Prenatal Diagnosis of Genetic Disease

Dr. Arvind Kumar

Introduction

  • Prenatal diagnosis refers to medical tests performed during pregnancy to detect genetic, chromosomal, and congenital abnormalities in the fetus.

  • These diagnostic methods help identify inherited disorders and developmental defects before birth.

  • Advances in genetics, molecular biology, and imaging techniques have greatly improved the accuracy of prenatal diagnosis.

  • Early detection allows timely medical intervention, appropriate pregnancy management, and informed parental decision-making.

  • Prenatal diagnosis plays a crucial role in reducing neonatal morbidity and mortality associated with genetic diseases.

  • It also provides an opportunity for genetic counseling, helping families understand risks, prognosis, and future reproductive options.

  • With increasing awareness and availability of advanced tests, prenatal diagnosis has become an integral part of modern antenatal care.

 

Genetic Diseases 

Prenatal diagnostic techniques help in early identification of a wide spectrum of genetic and congenital disorders. These diseases can be broadly classified into the following categories:

Chromosomal Disorders

These result from numerical or structural abnormalities of chromosomes and are among the most commonly detected prenatal conditions.

  • Down syndrome (Trisomy 21)

  • Edwards syndrome (Trisomy 18)

  • Patau syndrome (Trisomy 13)

  • Turner syndrome (45,X)

  • Klinefelter syndrome (47,XXY)

  • Structural rearrangements (deletions, duplications, translocations)

Detected by:

  • NIPT

  • Amniocentesis

  • Chorionic villus sampling

  • Karyotyping / FISH

Single-Gene (Mendelian) Disorders

These are caused by mutations in a single gene and follow Mendelian inheritance patterns.

Autosomal Recessive Disorders

  • Thalassemia

  • Sickle cell anemia

  • Cystic fibrosis

  • Phenylketonuria

Autosomal Dominant Disorders

  • Achondroplasia

  • Osteogenesis imperfecta

X-Linked Disorders

  • Hemophilia

  • Duchenne muscular dystrophy

Detected by:

  • PCR-based tests

  • DNA mutation analysis

  • Next-generation sequencing

Congenital Structural Anomalies

These involve abnormal development of organs or body structures.

  • Neural tube defects (spina bifida, anencephaly)

  • Congenital heart diseases

  • Cleft lip and palate

  • Skeletal dysplasias

  • Renal malformations

Detected by:

  • Ultrasonography

  • Fetal anomaly scan

  • Maternal serum markers

Inherited Metabolic Disorders

These result from enzyme deficiencies affecting metabolism.

  • Maple syrup urine disease

  • Galactosemia

  • Tay-Sachs disease

  • Urea cycle disorders

Detected by:

  • Enzyme assays

  • Molecular genetic testing

  • Targeted mutation analysis

Sex-Linked and Sex Determination Disorders

  • Disorders of sex development

  • X-linked genetic diseases (for carrier mothers)

Detected by:

  • Fetal karyotyping

  • Molecular sex determination

 

Methods of Prenatal Diagnosis

Prenatal diagnosis involves a variety of screening and diagnostic techniques used during pregnancy to detect genetic, chromosomal, and structural abnormalities in the fetus. These methods are broadly classified into non-invasive and invasive techniques.

A. Non-Invasive Prenatal Diagnostic Methods

These tests are safe and performed routinely during pregnancy.

Ultrasonography (USG)

  • First-trimester dating scan

  • Nuchal translucency (NT) measurement

  • Detection of fetal structural anomalies

  • Assessment of fetal growth and development

Detects:

  • Neural tube defects

  • Congenital heart defects

  • Skeletal abnormalities

Maternal Serum Screening

Biochemical markers measured in maternal blood.

  • Double test (β-hCG, PAPP-A)

  • Triple test (AFP, β-hCG, unconjugated estriol)

  • Quadruple test (Triple test + inhibin A)

Used for screening:

  • Down syndrome

  • Trisomy 18

  • Neural tube defects

Non-Invasive Prenatal Testing (NIPT)

  • Based on cell-free fetal DNA in maternal blood

  • Can be done after 10 weeks of gestation

  • Very high sensitivity and specificity

Detects:

  • Trisomy 21, 18, 13

  • Sex chromosome abnormalities

B. Invasive Prenatal Diagnostic Methods

These tests provide definitive diagnosis.

