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Population Genetic Screening in the “Omics-age”
Joaquin Santolaya-Forgas, MD,PhDProfessor of Obstetrics and Gynecology and Genetics
Head of Reproductive Genetics
Rutgers-Robert Wood Jonson Medical School , NJ, USA
“How genetic variation are analyzed to improve health care”
Cause of Death Newcastle London
Chromosomal 2.5% 12.0%
Single gene 8.5% 25.5%
Polygenic 31.0% 25.5%
Nongenetic/unknown 58.0% 62.5%
Total deaths 1041 200
Empiric data
Childhood Mortality, UK 1998 Gelernter, Collins and Ginsburg. Principles of Medical Genetics, 1998
Childhood Mortality in London attributed to genetic causes:1914 (14%) and 1954 (25%) (Rimoin DI, et al 1997)
Genetic Screening, NJ 2014
• Tandem mass spectrometry to screen for 31 metabolic disorders
• Hearing loss
Newborn Screening has
spared 1000s from
suffering through pre-
symptomatic diagnosis
and therapy
Goals: Early recognition of individuals with a
disease causing mutation allows for interventions
that improve health and for consideration of
alternative reproductive options
4-Basic principles of screening:1) Disease characteristics, frequency, clinical relevance and
treatment are known (+ cost/benefit ratio)
2) The test is acceptable, easy to perform, inexpensive,
statistically efficient and clinically efficacious
3) Strategy in place for informative consent, efficient
communication of results and alternative clinical strategies with
realistic positivism, avoiding technical overload, listening
carefully and based on current medical standards
4) Refer family to the appropriate multispecialty resources early
Genetic history “sweeps”
• 8 general questions will elicit information indicative of Genetic Consultation�Family history of MR/Autism�Family history of birth defects/infant surgery�Family history of stillbirth, recurrent SAB, infant
death�Family history of genetic conditions�Family history of cancer�Consanguinity�Teratogens�Positive genetic screening test
Society Norms In the 1980s sense of moral obligation to screen/te st?
Good parents test – “doing what’s best” in spite of limited understanding of limits of tests or options. Belief medically required
Desire for control and reassurance?Implied values simply in offering the test to promote a sense ofknowledge as power: some desire for “quality control”
�Fear of liability led to ACOG alert: “Imperative” to advise every OB patient of MSAFP screening in 1985 with a National goal to screen 90% of patients. This created a new standard of care in spite of the uncertain value and with a very limited discussion of meaning/purpose
�Very general description of conditions screened for and with little explanation of options/decisions if positive; Many patients didn’t understand it was voluntary
Recommended Genetic Screening (ACOG)
African-
American
Sickle CellCystic Fibrosis
Beta-Thalassemia
Natural selectionGene flow with
population migration
Ashkenazi
Jewish
Gaucher diseaseCystic Fibrosis
Tay-Sachs diseaseDysautonomia
Canavan disease
Bottle neck
Asian Alpha-ThalassemiaBeta-Thalassemia
Natural selection
European-
American
Cystic Fibrosis Natural selection
French-
Canadian, Cajun
Tay Sachs disease Founder Effect
Hispanic Cystic FibrosisBeta-Thalassemia
Gene flow
Mediterranean Beta-ThalassemiaCystic Fibrosis
Sickle Cell
Natural selection
Chromosomal &
Congenital anomalies
Human Genome Sequence Medical genetic analysis to determine disease risk profile
DNA Library 2, Individual 2
DNA Library 1, Individual 1
DNA Library 3, Individual 3
Next-generation sequencing: Computerized alignment process of parallel reads of thousands of pieces of DNA
“Omics platforms” , including array Comparative Genomic Hybridization (aCGH), Single nucleotide polymorphisms (SNPs) genotyping, and Next-generatio n sequencing are allowing for determination of
Position of DNA Variants and Frequencies
