Transcript Basic genetic evaluation in obstetrics

Basic genetic evaluation in
obstetrics
Yashodhara Pradeep
Professor
Dept of Ob Gyn
King George Medical University
Lucknow
Obstetrician Gynecologist as Primary Genetic
Counselors
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Initiation of genetic counseling
Explain the Risk
Options for Genetic Testing
Referral to Genetic consultants
Basic Genetic Evaluation
• Medical genetics is the investigation of individual variation in
the incidence of susceptibility to disease, as well as disease
mechanism, response to therapy, and results of tests.
• 2-3 % Children born with a congenital birth defect, by age 18
Approximately 8% are discovered to have one or more
anomalies
• 2/3 of population will experience a disease with a genetic
component in their lifetime and if cancer included it is 91%
Family Medical History
• Spinal muscular atrophy ( SMA) Autosomal recessive neuro
muscular disorder mutation in SMN1 gene 1:10,000 birth
carrier frequecy 1:53 in Asians
• Carrier screening for Hemoglobinopathies
• Cystic Fibrosis
• Thrombophilias
• Fragile X syndrome (pre mutation FMR1 gene )
• Potential genetic risk to offspring
Referral to genetic counselor
Minimal Information to be given:
• Indication for referral
• Significant Medical History along with pertinent laboratory
test results
• Role of Genetic professionals Analysing pedigree data of three
generations (family information) risk assessment, tests
offered, patients uptake of testing, interpretation of results
molecular and genetic tests & provides genetic counseling and
prenatal diagnosis, follow up plan along with consultation
summary
Genetics In Obstetrics
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Chromosomal Abnormalities
Single Gene ( Mendelian ) Disorder
Non Mendelian Patterns of Inheritance
Molecular Genetics
Types & Frequency of Genetic Disease
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Chromosomal Disorder:
1.8
Single gene disorder
3.6
Multifactorial disease
48.4
Somatic cell genetic disorder ( cancer )
• Total
4
20
646
240
906/1000
Chromosomal disorder
• Chromosomal disorders are numerical and structural
• Duplication or deletion of chromosome or part of chromosome can be
associated with severe outcomes like mental retardation , minor or major
structural defects
• Balanced chomosomal rearrangements like reciprocal translocation or an
inversion are not associated with phenotypic abnormalities total DNA
content is not altered
• Conceptus with major chomosomal imbalance are spontaneously aborted
• Disorders caused by deletions cannot be diagnosed by traditional
cytogenetic techniques , they require FISH eg Prader-willi syndrome,
Angelman syndrome, William syndrome
Chromosomal Abnormalities
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Standard Nomenclature
Aneuploidy
Paternal Defects
Autosomal Trisomies
Sex Chromosome Abnormalities
Chromosomal Translocations
Chromosomal Deletions
Chromosomal Inversions
Ring Chromosomes
Chromosomal Mosaicism
Nomenclature
• Aneupolidy: Most common & easily recognizable
Numerical anomalis :
• N 46 XX or 46 XY
• 47 XX
• 47 XY,+21/46XY
• 46XY,del(4)(p14)
• Trisomy 21, 13, 18
• Monosomy Turner syndrome
• 47XXX, 47XXY, 47XYY,
• Polyploidy, Triploidy, Tetra ploides
Chromosomal translocations
• Reciprocal translocations
• Robertsonian translocations
• Isochromosomes 2q or2 p are fused together
Chromosomal Mosaicism
• Two or more cytogenetically distinct cell lines in the same
individual. Mosaic Down Syndrome one cell line with 47
chromosomes and a normal cell line with 46 chromosomes
• Phenotypic expression depends on many factors involvement
of only placenta, both placenta & fetus or fetus only
• Gonadal Mosaicism as a result of meiotic error in zygote
Achondroplasia, Osteogenesis imperfecta, X linked disease
Duchenne muscular dystrophy
Single gene disorder
• Disorder caused by defect (mutation) single gene or
monogenic disorder
• Follow Mendelian principles of inheritance
• More than 5000 monogenic disorders are identified
• These disorders are caused by various genes on autosomes,
sex chromosomes, or on the mitochondrial genome
• Monogenic disorders involving each system of the body, some
of them predominantly involve one system of body eg.
