
• Organogenesis (organ forming) is from 18-60 days, the most sensitive period
• Neurobehavioral effects can be seen in some exposure throughout the whole gestational period
• eg. Alcohol

[image]

• An animal model duplicates the effect in humans
• In exposed individuals, a group may be at increased risk owing to an underlying genetic susceptibility

HD014

Maternal factors or disease for Teratogens

Environmental and Physical factors

FX of smoking

1. Infections (Rubella)
2. PKU (Phenylketonuria – high levels phenylalanine in mother -> toxicity to fetus)
3. Diabetes
4. obesity

1. Radiation: cosmic, medical diagnostic vs. therapeutic
2. Hyperthermia

• Low birth weight
• Preterm delivery
• Variants of CYP1A1 and NAT2 genes may modify risk greater risk of:
• orofacial clefts
• Interaction via GSTT1-null deletion
• limb reduction defects
• Urinary tract anomalies
• craniosynostosis

HD014

3 Facial FX seen in FAS

FAS is Only the...

1. Short Palpebral fissures (corner to corner of eye)
2. Smooth Philtrum (Hitler moustache space)
3. Thin upper lip

Tip of the Iceberg: There is also...

1. Partial FAS – normal growth with some behavioral problems (brain fx)
2. ARBD – Alcohol related brain defects
3. ARND  - alcohol related nuerodevelopmental defects
• Clinically appear normal, often behaviour reveals  their deficit(s)

[image]

HD014

FAS can be associated with...(4)

RFs Associated With FASD (7)

1. growth impairment pre- and post-natally
2. characteristic face
3. cognitive and behavioral abnormalities
4. Major affect is on brain with a brain injury pattern on psychological evalaution

1. Poor nutrition
2. Smoking and other drugs
3. Maternal age
4. Lower socioeconomic status/educational status
5. Previous affected child with FAS
6. Paternal alcohol and drug abuse
7. Polymorphisms of Alcohol Dehydrogenase (ADH1B)
• Both maternal and fetal ADH1B*2
• ADH1B*3 appears to afford protection (Af. Americans)

HD014

Mechanisms of Alcohol Teratogenesis

FAS FX on Brain

1. Disrupted cellular energetics
2. Impaired cell acquisition
3. Altered regulation of gene expression
4. Disrupted cell-cell interactions
5. Interference with growth-factor signaling or other cell-signaling pathways
6. Cell damage/cell death

1. Reduced brain size
2. Parietal lobe disproportionately affected
3. Relative increase in gray matter, decrease in white matter
4. Reduced brain growth in ventral portions of left frontal lobe, inferior parietal and perisylvian areas
5. Reduction in cerebellar volume
6. Smaller corpus callosum; displaced
7. Reduced basal ganglia volume especially the caudate nucleus

HD014

Secondary Prevention of FAS

Thalidomide

Infectious Teratogens

Accutane

1. Alcohol rehabilitation and counselling
2. Antioxidant supplements, vitamins C and E 
3. 5-HT1A agonists to prevent serotonergic dysgenesis
4. Neuroprotective proteins
• eg. NAPVSIPQ and SALLRSIPA
5. Choline supplementation

~1960 (morning sickness) had FX at 27-40 day critical period. Resulted in:

• limb reduction defects, urogenital, renal, GI, orofacial, cranial nerve, microtia (small ears)

1. Congenital Rubella Syndrome (CRS) - Preventable
    w/ immunization
• Classically IUGR (Intrauterine Growth Restriction)
• Microcephaly
• Cataracts
• Deafness
• Patent ductus arteriosus, VSD
• Mental handicap
• Autism & Savant
2. CMV
3. Toxoplasmosis
4. Varicella
5. Venezuela equine encephalitis

Leads to XS Vit A. Causes:

• microtia, cleft palate, eye anomalies, CNS anomalies, congenital heart defects

HD014

Antiepileptic Drugs (AEDs)

When is Amniocentesis done?