Personal Genome Project (PGP)2008: Announcement of the $5,000 Genome
Scientific American, 2006
Launch Platform List Cost Counselor
deCODEme Nov-07 Illumina $985 Referrals
23andMe Nov-07 Illumina $399 No
Navigenics Apr-08 Affymetrix $2500+$250 annual sub
On staff
SeqWright Jan-08 Affymetrix $998 No
Bio-IT World November, 2008
Genetic predisposition
for Carcinogenesis
BRCA1/2 Involved in DNA repair
Autosomal dominant breast cancer (~10% of cases):
Familial aggregation due to genetic predisposition
for early-onset breast and ovarian cancerBRCA1 and 2; p53 (Li-Fraumeni syndrome; PTEN (Cowden disease with
hamartomas and breast cancer); AT (ataxia telangiectasia); MSH2 and
MLH1 (HNPCC and breast cancer)
Clinical Genetics -Updates in the “Omics-Age”
Q. Can we assign a risk for a genetic disorder to a consultand
that has no symptoms? A. Yes
Objectives is to review how we can calculate genetic risks:
1. Analysis of allele frequency in a population in Hardy-Weinberg Equilibrium and the forces behind genetic variations in distinct populations
2. Analysis of the Pedigree
3. How to apply Bayesian analysis to refine Mendelian risk
Gene flow• Gene flow refers to the diffusion of different configurations of a gene
(allele) across cultural, ethnic, or geographical barriers. Alleles from
migrants gradually merge into the gene pool of the population into which
they have migrated. The rate at which an allele migrates into a
population does not equal the rate at which alleles migrates out of the
population. Until the equilibrium between alleles is reached the
population is stratified
• Changes in base pair sequence convert one allele into another. The rates
of inter-conversion of alleles are seldom equal: Rate of A a ≠ a A
leading to changes in allele frequencies over time
• Alleles highly deleterious or affecting the capacity to reproduce are
“genetically lethal”, mostly occur “di novo” and are rare in the population
Using information from the population for
individual risk estimates ”The chance that a genetic disorder will occur using observed frequency of the disease in the population”
Hardy-Weinberg calculation:
The frequencies for 2 alleles (A and B)* in a population
in equilibrium can be calculated:
Types of Genotypes in the population: AA = p2, BB = q2, AB = 2pq . ( p + q = 1)
Remember: For X-linked recessive traits males are hemizygous for A or B; Females can be AA,BB or AB!
Assumptions for a Population in H-W Equilibrium!Random mating: e.g. Allele contribution from AA mother and Aa father = p2 x 2pq
(similar calculations could be done for all possible combinations of parental genotypes
No changes in population due to large migration
No random fluctuations in allele frequency caused by: Natural selection/ genetic drift/
founder effect/ bottleneck/ inbreeding
No positive or negative selection: all 3 Genotypes reproduce equally well
* For simplicity we have considered only 2 alleles with frequencies p and q. HWE holds regardless of the number of alleles although the algebra must be calculated with a computer!
Applications of HWE: Q. What is the probability for a
child with Cystic Fibrosis in this family?
1. The probability that the mother is a carrier fo r A.R. disease can be estimated from Mendel’s Laws using this pedigree analysis = 2/32. The probability that the father is a carrier can be estimated from the population frequency (HW) 3. Molecular analysis: Affected family, genetic panel /or sequence of the entire gene can be offered to husband 4. Reproductive options: CVS/ Amniocentesis/ NIPT?/ IVF-Pre-implantation analysis for CF testing
Ireland 1 per 1,700
Caucasian 1 per 2,500
Sweden 1 per 7,000
Mexico 1 per 8,500
US Black 1 per 17,000
Native Hawaiians 1 per 90,000
C.R. Scriver et al. The Metabolic and Molecular Bas es of Inherited Disease 7 th Ed p. 3848
CF Disease Frequency?
