Clinical genetics is one of the most rapidly advancing fields in medicine. Spectacular progress has been achieved in this century with unravelling of the entire draft sequence of the human genome. A major contribution of these advances has been in diagnosis, management and prenatal diagnosis of genetic disorders as treatment in most cases is difficult or impossible and where available beyond the means of most families. Genetic technology is advancing rapidly, bringing new, safer and more sensitive ways to diagnose genetic conditions pre- and postnatally. These advances will bring about profound changes in the way we deliver obstetric services to women and their families. Diagnosing a genetic disorder not only allows for disease-specific management options but also has implications for the affected individual's entire family. Hence, a working understanding of the underlying concepts of genetic disease is important for all practicing clinicians. Although it is impossible to know all aspects of clinical and molecular genetics, basic knowledge of certain topics is a must for all practicing obstetrician/gynecologists.

1.
ESSENTIA
AL GENETTICS FOR O
OBSTETRICCIANS

2. Review Article
BACKGROUND
Genetic diseases are not as rare as once believed. In fact,
genetic disease is a major cause of illness and death.
Approximately 2% to 3% of all pregnancies result in a
neonate with a serious genetic disease or a birth defect that
can cause disabilities, mental retardation, and in some cases
early death. Genetic factors are present from conception,
and their expression may vary throughout development,
whereas environmental influences are changing constantly.
Many conditions previously thought to be nongenetic are
now understood to be multifactorial diseases with the
contribution of various genetic and environmental
determinants being recognized increasingly.
A genetic disorder is a disease that is caused by an
abnormality in an individual’s DNA. Abnormalities can
range from a small mutation in a single gene to the addition
or subtraction of an entire chromosome or set of
chromosomes. Genetically determined disorders often are
subdivided into 3 major groups: single gene, chromosome,
and multifactorial (polygenic) diseases. Somatic cell
genetic defects play a role in human cancer and constitute a
fourth group.
Single-gene disorders
This type is caused by changes or mutations that occur
in the DNA sequence of one gene. Individually single gene
disorders are rare (1 in 10,000-15,000) but collectively they
can affect upto 1-2% of all births. Some conditions are
highly prevalent in selected populations like sickle cell
disease in Africans, thalassemia in the geographical belt
extending from the Mediterranean countries to South East
Asia. Since the late 1970s, the number of disorders
classified as single gene has increased from an estimated
2500 to approximately 14,000 (as ofApril 2003). Of these
14,000 single gene disorders, 93.7% are classified as
autosomal, 5.6% as X-linked, and 0.7% as other [1].
Considering that the human genome consists of
approximately 30,000 genes, the number of diseases
classified as monogenic is expected to increase. Compared
to general population, the risk of occurrence of genetic
diseases in affected families is very high depending on the
pattern of inheritance. However, previous occurrence of
the disease in the family is not necessary. The defect may
arise de novo for the first time in any individual or there
may be silent carriers in the family who give birth to an
affected child without a positive family history (autosomal
recessive disorder). The four most common patterns of
mendelian inheritance are based primarily on two factors:
on which type of chromosome (autosome or sex
chromosome) the gene locus is found and whether the
phenotype is expressed only when both chromosomes of a
pair carry the abnormal allele (recessive) or whether the
phenotype can be expressed when just one chromosome
carries the mutant allele (dominant). Single-gene disorders
are inherited in recognizable patterns: autosomal
dominant, autosomal recessive, and X-linked.
If a person carries the dominant gene for a disease, he
251 Apollo Medicine, Vol. 6, No. 3, September 2009
ESSENTIAL GENETICS FOR OBSTETRICIANS
Neerja Gupta
Consultant Clinical Genetics, Department of Genetics, Indraprastha
Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India.
e-mail- neerjaagarwal@yahoo.co.in
Clinical genetics is one of the most rapidly advancing fields in medicine. Spectacular progress has been
achieved in this century with unravelling of the entire draft sequence of the human genome. A major
contribution of these advances has been in diagnosis, management and prenatal diagnosis of genetic
disorders as treatment in most cases is difficult or impossible and where available beyond the means of most
families. Genetic technology is advancing rapidly, bringing new, safer and more sensitive ways to diagnose
genetic conditions pre- and postnatally. These advances will bring about profound changes in the way we
deliver obstetric services to women and their families. Diagnosing a genetic disorder not only allows for
disease-specific management options but also has implications for the affected individual’s entire family.
Hence, a working understanding of the underlying concepts of genetic disease is important for all practicing
clinicians. Although it is impossible to know all aspects of clinical and molecular genetics, basic knowledge of
certain topics is a must for all practicing obstetrician/gynecologists.
Key Words: Genomics, Prenatal diagnosis, Genetics, Genetic disorders.