Epi of Neural Tube Defects

• Overall risk of congenital anomalies is 2 to 3 times greater of the CNS, CVS, GU, skeletal and GI systems
• Fetal Anticonvulsant syndrome: cranio-facial anomalies, growth retardation, distal digital hypoplasia
• Risk may be related to genotype in mother (epoxide hydrolase system) in Folate metabolism (homozygous C677T variant of MTHFR gene)
• Neural Tube Defetcs (NTD) has been seen in 1-2% of infants born to mothers taking valproic acid or carbamazepine

• 15-16 weeks
• Results in 2 -3 weeks
• 1/200 procedure related pregnancy loss rate
• Can be used to obtain fetal karyotype, analyze amniotic AFP levels, or perform DNA or metabolic tests
• Very sensitive (>99% detection rate for spina bifida and aneuploidy)

Includes Spina Bifida, Anencephaly, Encephalocele

• 1-2/1000 livebirths
• 5-10% positive family history
• 90-95% negative family history

HD005

Maternal Serum Alpha-Fetoprotein (MSAFP)

An inc. MSAFP + inc. AFAFP is a sign of...

An inc. MSAFP + normal AFAFP is a sign of...

• detects (w/specificity):
      95% Anencephaly
      80% Spina Bifida
      5% Closed Spina Bifida
• Measured between 15-24 weeks
• >2.3 -> bad

Amniotic Fluid Alpha Fetoprotein (AFAFP)

• NTD (Neural tub defect)
• Abdominal Wall Defect
• Fetal death
• Triploidy
• Finnish Congenital Nephrosis
• Congenital Skin Disorders
• Saccrococcygeal Teratoma

• Twins etc
• Perinatal Death
• IUGR
• Maternal Hypertension / Pre-eclampsia
• Oligohydramnious

HD005

What is Triple Screening?

Other Screening options (Table)

What happens to testing as maternal age increases?

Screening of:

• AFP
• HCG
• Increased levels may indicate aneuploidy
• Unconjugated Estriol (UE3)
• Reduced levels may indicate aneuploidy, very low levels may indicate Smith-Lemil-Opitz syndrome

[image]

False Positive rates and Detection Rate both increase

HD005

How do you qualify for Prenatal Amnio Screening?

How does Chorionic Villus Sampling work?

Ultrasound

• Maternal Age >=40
• Positive maternal serum screening
• Previous Chromosome anomaly
• Chromosome rearrangement
• Family hx of multiple trisomies
• Abnormal ultrasound
• Metabolic/DNA

• Performed at about 11-13 weeks gestation
• Risks include:
• Miscarriage (0.5% higher risk than for amniocentesis)
• Fetal limb defects
• No longer performed in Manitoba

• Routine test offered to all pregnant women at about 18-22 weeks gestation
• Nuchal translucency = fluid in posterior aspect of neck -> Screening test for aneuploidy
• There are some characteristics “soft signs” that are associated with increased risk of Down Syndrome: 
• Echogenic bowel
• Echogenic foci in left ventricle
• Short femurs & humeri
• Dilation of renal pelvis
• Absence/hypoplasia of nasal bones
• Minimal risks/complications

HD105

Genetic Drift

Hardy-Weinberg Equilibrium

Disturbance in the Hardy-Weinberg Equilibrium

Try the...

change in allelic frequencies due to chance

p² + 2pq + q² = 1, where 2pq = frequency of carriers

The most important clinical application of the Hardy-Weinberg Law is the calculation of frequencies of carriers of autosomal recessive and X-linked traits

↓ trait frequency → ↑ proportion of recessive genes that occur in heterozygotes

Altered mutation rates

• mutations – may affect single genes, groups of genes, a chromosome or a chromosome complement
• genetic lethal – affected individuals never reproduce

Selection: may be negative or positive

• autosomal dominant – any increase in fitness will immediately have an effect on the gene frequency
• autosomal recessive – changes in gene frequencies occur slowly when fitness changes

Non-random (assortative) mating

• ex. consanguinity or the mating of genetic relatives

Small populations

• Founder effect – A small group of individuals that becomes genetically isolated and later we can trace their ancestry back to a single individual (ex. tyrosinaemia)

Try the Self-Evaluation Questions

HD007

Categories of Inborn Errors of Metabolism (IEMs)

When to consider an IEM in neonate

In a Patient Evaluation what are we looking

for on the  Physical Examination

• Disorders of protein metabolism (eg, amino acidopathies, organic acidopathies, and urea cycle defects)
• Disorders of carbohydrate metabolism
• Lysosomal storage disorders
• Fatty acid oxidation defects
• Mitochondrial disorders
• Peroxisomal disorders