18 yo CF 26yo 27yo
??Consultand AA Spanish
AAGerman
The frequency of the disease in the population is known
Hardy-Weinberg: p + q =1; normal allele = p; disease-producing allele = q
q2 = 1/2500; (q) = 1/50 = 0.02; (p) = 1-0.02 = 0.98
Husband carrier (Htz = 2pq) = 2(0.02)(0.98) = 0.039 = 4% (~1/25)
A1. Fetus = 2/3 x 1/25 = 2/75 = 1/40 CF risk!
Applications of HWE: Q. What is the probability for
an affected child in this family after genetic screening?
1. The probability that the mother is a carrier can be estimated from Mendel’s Laws using this pedigree analysis2. The probability that the father is a carrier can be estimated from the population frequency (HW) 3. Molecular analysis: Affected family, genetic panel /or sequence of the entire gene can be offered to husband 4. Reproductive options: CVS/ Amniocentesis/ NIPT/ IVF-Pre-implantation analysis for CF testing
18 yo CF 26yo 27yo
??Consultand AA NJ- Italian
A2. After molecular testing the adjusted risk to
the Fetus = 1 x 1/250 = 1 in 250 CF risk!
Efficiency of CF test by Ethnic background
Ethnicity Carrier Frequency Detection%
Caucasian 1:25 88.2%
Ashkenazi
Jewish 1:26 94%
African
American 1:65 64.5%
Hispanic 1:46 71.2%
Asian American 1:90 48.9%
non-Ashkenazi J Varies by country of origin
Mixed ancestry Varies by country of origin
. N
The frequency of the disease in the population is known
Hardy-Weinberg: p + q =1; normal allele = p; disease-producing allele = q
q2 = 1/2500; (q) = 1/50 = 0.02; (p) = 1-0.02 = 0.98
Husband carrier (Htz = 2pq) = 2(0.02)(0.98) = 0.039 = 4% (~1/25)
A1. Fetus = 2/3 x 1/25 x 1/4 = 2/300 = 1/40 CF risk!
We use CF genetic platforms for 98 mutations
Caution with Pedigree Risk analysis
1. Pleiotropy and Variable Expression, 2. Penetrance, 3. Heterogeneity, 4. Phenocopies, and 5. Imprecise
definitions of the disease or trait
For all of these reasons + sample size + quality of controls GWAssociation studies for
potential risk factors must be interpreted cautiously!
Phenotypic patterns that could have
Multifactorial, Dominant, Recessive,
Chromosomal or Mitochondrial
familial transmission
Although pattern analysis can be used to determine
probability of recurrence remember these concepts
Hemophilia A: X-linked recessiveF-VIII gene pathogenic mutation: most common intron 22-A and intron-1 inversion
The incidence of the disease is 1 in 4,000 males/rare in females (10-15% de novo)
Penetrance is 100% in males / 10% in females
The consultand’s mother is informative in only one of these 2 pedigrees
Severe deficiency in the factor-VIII clotting activity assay is associated with
spontaneous joint or deep tissue bleeding; Moderate/mild deficiency is
associated with prolonged bleeding after tooth extractions, surgery or injuries
1/2 risk for carrier?Mendelian risk for carrier 1/4?Bayesian analysis?
Bayesian terminology• Prior probability: Mendelian probabilities that mother is or is
not a carrier
• Conditional probability: other information: in this family is the daughter a carrier considering that her 4 brothers are unaffected
• Joint probability: product of prior and conditional probabilities
• Posterior probability: ratio of the joint probability of one outcome to the sum of all joint probabilities
Formulas for Calculating Probabilities:* When 2-events are independent (p1) and (p2) the probability for both occurring
together is P1 x P2.