Thalassaemia, haemophilia, achondroplasia
• Monogenic disorders involveing many systems of body are
mucopolysaccharidosis, galactosemia, and mitochondrial
disorders
Single gene ( Mendelian ) Disorder
• Autosomal Dominant
• Autosomal Recessive
• Consanguinity
• Co- Dominant Genes
• X-linked & Y –linked Genes
The advance knowledge of pathogenesis of disease tells no
disease is monogenic many other genes and environmental
factors interact with diseases causing gene and modify the
phenotype
Single gene Mendelian Disorder
• Autosomal Dominant : Achondroplasia, Acute intermittent
porphyria, Adult polycystic kidney disease, BRACA1, BRCA2
Breast cancer, Familial hypercholesterolemia , Familial
hypertrophic cardiomyopathy, Marfan syndrome, Huntington
chorea , Myotonic dystrophy, Neurofibromatosis, etc
• Autosomal Recessive : Albinism, Cystic fibrosis, Deafness,
Sickle cell Anemia, Beta Thalassemia, inborn errors of
Metabolism
• X linked Chronic granulomatous disease, color blindness,
Fragile X syndrome, Hemophilia A& B, Testicular Feminization
• Risk of recurrence depends upon penetrance, variable
expressivity, anticipation
Characterestic of inheritance
• Autosomal Dominant:
• Successive or multiple generations are affected
• Both males and females are effected in equal proportions
• Both males and females can transmit the disease to their
offspring of either sex
• Risk of recurrence 50 %
• Examples ----Achondroplasia, Acute intermittent porphyria,
Adult polycystic kidney disease, BRACA1, BRCA2 Breast
cancer, Familial hypercholesterolemia , Familial hypertrophic
cardiomyopathy, Marfan syndrome, Huntington chorea ,
Myotonic dystrophy, Neurofibromatosis, etc
• Autosomal recessive :
• Both males and females are affected
• Disorder normally occurs in only one generation, usually with
in single sibship
• The parents can be consanguineous especially if the dis order
is rare
• Risk of recurrence parents are obligate carriers, the risk of
second child being affected is 25%, 50% will be carriers, high
chance of relatives are carrier
• If heterozygous of an autosomal disorder marries a normal
person 50% of his children will be hetrozygous like him but
there is no risk of having any affected child
Common AR diseases are
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Albinism
Congenital adrenal hyperplasia
Cystic fibrosis
Deafness
Friedreich ataxia
Homocystinuria
Hemochromatosis
Thalassemia Syndrome
Sickle cell Anemia
Phenylketonuria ( In born error of metabolism )
Taysachs diseases
Consanguinity and Autosomal recessive
inheritance
• Consanguineous couple means having common ancestor in
preceding five generations, the likelihood of their inheriting
an identical allele ( from their common ancestor) and passing
it to their child is high
• Sharing of Genes
• Mating between third degree relatives who share 1/16 of
genes EX mating between first cousin, a half uncle or aunt, a
half niece or nephew or more distantly related individual
• More common to produce Autosomal recessive or
multifactorial diseases like osteoporosis (3-17%),
Thalassaemia major (2-3%)
X-linked inheritance
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It is due to the presence of recessive genes on Xchromosomes
Females are carriers as homozygous mutations are rare
Males are affected almost exclusively
All affected males are related through unaffected females
(carriers)
• Male to male transmission is never observed because the Xchromosome in a male is always contributed by mother
• An effected male can pass on the disorder to his grandsons
through his unaffected carrier daughter
• Risk of Recurrence is variable 50% will be affected, 50%
daughter will be carrier, Mother carrier father affected, Father
is affected Mother is carrier
Non Mendalian Patterns of Inheritance
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Hereditary Unstable DNA
Imprinting
Uniparental Diasomy
Mitochondrial Inheritance
Polygenic and Multifactorial Inheritance
Non Mendelian Patterns of Inheritance
• Fragile X syndrome
• Myotonic Disorder
• Huntington disease
Molecular Genetics
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Organization of the Genomes
Coding DNA
Control OF Gene Expression
New Mutations and Gene REGULATION
Non Coding DNA
Genetic Tests
Genetic Test
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Cyto genetic tests
FISH
Spectral Karyotype Analysis
Linkage analysis RELPs, STRs
Complementary DNA
Fluorescence- activated Chromosome sorting
Gel separation
PCR
Southern blot
MLPA
Types of Problems in Morphogenesis
• Malformation
• Deformation
• Disruption
Preconceptional Counseling
• Diet & Nutrition
• Risk reduction
1. Review of medication for potential teratogenicity
2. Review of immunization
3. Cessation of Smoking
4. Control of Diabetes
5. Control of HT
6. Control of Infections eg UTI, PTB,
7. Control of Anemia
8. Detection of HBSAg , HCV, HIV, VDRL