• Neonatal catastrophe
• Overwhelming neonatal illness
• Acute illness
• Lethargy and coma
• Hypotonia
• seizures (intractable)
• Apnea or respiratory distress
• Sepsis, particularly with E. coli.
• Unusual odor
• Dysmorphic features
• developmental Delay/Regression
• Organomegaly
• Myopathyand cardiomyopathy

• General - dysmorphisms, ODOUR
• Ocular - cataracts, cherry red spot
• CNS - tone, seizures, LOC
• Resp - tachypnea
• CVS - cardiomyopathy
• Abdo- hepatomegaly
• Skin - jaundice

HD007

Newborn Screening in Manitoba:

the Past and the future

What is tested in the Oji-Cree population

What is tested in the Hutterite population

PKU
When Phenylalanine can't go to Tyrosine it -> Phenylpyruvic acid -> Phenyllactic phenylpyruvic

Build up can lead to:

Severe mental retardation

Microcephaly

Seizures

Galactosemia
Biotinidasedeficiency
Hypothyroidism
Congenital adrenal hyperplasia
Duchennemuscular dystrophy

Now: We use mass spec - 1 blood spot -> 40 disorders including Organic acidurias, Fatty acid oxidation disorders, Amino acid disorders

Glutaric acidemia Type1: Glutaryl co A dehydrogenase

Carrier: 1:10

It is a Neurologic disorder

Hepatic CPT1 deficiency: CPT1

Carrier: 1:16

Hepatic disorder

HD007

Modes of Treatment for IEMs (w/ examples of disorders)

Treatment Modalities for IEM

Substrate restriction - PKU
Substrate reduction - Gaucher Disease
Removal of toxic products - Urea Cycle Defects
Enzyme replacement - Gaucher Disease
Cofactor supplement - Homocystinuria
Bone marrow transplant - ALD
Gene therapy - Hypercholesterolemia

Drug therapies

• Carnitine to facilitate metabolic excretion
• Sodium benzoate, phenylacetate-urea cycle disorders
• Phosphocysteamine for cystinosis
• Betaine for homocystinuria
• Bisphosphanates for OI

Hemodialysis/ CRRT
Organ transplantation
Bone marrow, stem cell transplantation
Enzyme replacement therapy

Gaucher, MPS 1, Pompe, Fabry, + others

HD096

Multifactorial/Complex Inheritance (when do we see it, and how do we calc it?)

Components of variance of a trait in the population (formula)

• Many Genes, Env, Behavior/Age/Stage of Development
• 600/1000 population prevalence (Diabetes, HD etc.)
• Effects can be qualitative (Type 1 DM, cleft lip±cleft palate, MS, Schizophrenia, Crohn’s disease) or quantitative (height, BMI, blood pressure, serum cholesterol conc.)
• Follows Bell curve

When do we expect it?

• If we see Familial clustering: the diseases is clearly familial but there is no obvious Mendelian pattern of inheritance
• If continuous traits are observed such that distinct phenotypes cannot be distinguished e.g. height, BMI, etc.

Relative Risk (λr) = Prevalence of the disease in the

                           relatives of an affected person/

                           Prevalence of the disease in the

                                  general population

λr = 1 = no ↑ risk

as λr ↑ = ↑ familial aggregation

Must take population frequency into consideration because if a trait is very frequent ↑ possibility that a the trait appears in the family coincidentally. But, aggregation may result from shared culture/behaviors, socioeconomic status, diet, environmental exposures.

V = V_G + V_C + V_E

G = Genetic, E = Env., C = Cultural

HD096

Twin studies & Concordence & Heritability

Monozygous twins (MZT): 100% shared genome, some shared env.

Dizygotic twins (DZT): 50% shared genome

For most traits MZT concordance is not quite 100% (b/c of somatic rearrangements), but is higher than DZT concordance.