* When one event can happen in 3-ways with individual probabilities of p1, p2, and
p3, then the overall probability is P1 + P2 + P3 and the probability that the event
will happen by way #1 is P1/(P1 + P2 + P3)
Bayesian estimation
of risk
Alternatives (A) (B) (C)
Mother carrier Y Y N
Consultand carrier Y N N
Prior Prob. Mother 1/2
carrier
1/2
carrier
1/2
non-carrier
Condit Prob. P(4 sons)
x P (consultand)
(1/2)4 (1/2) (1/2)4(1/2) (1)4(1)
Joint Probability (1/2)(1/2)4(1/2)
= 1/64 = 0.01
(1/2)(1/2)4(1/2)
= 1/64 = 0.01
(1/2) (1)4(1)
= ½ = 0.5
Posterior probability 0.01/(0.01+0.01+0.5)
= 2%
0.01/(0.01+0.01+0.5)
= 2%
0.5/(0.01+0.01+0.5)
= 96%
P(A) + P(B) + P(C) = 1
In this case Mendelian analysis would suggest that the mother of the
consultand has 50% risk and the consultand 25% risk (1/4) to carry
the F-VIII mutation. However, the
consultand has 4-unaffected brothers which should modify the 25% risk of being
a carrier
Hemophilia AX-linked Recessive
Huntington Disease
• His grandmother died of Huntington's disease. His 60-year-old father is (so far) disease-free. The consultand would like to know the risk to have a HD child and reproductive options to avoid the odds of this outcome?
• For known carriers of HD, ages of manifestation of the disease have been tabulated: Probability of remaining asymptomatic by age 60 = ~10%; Probability of being asymptomatic by age 35 = ~80%
• Mutation analysis?
Founder effect: HD frequency in a region close to Maracaibo was ~17 in 100
HD (Chr4) A.D. disorder affecting 1 in 20,000 individuals is a classical example of age dependent penetrance of a devastating
neurologic deterioration disorder with very few individuals manifesting signs during childhood and 100% by age 80 - no signs of being
affected at childbearing age. There is an insidiously progressive development of personality changes, memory loss, abnormal body
movements “chorea” together with loss of cognitive skills and psychiatric depression until death with loss of the basal ganglia of the
brain specially the caudate nucleus. In HD there were no chromosomal abnormalities that could help with a functional mapping and
cloning approach. HD was 1 of the first disorders subjected to “ large family genome polymorphic markers scan and positional cloning ”
making in 1981 for linkage-based diagnosis using haplotype analysis in pre-symptomatic patients. Today there is direct molecular
testing for HD obviating the need for a family analysis. However, HD DNA-testing has brought increasing number of social and ethical
concerns because there is no cure for HD and the Dx. has the risk for discrimination for Jobs or health/life Insurance as well as for
other psychological hurdles – e.g. in non affected there is the guilt for escaping a fate their siblings may still face!
Bayesian estimation
of risk
Alternatives (A) (B) (C)
Father Father not a carrier and
asymptomatic at age 60
Father is a carrier and
asymptomatic at age 60
Father is a carrier and
asymptomatic at age 60
Consultand Not a carrier Not a carrier Carrier and asymptomatic
at age 35
Prior Prob. father carrier &
without Sx at age 60
(1/2)(1) (1/2)(1/5) (1/2)(1/5)
Condit Prob. Son is/is not
carrier & Sx at age 35
(1)(1) (1/2)(1) (1/2)(8/10)
Joint Probability (1/2)(1)(1)(1)
= ½ = 0.50
(1/2)(1/5) (1/2)(1)
= 1/20 = 0.05
(1/2)(1/5)(1/2)(8/10)
= 0.04
Posterior Probability 0.50/(0.50+0.08+0.04)
= 0.81
0.08/(0.50+0.08+0.04)
= 0.13
0.04/(0.50+0.08+0.04)
= 0.06
P(A) + P(B) + P(C) = 1
Huntington’s
1. Conventional population reproductive screening tests
2. How is the analysis of allele frequency in a population in
HWE is done and which are the forces behind genetic
variations in distinct
3. How to interpret the genetic information contained in a
family pedigree
4. How to apply Bayesian analysis to refine Mendelian risk
In summary we have reviewed
Physician’s have Scientific and Economic responsibilities
to Patient’s and to the Health Care system
• Physicians provide consultations, order tests, interpret
tests, offer management plans and treat patients
• Considerations for an Ethic-basedpractice in the “Omics” age world
Innovation and the order to conquer Innovation and the order to conquer
Information is not knowledgeInformation is not knowledge
Opinion is not scientific evidenceOpinion is not scientific evidence
Genes affect disease dynamics,
but the environment
determines how!