3. Apollo Medicine, Vol. 6, No. 3, September 2009 252
Review Article
or she will usually have the disease and each of the person’s
children will have a 1 in 2 (50%) chance of inheriting the
gene and getting the disease. Diseases caused by a
dominant gene include achondroplasia (a form of
dwarfism), Marfan syndrome (a connective tissue
disorder), and Huntington disease (a degenerative disease
of the nervous system).
People who have one recessive gene for a disease are
called carriers, and they don’t usually have the disease but
they are at risk of producing children with autosomal
recessive diseases (Fig. 1) such as Cystic fibrosis, Sickle
cell anemia , and thalassemia are caused by recessive
disease genes from both parents coming together in a child.
Some recessive genetic variants are carried only on the
X chromosome, which means that usually only boys can
develop the disease because they have only one X
chromosome. Girls have two X chromosomes, so they
would need to inherit two copies of the recessive gene to get
the disease. Examples are hemophilia and Duchenne
muscular dystrophy.
In X-linked dominant inheritance, both male and
female children have a 1 in 2 risk of inheriting the mutant
allele from the affected mother and thus being affected as
well. Sons of an affected male do not inherit the condition,
whereas all daughters are affected clinically.
Chromosomal
Chromosomes are carriers of genetic material. Any
abnormality in chromosome structure as missing or extra
copies or gross breaks and rejoining (translocations) can
result in disease.
Some chromosome anomalies are “balanced” and
include the full complement of genetic material in a
rearranged form. Although balanced rearrangements have
been associated with infertility and medical complications
(perhaps because of breakpoints in important genes or
secondary to positional effects of gene expression), most
people with balanced chromosome rearrangements are
healthy.
Statistically, numerical chromosome abnormalities are
the most common type of chromosome disorder.
Chromosome aneuploidy occurs when there is other than a
multiple of the typical haploid set. About 60% of the
chromosomal abnormalities are spontaneously aborted in
the first trimester. This prevalence goes down
approximately 5% in the late abortions and stillbirths. At
birth, only 0.6% of the newborns have been found to have a
chromosomal abnormality.Although trisomy 16 is the most
common autosomal trisomy in miscarriages, trisomies 21
(Down syndrome), 18 (Edwards syndrome), and 13 (Patau
syndrome) are seen at considerable frequencies in
newborns. Of these, Down syndrome or trisomy 21 is the
commonest one. Notably, the risk of having a newborn with
any of these chromosome trisomies increases with maternal
age, although not all chromosome aneuploidy is associated
with maternal age. Turner syndrome (45, X) is most often
caused by loss of the paternal X chromosome and is present
in 1% of all conceptions; however, 98% result in
miscarriage. Chromosome polyploidy occurs when the
number of chromosome sets is other than two. The most
common type of chromosome polyploidy is triploidy (69
chromosomes), present in 1% to 3% of all conceptions.
Triploidy is a sporadic occurrence and most commonly
happens when 1 haploid egg is fertilized by 2 haploid
sperm.
Another group of chromosome disorders includes those
resulting in genetic imbalance despite retention of the
normal number of 46 chromosomes. This group includes
chromosome translocations in their unbalanced form,
deletions, and duplications. In these situations, there is
some net loss or gain of genetic material.
Chromosomal disorders are often suspected by the
presence of mental retardation, facial dysmorphism,
multiple congenital abnormalities, and failure to thrive.Fig.1. Autosomal recessive inheritance

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253 Apollo Medicine, Vol. 6, No. 3, September 2009
Standard chromosome analysis using G-banding allows
only the detection of relatively large structural rearrange-
ments (3-4 megabases) and depends on the band resolution.
Multifactorial
Many genetic disorders appear familial but do not
follow a single gene pattern of inheritance. These
multifactorial (polygenic, complex) disorders are the result
of a combination of alterations in multiple genes with
varying degrees of effect that act in concert with
environmental factors, thus producing a clinical phenotype
when a developmental threshold is reached [2]. These
disorder occur with high frequency in close relatives as
compared to the general population. Examples include
heart disease, hypertension, Alzheimer’s disease, arthritis,
diabetes, and obesity. Another important group of
multifactorial disorders is congenital malformation. Recent
advances in various molecular techniques like array CGH
etc have opened the possibility of identifying major genes
that can predispose to these disorders.
Genetic Counseling
An accurate diagnosis of the disorder is very essential
for any genetic counseling [3-5]. It is defined as “the
process by which patients or relatives at risk of a disorder
are advised of the consequences of the disorder, the
probability of developing and transmitting it, and ways in
which this can be ameliorated” [1]. It also helps the
individual or family to choose a course of action which
seems to them appropriate in view of their risk, their family
goals, and their ethical and religious standards and act in
accordance with the decision and also to make the best
possible adjustments to the disorder in an affected family
member and/ or to the risk of recurrence of that disorder.
There are certain situations which can be identified
before or after conception in which genetic counseling and
prenatal diagnosis may be required. These indications are
• Advanced maternal age (>35 years)
• Recurrent miscarriages (3 or more) / Infertility /
primary ammennorhea
• Previous child with
– dysmorphism /single or multiple malformations
like cardiac renal, brain defects/short stature/
neuromuscular disorder/neurogenetic disorder/
Metabolic disorder/Unexplained MR/Cerebral
Palsy / autism / Chromosomal abnormality /
Deafness/ thalassemia/Hemophilia
• Previous unexplained still birth/s, neonatal or
infantile deaths with or without congenital
malformations
• Family history of a genetic disorder like any
chromosomal abnormality like Down syndrome,
thalassemia, spinal muscular atrophy, hemophilia,
congenital deafness or Gaucher disease
• Consanguinity especially with a history of suspected
genetic disorder
• Maternal disease like diabetes, hypothyroidism to
identify high risk fetuses through level II ultrasound
• Positive maternal serum screen either first or second
trimester/Abnormal fetal ultrasound
• Exposure to known or suspected teratogen during
pregnancy
• Amniotic fluid abnormalities in second/third trimester
especially in association with growth retardation
• Maternal Infection (TORCH infection)
Steps in an antenatal case Management [3,4]
The skills required to make a genetic diagnosis are
similar to those used for more common health problems,
including history taking, physical examination, and proper
laboratory testing.
History- The pregnancy history of the patient’s mother
might disclose maternal disease potentially causative of or
related to the fetal condition, as seen in certain metabolic
disorders such as untreated maternal PKU or fatty acid
oxidation disorders. Sometimes, maternal disorders
(diabetes) environmental or drug exposures (valproate,
warfarin etc) during pregnancy can cause multiple
malformations such as in fetal valproate syndrome or
warfarin embryopathy. Medical history of maternal
disorders like SLE, hypothyroidism is also important for
better fetal outcome.
Family History - A thorough family history includes
detailed information on relatives’ ages, current and past
medical health (including developmental or learning
problems), birth defects, obvious dysmorphism, and
surgeries. Specifically, questions about miscarriages,
stillbirths, and infant deaths, as well as infertility, should be
asked. For deceased family members, age and cause of
death should be documented. The racial and ethnic
background is of importance in identifying higher risk
groups. In addition, the possibility of consanguinity in the
family history should be explored when clinically relevant.
Drawing a family tree (pedigree) that symbolically (Fig.2)