Chorionic Villus Sampling (CVS)

  • Performed at 10–12 weeks

  • Placental tissue is sampled

  • Early diagnosis possible

Used for:

  • Chromosomal analysis

  • Single-gene disorders

  • DNA mutation testing

Amniocentesis

  • Performed at 15–20 weeks

  • Amniotic fluid containing fetal cells is analyzed

Gold standard for:

  • Karyotyping

  • Neural tube defect detection

  • Inherited metabolic disorders

Cordocentesis

  • Fetal blood obtained from umbilical cord

  • Used when rapid diagnosis is needed

Used for:

  • Hematological disorders

  • Fetal infections

  • Rapid chromosomal analysis

C. Molecular and Cytogenetic Techniques Used

  • Karyotyping

  • Fluorescence in situ hybridization (FISH)

  • Polymerase chain reaction (PCR)

  • Chromosomal microarray

  • Next-generation sequencing (NGS)

 

Laboratory Techniques

Laboratory techniques form the backbone of prenatal diagnosis by enabling accurate detection of chromosomal, genetic, and metabolic abnormalities. These methods analyze fetal cells or fetal DNA obtained through invasive or non-invasive procedures.

Karyotyping

  • Microscopic analysis of fetal chromosomes

  • Detects numerical and structural chromosomal abnormalities

  • Requires cultured fetal cells

Detects:

  • Trisomy 21, 18, 13

  • Turner syndrome

  • Translocations and deletions

Sample:

  • Amniotic fluid

  • Chorionic villi

  • Fetal blood

Fluorescence In Situ Hybridization (FISH)

  • Uses fluorescent DNA probes targeting specific chromosomes

  • Provides rapid results (24–48 hours)

Detects:

  • Common aneuploidies

  • Microdeletions

  • Sex chromosome abnormalities

Advantage: Faster than karyotyping
Limitation: Cannot detect all chromosomal changes

Polymerase Chain Reaction (PCR)

  • Amplifies specific DNA sequences

  • Highly sensitive and specific

Used for:

  • Single-gene disorders

  • Point mutations

  • Carrier detection

Detects:

  • Thalassemia

  • Sickle cell anemia

  • Cystic fibrosis

Chromosomal Microarray Analysis (CMA)

  • High-resolution technique analyzing copy number variations (CNVs)

  • Does not require cell culture

Detects:

  • Submicroscopic deletions and duplications

  • Unexplained developmental anomalies

Advantage: Higher resolution than karyotyping
Limitation: Cannot detect balanced translocations

Next-Generation Sequencing (NGS)

  • Massively parallel DNA sequencing

  • Allows whole-exome or targeted gene analysis

Used for:

  • Rare genetic disorders

  • Multiple gene mutations

  • Complex syndromes

Advantage: Comprehensive genetic analysis
Limitation: High cost and complex interpretation

Biochemical and Enzyme Assays

  • Measure enzyme activity or metabolite levels

  • Useful in diagnosing inherited metabolic disorders

Detects:

  • Phenylketonuria

  • Galactosemia

  • Urea cycle defects

 