Genomics & Informatics applied Genomics & Informatics applied
for enhancing screening, diagnosis for enhancing screening, diagnosis
and to define the gene pathways and to define the gene pathways
and networks governing biological and networks governing biological
processes and diseases processes and diseases
Human Genome: Instruction manual for assembling the molecules that make different cells and also keep them alive and healthy!
Population Genetic Screening
in the “Omics-age”
Joaquin Santolaya-Forgas, MD,PhDProfessor of Obstetrics and Gynecology and Genetics
Section Head of Reproductive Genetics
RWJMS & JSUMC-Meridian Health Care System
Rutgers- Robert Wood Jonson Medical School
Cystic Fibrosis Carrier ScreeningGenetic variations affects the efficiency of Population genetic screening tests
(Platforms for 23 vs 32 vs 98 mutations; 23 are recommended by ACMG)
Mutation Rates of CF by Ethnic background: Heterogeneity
Ethnicity Carrier Frequency Detection%
Caucasian 1:25 88.2%
Ashkenazi Jewish 1:26 94%
African American 1:65 64.5%
Hispanic 1:46 71.2%
Asian American 1:90 48.9%
Jewish, non-Ashkenazi Varies by country of origin
Other or Mixed ancestry Varies by country of origin
CF is multisystem genetic disease in which abnormal chloride metabolism across membranes causes dehydrated
secretions (thick sticky mucous in lungs & pancreas) and high sweat chloride. Over 1300 mutations in CF
transmembrane conductance regulator (CFTR) gene that maps to chr7. Median survival: 40 years. Treatment with
pancreatic enzymes, high fat, high carb diet, respiratory therapy with chest percussion/ inhaled therapy/DNAse and
antibiotics. Males can be infertile due to congenital bilateral absence of the vas deferens (CBAVD).
Recurrence of Multifactorial disorders:
(Empiric data)
Recurrence Risk
Future Males Future Females
Normal Parents of
Defects 1 Affected Child
Cleft lip with or without cleft palate 4-5%
Cleft palate alone 2-6%
Cardiac defect (common types) 3-4%
Pyloric stenosis 3% 4% 2.4%
Hirschsprung anomaly 3-5%
Clubfoot 2-8%
Dislocation of hip 3% 0.5% 6.3%
NTD/ Meningomyelocele 3-5%
Scoliosis 0-15%
e.g. Congenital Rubellae.g. Congenital Rubella
Gestation (weeks) % affected fetuses overall risk of defects (% of those infected) Main manifestations
<11 100 90 brain, eye, heart
11-12 67 33 Deafness
13-14 67 11 Deafness
15-16 47 24 Deafness
17-36 37 0 None
>36 100 0 None
Phenocopies & Teratogenesis
COUNSELING!