Heritability (h²) 0 = non-genetic, +1 = 100% Genes

h² = (V in DZ pairs – V in MZ pairs)/V in DZ pairs

HD037

Imprinting

• Differential expression of the maternal & paternal alleles during development (one is active, other is inactive)
• Involves one or many genes (conserved cluster)
• Imprint occurs by methylation of CpG dinucleotides
• Confers transcriptional silencing
• Transmitted with stability through mitosis in somatic cells
• Must occur in egg or sperm (before fertilization)
• Reversible when passing through the opposite parental germline?
• X inactivation is an example of normal imprinting
• Aberrant imprinting leads to: (silenced when shouldn’t, or not silenced when it should)
• tumour development
• growth abnormalities
• patients with intellectual disability
• syndromes

HD037

Prader Willi Syndrome

Caused by a lack of paternal transcripts in the region of chromosome 15q11-13

Paternal deletion (70%)
Maternal UPD (uniparental Disomy) (28%)
Rarely, translocation disrupting critical region (1%)

Presents with:

• Moderate intellectual disability
• Neonatal hypotonia
• Hypogonadism
• Hyperphagia -> insatiable appetite (2-8 y/o)
• Obesity
• Short stature, Small hands and feet
• Characteristic face

Caused by a lack of maternal transcripts in the region of chromosome 15q11-13

Maternal deletion (68%)
Paternal UPD (7%)
Imprinting centre mutation (3%)
Mutation in UBE3A (11%)

Presents with:

• Severe intellectual disability
• Seizures
• Absent speech
• Paroxysms of inappropriate laughter
• Tongue protrusion
• Stiff ataxic gait
• Characteristic face

HD037

Uniparental Disomy

Mitochondrial Disorders

Heteroplasmy

• Both homologues of a chromosome pair are from the same parent
• If two chromosomes are identical
• meiotic  II error-uniparental isodisomy
• If  two chromosome are different
• meiosis I-uniparental heterodisomy

Mutations can lead to energy failure -> ragged red muscle fibres and Lactic acidosis common signs

Virtually all mitochondria are of maternal origin (passed from mothers only to both sons and daughters)

Threshold Expression:

CNS>Heart>Skeletal >Renal>Endocrine>Liver

No treatment: Vit B, E, C....

• Different cells contain different proportions of wild and mutant mitochondria
• Occurs due to passive segregation of mitochondria when cells divide
• Accounts for variable expression of mitochondrial disorders

HD037

DNA Triplet Repeat Sequences

Gonadal Mosaicism

Digenic inheritance

• 3 DNA base pairs that repeat themselves in sequence eg (CGG)n
• May be benign
• Anticipation - increase in the severity of phenotype with the increase in the number of repeats and in subsequent generations

Ex

• Fragile-X syndrome-CGG/5’UTR
  
• Mild to severe intellectual disability in males and mild to moderate in females.
• Accelerated growth, characteristic facies
• Macro-orchidism post puberty
• Size of expansion correlates with degree of intellectual disability
• Normal-5-45 CGG repeats
• Premutation-55-200 CGG repeats
• Normal intelligence but at risk for ataxia-
• tremor or premature ovarian failure 
• Full->200 CGG repeats
• Myotonic Dystrophy-CTG/3’UTR
  
• Huntington disease-CAG/5’
  
• Spinocerebellar ataxias-CAG
  

• Autosomal dominant
• Sex-linked recessive
• Clinically normal parent with mutation only in the gonadal cells
  
  Examples: Achondroplasia, Osteogenesis imperfecta, Duchenne muscular dystrophy

Mutations in two different genes (digenic) causes genetic condition (double heterozygote)

Ex

1. Retinitis Pigmentosa - affected individuals are heterozygous for mutations in two different recessive genes

1 mutation in Peripherin and 1 mutation in ROM1

2. Autosomal Recessive Neurosensory Hearing loss

1 mutation in GJB2, 1 in GJB6

HD038 - Tutorial - Few good cases to look at - Read it over

HD102

Types of Genetic Screening

1.  Prenatal screening

2.  Newborn screening

• population-based attempts to identify disorders in neonates that, if undetected, would lead to mental retardation or have life-threatening consequences and where treatment is available
• e.g. PKU

3.  Carrier screening

• attempts to detect (phenotypically normal) individuals who carry a disease-related allele of an autosomal recessive or X-linked disorder and whose children would thus be at increased risk for developing the disorder
• Advantages:
• disease clearly defined, high population frequency
• rapid inexpensive test w/ few FP/FN
• diagnosis affects therapy
• can be targeted at high-risk groups, ex. Hutterites or for a general population

