Basic genetic evaluation in obstetrics

Yashodhara Pradeep Professor

Dept of Ob GynKing George Medical University

Lucknow

Obstetrician Gynecologist as Primary Genetic Counselors

• 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

• Chromosomal Abnormalities• Single Gene ( Mendelian ) Disorder • Non Mendelian Patterns of Inheritance• Molecular Genetics

Types & Frequency of Genetic Disease

• Chromosomal Disorder: 1.8 4• Single gene disorder 3.6 20• Multifactorial disease 48.4 646• Somatic cell genetic disorder ( cancer ) 240•

• Total 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

• 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 recognizableNumerical 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 GenesThe 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

• 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

• 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 X-

chromosome 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

• 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

• Organization of the Genomes• Coding DNA• Control OF Gene Expression• New Mutations and Gene REGULATION• Non Coding DNA• Genetic Tests

Genetic Test

• 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 reduction1. Review of medication for potential teratogenicity2. Review of immunization3. Cessation of Smoking4. Control of Diabetes 5. Control of HT6. Control of Infections eg UTI, PTB, 7. Control of Anemia8. Detection of HBSAg , HCV, HIV, VDRL