Alpha Thal
Carrier
Beta Thal
Carrier
Sickle Cell
Carrier
MCV <80 <80 <80
Hb Type AA AA AS
Hb A2 <3% >4% >4%
Hb F Normal Elevated Elevated
Inherited Hemoglobin DisordersQuantitative α or β globin synthesis (Thalassemia's)
Qualitative β globin function due to aa substitution (SCD)
In USA: 60.000 individuals with SCD. 1/400 African-American newborn has SCD
Hb SS, Hb CC & Hb SC (Monogenic, A.R. Hemoglobin Disorders)
=+
Hb S Hb C-Harlem Hb SC
+=
ββββ6 Glu-LysWestern Africa
�Billiard ball cells�Folded cells
�Mitten shape
ββββ6 Glu-ValEastern Africa
�Sickle-like cells�Folded cells
Notes: ββββ6(A3) parentheses designate the helical segment and amino acid sequence in that segment affected
�Hb E (ββββ26 Glu-Lys) moves with Hb A2 in Hb Electrophoresis field (false high Hb A2)
Site of
Sickling
Clinical Features Symptomatic Management
Bone Painful crises Opiates and hydration,
Hydroxyurea
Lung Acute chest syndrome Blood Transfusions, folate, iron
chelation, Opiates and
hydration
Brain Stroke Blood Transfusions
Heart Myocardial infarction Blood Transfusions, Opiates and
hydration
Spleen Acute splenic sequestration Blood Transfusions, Opiates and
hydration
Spleen Hyposplenism Pneumococcal vaccination
(pneumovax)
Retina Proliferative retinopathy Retinal surveillance, Laser
Sickle Cell Anemia – Management
Hemopoietic cell based therapy using UCB banks: Celocentesis Vs. Post partum treatment
Malaria
Protozoan infection of the genus Plasmodium which
enters the bloodstream via the saliva of mosquito and
is captured by liver cells. After 1-week of proliferation
they are released and enter Red Cells through
receptor-mediated endocytosis and create vacuoles
(trophozoites) and feed on hemoglobin excreting
brownish ferri-heme
6 12 18 24 30 36
Birth
6 12 18 24 30 36 42 48
Spleen
Liver
Yolk Sac
10
20
30
40
50
Post-conception age (weeks ) Post-natal age (weeks)
% o
f t
ota
l glo
bin
sy n
thes
isE
ryth
ro-
po
i es i
s
ββββ
αααα
ϒϒϒϒ
εεεεςςςς
δδδδ
Bone Marrow
97% HbA (αααααααα2ββββββββ22) ; 3% ) ; 3% HbA2 (αααααααα2δδδδδδδδ2) ; HbF (αααααααα2ϒϒϒϒϒϒϒϒ2)
HbE: Gower I (ςςςςςςςς2εεεεεεεε2); II ((αααααααα2εεεεεεεε2); Portland (ςςςςςςςς2ϒϒϒϒϒϒϒϒ2)
Inherited Hemoglobin Disorders
Joint Center for Sickle Cell and Thalassemia Disorders: http://www-
rics.bwh.harvard.edu/sickle/ (Overview of sickle cell disease, thalassemia
and iron kinetics). The Sickle Cell Information Center, Emory University:
http://www.emory.edu:80/PEDS/SICKLE/
(Includes PowerPoint presentations on sickle cell disease)
Fragile X Syndrome (FXS): Screening?
In a 2009 survey of physician geneticists and genetic counselors, about 60% supported newborn screening for FXS but were less
supportive of identifying carriers. When asked to choose the best screening model, 29% selected pre-conception, 43% high-risk
populations and 28% did not endorse screening at this time
Acharya K, Ross LF. Fragile X screening: attitudes of genetic health professionals. Am J Med Genet A 2009;149A:626–32
ACMG and a joint statement by the Child Neurology Society and the American Academy of Neurology recommend test children with unexplained delays The National Society of Genetic Counselors and a mu lticenter working group of genetic counselors test possibly affected individuals followed by cascade testing of extended family members once a target individual has been confirmedAGOG test any child with developmental delay, autism, or autistic behavior and family; and offer carrier testing to women <40 years old with ovarian failure or an increased follicle-stimulating hormone levelThe American Academy of Pediatrics has no formal position on FX testing!
Which are the forces behind genetic variations?