4.  Presymptomatic screening

• Attempts to detect genetic alterations that indicate a susceptibility to, but not the certainty of, disease
• Currently applies to multifactorial or polygenic disorders, or single-gene disorder with high levels of etiologic heterogenity

5.  Predisposition screening 

• Attempts to detect genetic alterations that indicate a susceptibility to, but not the certainty of, disease
• Currently applies to multifactorial or polygenic disorders, or single-gene disorder with high levels of etiologic heterogenity

2 Types of Predisposition screening

1. Adult-onset neurologic disorders (no treatment)
-Huntington disease, CADASIL, Familial Alzheimer, Spinocerebellar Ataxias, Mitochondrial diseases, Familial Breast Cancer
2. Adult-onset disorders (treatment/surveillance available)
-AD Polycystic Kidney Dis, Von Hippel Lindau, FAP, Hereditary Non-Polyposis Colonic Cancer, Hypertrophic cardiomyopathy, α1antitrypsin def., Porphyria, Gaucher, Fabry

HD102

Ethics points for Screening

When to test?

Missed Info!

Personal Ethics
Impacts on whole family
Voluntary, confidentiality assured, avoid stigmatization, “survival guilt”
Ethics of Clinical Practice
    -no disclosure of information to third party
    -non-medical use of genetic information
    -DNA banking and consent

Avoid times of emotional distress (ex. loss, job change)

• When distress present, delay test and deal with the distress
• Limited to persons > 18 years (except for prenatal)

Usually involves 2-3 pre-test (predicitve pretesting program), in-person sessions

• An individual can decide not to come back, change mind

There was info on CRC, Tay Sacs and thallasemias not covered in the objectives. Look over it, but don't focus on it?

HD125

FISH

Metacentric, Submetacentric & Acrocentric

p and q

Fluorescence In Situ Hybridization:

• FISH allows for easy detection of aneuploidy and chromosomal rearrangements in interphase nuclei
• FISH is also important in the detection of micro-deletion, microduplication and gene-amplification (e.g. oncogenes)
• FISH does not require culturing of cells - allows for faster analysis of cells

Metacentric: Equal L
Submetacentric: Long arm and Short arm
Acrocentric: The majority of the chromosome is made up of the long arm. The short arm is made up of small amounts of genetic material

q - long arm of the chromosome
p - short arm of the chromosome

HD125

Aneuploidys: Autosomal (3)

Down Syndrome (Trisomy 21)
Clinical findings:
Charachteristic facial features (slanting palpebral fissures, characteristic epicanthal folds, flat nasal bridge, low-set ears, brushfield spots around the margin of the iris and open mouth with protruding tongue)
Congenital Abnormalities: Cardiac anomalies, increased susceptibility to respiratory infections and leukaemia
Cytogenetics:
Typically due to uniparental disomy (i.e. extra copy of 21 inherited from one of the parents - typically the mother)
Unbalanced Robertsonian Translocation - potentially inherited form a balanced carrier.

Edward Syndrome (Trisomy 18)
Clinical findings:
Mental and growth retardation, cardiac and renal anomalies, Angelic face, rocker-bottom feet
90% mortality in first year of life (only 5% make it to birth)
Cytogenetics
Non-disjunction in maternal meiosis II
20% caused by unbalanced translocations

Patau Syndrome (Trisomy 13)
Clinical findings:
Bilateral cleft lip and palate, polydactyly, microcephaly, omphalocoele, renal abnormalities many other congenital defects

Low survival rates
Cytogenetics:
About 80% caused by extra chromosome 13
20% from unbalanced translocations

HD125

Aneuploidys: Sex Linked (4)

Turner Syndrome (XO)
Clinical Findings
Short stature, characteristic facial features, neck webbing, low posterior hairline, broad chest with widely spaced nipples, gonadal dysgenesis
Cytogenetics
Maternal meiosis non-disjunction 80% of the time

Kleinfelter’s Syndrom (XXY)
Clinical findings:
Patients are male, tall with long thin legs, Hypogonadism, lack of secondary sex characteristics, infertile, learning disabilities

Cytogenetics
Half receive extra chromosome paternally (non-disjunction in meiosis I)
Half receive extra chromosome maternally (~60% non-disjunction in meiosis I and the remainder from meiosis II)

Trisomy X (XXX)
Clinical findings:
Tall, Puberty usually normal, severe learning problems
Cytogenetics
Almost all due to non-disjunction in maternal meiosis associated with increased maternal age