MCQs

1. Prenatal diagnosis is mainly performed to detect:

A. Maternal infections
B. Genetic and chromosomal disorders
C. Postnatal diseases
D. Nutritional deficiencies

Answer: B

2. The safest prenatal diagnostic technique is:

A. Amniocentesis
B. CVS
C. Cordocentesis
D. Ultrasonography

Answer: D

3. Nuchal translucency measurement is done during:

A. Second trimester
B. Third trimester
C. First trimester
D. Postnatal period

Answer: C

4. Down syndrome is caused by:

A. Trisomy 18
B. Trisomy 21
C. Trisomy 13
D. Monosomy X

Answer: B

5. The most common chromosomal abnormality detected prenatally is:

A. Turner syndrome
B. Klinefelter syndrome
C. Down syndrome
D. Edwards syndrome

Answer: C

6. Which test detects cell-free fetal DNA?

A. Triple test
B. Amniocentesis
C. NIPT
D. CVS

Answer: C

7. NIPT can be performed after:

A. 6 weeks
B. 8 weeks
C. 10 weeks
D. 20 weeks

Answer: C

8. Chorionic villus sampling is usually done at:

A. 6–8 weeks
B. 10–12 weeks
C. 15–18 weeks
D. After 20 weeks

Answer: B

9. Sample used in amniocentesis is:

A. Placental tissue
B. Fetal blood
C. Amniotic fluid
D. Maternal serum

Answer: C

10. Gold standard test for fetal karyotyping is:

A. Ultrasonography
B. Amniocentesis
C. NIPT
D. Double marker test

Answer: B

11. Cordocentesis is also known as:

A. CVS
B. PUBS
C. Amniocentesis
D. FISH

Answer: B

12. Triple test includes all EXCEPT:

A. AFP
B. hCG
C. Unconjugated estriol
D. Inhibin A

Answer: D

13. Quadruple test includes:

A. AFP, hCG, Estriol
B. AFP, hCG, Estriol, Inhibin A
C. AFP only
D. hCG only

Answer: B

14. Neural tube defects are best detected by:

A. FISH
B. Ultrasonography
C. PCR
D. NIPT

Answer: B

15. Which marker is increased in neural tube defects?

A. hCG
B. Estriol
C. AFP
D. Inhibin A

Answer: C

16. Turner syndrome karyotype is:

A. 47,XXY
B. 46,XX
C. 45,X
D. 47,XXX

Answer: C

17. Klinefelter syndrome is:

A. 45,X
B. 46,XY
C. 47,XXY
D. 47,XYY

Answer: C

18. Which technique detects microdeletions?

A. Karyotyping
B. PCR
C. Chromosomal microarray
D. Ultrasonography

Answer: C

19. FISH is mainly used for:

A. Whole genome sequencing
B. Rapid aneuploidy detection
C. Enzyme estimation
D. Protein analysis

Answer: B

20. PCR is mainly useful for detecting:

A. Structural anomalies
B. Enzyme activity
C. Single-gene disorders
D. Gross chromosomal changes

Answer: C

21. Thalassemia is diagnosed prenatally by:

A. Ultrasonography
B. PCR
C. AFP estimation
D. NT scan

Answer: B

22. Inherited metabolic disorders are detected by:

A. Enzyme assays
B. Ultrasonography
C. NT scan
D. Triple test

Answer: A

23. Which test carries the highest fetal risk?

A. Ultrasonography
B. NIPT
C. Amniocentesis
D. Cordocentesis

Answer: D

24. CVS sample is obtained from:

A. Amniotic fluid
B. Placenta
C. Umbilical cord
D. Maternal blood

Answer: B

25. A screening test gives:

A. Definitive diagnosis
B. Risk estimation
C. Treatment plan
D. Cure

Answer: B

26. Definitive diagnosis is provided by:

A. Screening tests
B. Invasive diagnostic tests
C. Ultrasonography only
D. Serum markers

Answer: B

27. Advanced maternal age is defined as:

A. >25 years
B. >30 years
C. >35 years
D. >40 years

Answer: C

28. Which disorder is X-linked?

A. Thalassemia
B. Cystic fibrosis
C. Hemophilia
D. Down syndrome

Answer: C

29. Duchenne muscular dystrophy is:

A. Autosomal recessive
B. Autosomal dominant
C. X-linked recessive
D. Mitochondrial

Answer: C

30. Balanced translocations are best detected by:

A. CMA
B. PCR
C. Karyotyping
D. NGS

Answer: C

31. NIPT is:

A. Diagnostic
B. Invasive
C. Screening
D. Therapeutic

Answer: C

32. First-trimester screening includes:

A. Triple test
B. NT scan + Double test
C. Quadruple test
D. AFP only

Answer: B

33. Amniocentesis is contraindicated before:

A. 8 weeks
B. 10 weeks
C. 14 weeks
D. 20 weeks

Answer: C

34. Which disorder results from enzyme deficiency?

A. Down syndrome
B. PKU
C. Turner syndrome
D. Edwards syndrome

Answer: B

35. Galactosemia is diagnosed by:

A. Karyotyping
B. Enzyme assay
C. NT scan
D. AFP

Answer: B

36. Most accurate test for chromosomal aneuploidy:

A. Double test
B. NIPT
C. NT scan
D. AFP

Answer: B

37. Main limitation of NIPT:

A. High cost
B. Risk of miscarriage
C. Poor sensitivity
D. Invasive

Answer: A

38. Ethical issue in prenatal diagnosis includes:

A. Sample collection
B. Genetic counseling
C. Pregnancy termination
D. Test accuracy

Answer: C

39. Genetic counseling is important to:

A. Perform tests
B. Interpret risks
C. Treat fetus
D. Replace diagnosis

Answer: B

40. Which test detects fetal anemia?

A. Amniocentesis
B. Cordocentesis
C. NIPT
D. NT scan

Answer: B

41. AFP is produced by:

A. Placenta
B. Maternal liver
C. Fetal liver
D. Amniotic sac

Answer: C

42. CMA cannot detect:

A. Microdeletions
B. Copy number variations
C. Balanced translocations
D. Duplications

Answer: C

43. NIPT sample is:

A. Amniotic fluid
B. Placental tissue
C. Maternal blood
D. Fetal blood

Answer: C

44. FISH uses:

A. Enzymes
B. Fluorescent probes
C. Antibodies
D. Proteins

Answer: B

45. Neural tube defects occur due to deficiency of:

A. Vitamin B12
B. Vitamin D
C. Folic acid
D. Vitamin C

Answer: C

46. Turner syndrome patients are:

A. Male
B. Female
C. Hermaphrodite
D. Intersex

Answer: B

47. Most common indication for prenatal diagnosis:

A. Infection
B. Family history
C. Advanced maternal age
D. Malnutrition

Answer: C

48. NIPT cannot detect:

A. Trisomy 21
B. Trisomy 18
C. Structural malformations
D. Sex chromosome abnormalities

Answer: C

49. Prenatal diagnosis helps in:

A. Treatment only
B. Risk prediction only
C. Informed decision-making
D. Preventing pregnancy

Answer: C

50. Ultimate goal of prenatal diagnosis is:

A. Detect disease
B. Reduce fetal mortality
C. Improve maternal care
D. All of the above

Answer: D