Genetic drift: Deviation from the random proportional distribution of alleles from one
generation to the next in small populations (e.g. Frequency of Ellis van Creveld syndrome in PA - short stature, polydactyly and heart disease -)
Founder effect: Establishment of a deleterious rare allele at a relatively high frequency in
a small/isolated population derived from an ancestor (e.g. Huntington Disease in Maracaibo)
Inbreeding: Consanguineous mating (between relatives) increases homozygosity
NOTE: subpopulation stratification by selective mating (positive arrangements) continues to increase homozygous and the probability of distinct phenotypic traits
for recessive disorders in some groups
Natural selection: against Homozygous for a distinct allele and advantage for those
who are Heterozygous in a given environment that also produce more surviving offspring (e.g. frequency of the Sickle Cell gene mutation in Africa due to environmental Plasmodium falciparum)
Population bottle-neck: Alleles at a relatively high frequency in a population due to
historical population constrictions (e.g. frequency of Gaucher, Tay-Sachs, Torsion dystonia in the
Ashkenazi Jewish population)
Genetic polymorphism: Allele frequency greater than 1 in 100
• Natural selection: heterozygotes for some disease causing mutations may have survival advantage in certain ecosystems, becoming so common in the population that the frequency of the deleterious allele (disease causing mutation) fits the statistical definition of polymorphism
e.g. Htz. “carriers” for Cystic Fibrosis (North European descent) Htz. “carriers” for Sickle Cell Anemia (Western African descent)
ConditionCarrier
FrequencyCystic fibrosis 1:26Tay-Sachs disease 1:30Canavan disease 1:57Familial dysautonomia 1:30Bloom syndrome 1:100Fanconi anemia (Group C) 1:89Gaucher disease 1:15Glycogen storage disease type 1a 1:71Maple syrup urine disease (MSUD) 1:81Mucolipidosis type IV 1:122Niemann-Pick Type A 1:90
Conditions and Carrier Frequencies in the Ashkenazi Jewish Population
• Screening should be offered to all couples in which one partner has at least 1-Ashkenazi Jewish grandparent
• Screening should be offered to the partner with the Ashkenazi Jewish ancestry for most risk reduction benefit
Screening panels in Ashkenazi Jewish
population
“Population bottlenecks”
Genetic polymorphism: Allele
frequency > 1 in 100
Genetics of Consanguinity
� Consanguinity increases the risk for multifactorial and recessive disease. Carrier testing should be done as appropriate, based on family history and ethnicity of parents. If multiple loops are noted in the pedigree “closed paths between the consultand and partner” to calculate the coefficient of inbreeding (f)
� First degree relatives (incest between father-daughter or brother-sister)
• Up to 40% for a significant abnormality. AR disorders (~12%), congenital malformations/SIDS (~18%), nonspecific severe intellectual impairment (~12%) and mild intellectual impairment (~14%)
� Second degree relatives (usually uncle-niece or half siblings)
• No good published estimates and the risk is scalable with (f). The overall risk for congenital anomalies lies between the risk for 1st cousins and children of incest I.e., ~6%-18%
� Third degree relatives (usually first cousins) sharing 1/8 of their genes
• Congenital anomalies ~2-3% above the Wt population risk. Increased risk for mental retardation , genetic disease. And ~ 4% risk for infant mortality
Empiric risks in non-informative families
NOTE: Consanguineous marriages and endogamy present in up to 60% in some
populations (geographic regions)
Back ground Risk in general Population~ Estimates for AD (1%); AR (0.25%); X-L (0.2%);Chromosomal (1%); Congenital Malformations (3-5%)
• Q1. Chances for the fetus to inherit a recessive allele identical by descent from his great-grandfather at any genetic loci? : start from the consultand closing the loop to the fetus in question (1/2)4 or 1 in 16. The same can be said for the great-grandmother giving an overall risk of passing an allele identical by descent from the great-grandparents of 1/16 + 1/16 = 1/8 = number of shared genes for 1st cousins
• Q2. Chance that the great-grandmother passes the red allele to both of her grand children, and then that they each pass it to the fetus, (1/2)6 or 1 in 64
• Q3. The great-grandmothers risk of being a CF carrier (a-allele) is calculated from HWE = 1/25. The risk for a fetus inherits 2 mutant CF alleles that are identical by descent would be 1/25 x 1/64 = 1/1,600 in stead of 1/65 x1/65 x ¼ = 1 in 17,000 for AA population
Consanguineous Mating in non-informative families
Consanguineous = Term dates from the times when genetic determinants were believed to circulate in the blood – ‘bloodline’ meaning ancestry.