“Super male” (XYY)
Clinical findings:
No abnormal phenotype, Taller than average, increased risk of behavioural problems, attention deficit, hyperactivity and impulsiveness
Cytogenetics
Typically due to non-disjunction event in paternal meiosis II

No risk of passing onto offspring

HD125

8 types of abnormalities of chromosome structure

1. Deletion - Ex Cri-du-Chat syndrome
2. Dicentric - Two centromeres
3. Duplication
4. Isochromosome - arms on either side of the centromere are identical. Can be viable in acrocentric chromosomes because short arm loss is not lethal.
5. Insertion
6. Inversions and Deletions (from 2 break aberrations)
If breaks are on the same side of the centromere:

• Acentric piece can be lost (deletion) - many not viable
• Piece may reinsert in opposite orientation - paracentric inversion - if no material is lost, this is viable and individuals are normal

If breaks are on opposite sides of the centromere

• Chromosome can reseal as a ring which is unstable and unbalanced
• Piece may reinsert in opposite orientation - pericentric inversion - if no material is lost, this is viable and individuals are normal

7. Ring
8. Translocation

• Balanced - No consequences for the carrier, but their offspring has an increased risk of having a an aneuploid disorder
• Unbalanced
• Robertsonian
• Involves only chromo 13, 14, 15, 21 and 22
• Long arms of two chromosomes fuse together at the centromere and short arms are lost.
• Balanced carriers are phenotypically normal
• Have a higher risk of having chromosomally unbalanced offspring. Down Syndrome and Patau’s Syndrome (trisomy 13) are clinically important

HD125

Contiguous gene/Microdeletion syndromes

Clinical indications for chromosome analysis (12)

Caused by a deletion of a continuous region of DNA with a loss of genes or gene function

• Syndromes that are caused by this include DiGeorge (VSD) Syndrome (22q11 deletion) and Williams Syndrome (7q)
• Angelman and Prader-Willi syndromes are the classic examples. Deletion at the same place on chromosome 15 (15q11), but Prader-Willi is caused by deletion on the paternal chromosome, while Angelman is caused by a deletion on the maternal chromosome

1. Otherwise unexplained Mental Retardtion
2. Multisystem anomalies
3. Neonatal death
4. Ambiguous genitalia
5. Inguinal masses in females
6. Cryptorchidism
7. Small testes
8. Hypogonadism
9. Primary amenorrhea
10. Infertility
11. Multiple Miscarriages or stillbirths
12. Stillborn infant

HD011

3 broad categories of Cancer Etiology

Mutation sources

Sporadic vs Familial Breast Cancer

Sporadic = 65-70% - Most cancers are the result of a buildup of mutations in our genes

Familial = 25%

Hereditary = 5-10%

>54 different hereitary cancer predisposition syndromes

Somatic (at the cell lvl) mutation = 90-95% of cancers

Inherited gene mutations are Germline mutations = 5-10% of cancers

Sporadic: Majority of cancer cases

• Single diagnosis in the family
• Onset later in life (>50)
• genetic consult not necessary

Familial:

• 2 or more affected 1st or 2nd degree relatives
• Late onset / unilateral
• Unclear pattern of inheritance
• Chance alone?
• Common environment?
• Genetic factors?
• genetic consult not necessary

HD011

BRCA1 and BRCA2

BRCA1/2 Testing Criteria

BRCA + and Breast and Ovarian Cancer Risk

Risks for Other Cancers When BRCA Positive

BRCA1 = On chromo 17

BRCA2 = On chromo 13

Both:

Autosomal Dominant Transmission

Pr. has role in genomic stability

• Anyone diagnosed < 35 years
• Any case of male breast cancer
• At least 2 individuals with breast cancer on the same side of the family, both < 50 years
• A woman with breast and ovarian cancer
• Ovarian cancer of the papillary–serous pathological type
• Ethnic specific testing - Ashkenazi Jewish, Ojibway, Icelandic, Eastern European descent