Consanguinity and inbreeding is one of the forces behind genetic stratification!
Consultand
1/21/2
1/2
IV
III
II
I
1/2
1/2
Cystic Fibrosis?
CaucasianAA
Thalassemia Iron Deficiency
RBC (3.7-5.3 x10E6/uL) N or
MCV (79-97 fL)
MCH (26.6-33 pg)
MCHC (31.5-35.7 g/dL)
Serum Fe (35-155 ug/dL) N or
Ferritin (15-150 ng/mL) N or
% Saturation (15-55) N or
TIBC (250-450 ug/dL) N or
Microcytic Anemia
EthnicitySickle
Cell TraitBeta
Thal TraitAlpha
Thal TraitWest African 1:6 1:50 1:30African American 1:12 1:75 1:30
Non-Hispanic Caribbean, West Indian 1:12 1:50-1:75 1:30Southern European 1:30-1:50 1:20-1:30 1:30-1:50Northern European rare rare rareAshkenazi Jewish rare rare rareHispanic Caribbean 1:30 1:75 variableHispanic Mexican, Central American 1:30-1:200 1:30-1:50 variableAsian rare 1:50 1:20Southeast Asian rare 1:30 1:20Asian Subcontinent (India, Pakistan), Middle Eastern 1:50-1:100 1:30-50 variable
Hemoglobinopathy Carrier Frequency by Ethnic backgr oundCarrier Rate for Inherited Hemoglobin Disorders240,000,000 SC carriers 200,000 Newborns with
SC Disease worldwide/year
Screening Recommendations!
1) Low Risk patients with MCV <80 must have Iron
studies and then Hb-Electrophoresis
2) High Risk group patients should have MCV & Hb-
Electrophoresis
3) Detection of SC/HbC mutation carriers requires
Hb-Electrophoresis
4) Carriers of Hb variants can have a normal MCV
Asymptomatic Mother with MCV of 69 & SC trait on Hb-Electrophoresis
ASC/A2
Mother
Familial Hemoglobin Disorders
Fragile X-linked Mental Retardation
Most common cause of inherited MR affecting 1:2,500-1:4,000 (IQ<50) males and 1:5,000-1:10,000 (IQ<70) females
Hyperkinetic /autistic
like behaviour/
learning disabilities
Macroorchidism
Induced by culturing in folate
depleted media in 60% cases
Likelihood of passing full mutation from mother to offspring increases with size of pre-mutation; 100% likelihood by 90 CGGs
Cytogenetic & Molecular Diagnosis
ACMG, 2008 suggested SMA Screening “ Drawbacks”
SMN - 1
Carrier of SMA
SMN - 1
SMN - 1
Non-Carrier of SMA
SMN - 1 SMN - 1
Carrier of SMA
CLINICAL TYPES of SMA•Type 1 is lethal in infancy•Types 2 and 3 are lethal in childhood/ young adulthood•Type 4 has onset in 4th or 5th decade with normal life expectancy
SMA A.R. disease: of progressive motor weakness from degeneration and loss of anterior horn cells (lower motor neurons) in the spinal cord and brain stem. SMN1 and SMN2 involved (~95% Hz deletions of exons 7 and 8 in SMN1 and 4-5% have a deletion on one chromosome and a point mutation on the other!