Genetic testing always begins with a cancer survivor

 BRCA 1 or 2 -> 80% Breast cancer lifetime risk

BRCA 1 -> 60% Ovarian cancer lifetime risk

BRCA 2 -> 30% Ovarian cancer lifetime risk

1. Prostate cancer – increase possible in BRCA1 and definite in BRCA2 mutation carriers
2. Male breast cancer – increase possible in BRCA1 and definite in BRCA2 mutation carriers
3. Pancreatic cancer – increase possible in BRCA1 and definite in BRCA2 mutation carriers
4. Melanoma (diffnt tha 1-3) – increase possible in BRCA2 mutation carriers

HD011

 Risk Reduction Options when BRCA +

Colorectal Cancer

• Tamoxifen - preventative chemo (breast odds go from 80 -> 40)
• Mestectomy (-90% for Breast)
• Oral contraceptives (Ovarian down 60%)

Third most common cancer in Canada-lifetime risk 5%

Hereditary CRC accounts for 5-10% of all cases
Most common hereditary colon cancers:
APC - Associated Polyposis Conditions

FAP, attenuated FAP (1%)

Hereditary Non-Polyposis Colon Cancer (HNPCC) (5-8%)

Peutz-Jeghers syndrome (STKII) 

HD011

HNPCC

+ HNPCC inc risks for....

• Most frequent cause for autosomal dominant predisposition to CRC
• Associated with extracolonic tumours
• Caused by mutations in at least 6 DNA mismatch repair (MMR) genes: MLH1 and MSH2 most common
• MMR Gene Mutation causes genomic instability and expansion or contraction of short repeated DNA sequences called microsatellites (MSI)
• MSI may allow accumulation of somatic mutations in oncogenes and tumour suppression genes
• Homozygous MLH1 mutations cause mild de novo NF1 (neurofibromitosis) and/or hematological cancers

Big inc:

CRC

Endometrial

Gastric

Ovarian

Risk for Second Cancer

5% inc or less:

Ureter/renal pelvis
Biliary tract
Small bowel
Pancreas
Brain
Sebaceous adenoma

HD011

Genetic Testing Criteria for HNPCC

1. At least 3 affected relatives, one with CRC and the other two with any combination of CRC, endometrial, ovarian, gastric, small bowel, hepatobiliary, ureter, transitional cell kidney cancer, and/or sebaceous adenoma/carcinoma
2. 2 of the 3 family members must be in a 1st degree relationship
3. At least two successive generations
4. 1 diagnosis < 50 years
5. FAP excluded

6. Individual affected with CRC and a second primary HNPCC-associated cancer.  1 Diagnosis < 50 year
7. Individual diagnosed with CRC < 35 years

HD011

APC - Associated Polyposis

FAP

• 100s-1000s precancerous colonic polyps develop beginning age 7-36 years (average 16y)
• By age 35, 95% of FAP pts have polyps
• Untreated- virtually 100% chance of developing cancer [average age of cancer diagnosis is 39 y]
• FAP Subgroups
• Profuse: >2000 polyps
• Sparse:100-500 polyps
• Attenuated: 50-100 polyps

HD094

5 Themes of Genetic Counselling

8 counselling guidelines suggested by WHO

1. Medical management  - diagnosis, probable cause, available treatment
2. Risk determination - appreciate hereditary contribution and risk of reoccurrence in relatives
3. Risk options - understand alternatives for dealing with issues of reoccurrence (adoption for ex)
4. Reproductive decision making – appropriate course of action based on risk, family goals, and ethical and religious standards
5. Support services - information on medical issues and referral to other support services such as support groups or individual counselling

1. Respect for persons & families
2. Preservation of family integrity
3. Full disclosure of relevant & appropriate information
4. Protection of privacy – from employers, insurers, schools
5. Duty to inform relatives who may benefit from the information
6. Accidental findings of non-paternity should not be disclosed
7. Children & adolescents should be involved in decisions affecting them (when possible)
8. Non-directive approach – exception of high risk of serious harm

HD094

8 suggestions regarding breaking the news about Down Syndrome after the “loss of the expected normal child”

1. Talk to both parents together when possible
2. Communicate the diagnosis ASAP
3. Choose a private, quiet place
4. Humanize the situation as much as possible
• Know the baby’s name (if decided upon), gender
• Avoid stigmatizing terms – ex. mongolism
5. Develop sense of realistic positivism
6. Answer the parents’ questions, but avoid technical overload
7. Listen actively – assume all feelings are natural & validate them
8. Refer family to appropriate resources early