5. Apollo Medicine, Vol. 6, No. 3, September 2009 254
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represents the family and demonstrates relationships
between affected family members is an efficient and highly
informative exercise.
History of any genetic disorders in the family- Family
photographs or medical records may be of help, particularly
if other family members are suspected to have the same
genetic disorder.
Examination of the couple is required especially when
there is a family history of a particular genetic disorder like
neurofibromatosis, tuberous sclerosis, or incontinentia
pigmenti.
Investigations are done based on the indications apart
from routine antenatal screening.
Specialized investigation
The importance of precise diagnosis for genetic
counseling cannot be over emphasized. However,
specialized tests like chromosomal analysis, enzyme
analysis, and DNA analysis are required to arrive at a final
diagnosis. Before these tests are ordered, information
should be obtained on the type and volume of the specimen
required (blood, urine, fibroblasts, amniocytes), type of
tube in which the specimen should be kept, and
conditions under which the specimen should be sent
(Appendix- A).
DNA based tests (Molecular tests)
DNA testing investigates alterations in a gene that result
in disease. Confirmed molecular diagnosis in index case
would also help in carrying out prenatal diagnosis (by
amniocentesis or chorionic villi sampling) for the
respective disorder. Unless the type of mutation/s in the
proband or carrier parents is identified, prenatal diagnosis
is not feasible. It should preferably be identified before next
pregnancy. Examples of widely available molecular
genetic tests include thalassemias , muscular dystrophies,
spinal muscle atrophy, Fragile X syndrome, hemophilia A
and B, cystic fibrosis, albinism, achondroplasia etc.
Chromosomal analysis (Cytogenetics)
Chromosomal abnormalities can be diagnosed after
birth using a blood test, or before birth using prenatal tests
(amniocentesis or chorionic villi sampling). Tissues most
commonly used are lymphocytes and amniocytes. Any
abnormal finding has its own implication and management.
Cytogenetic analysis on bone marrow also helps in
diagnosis and prognosticating, especially in cancers. It
takes on average 1 to 3 weeks to obtain a definitive result,
the time depending on the method.
Newer diagnostic techniques include: (i) Rapid-FISH
(rapid fluorescence in situ hybridization); (ii) MLPA
(multiple ligation PCR amplification), and (iii) QF-PCR
(Quantitative Fluorescent Polymerase Chain Reaction).
These methods of analysis do not require culturing, the
amount of the sample material may be very small and the
result is obtained in just few days. In comparison, classical
cytogenetic analysis (karyotyping) after amniocentesis
requires 15-20 mL of amniotic fluid, culturing of fetal cells
(amniocytes) and takes around 10 to 21 days to produce the
result.
Biochemical testing
Biochemical testing refers to analyses of metabolites
that are either the substrates or the products of a deficient
enzyme. Thus, increases or decreases of metabolite
concentrations are indirect indicators of metabolic
disorders caused by an enzyme deficiency.If abnormal
metabolites are identified, the disease may then be
confirmed by enzyme analysis when available like in
mucopolysacharidoses, Gaucher disease, Tay Sachs
disease, etc. Enzyme analysis often requires a fibroblast
culture or a fresh liver biopsy. Some enzyme tests can be
done on serum, red blood cells, or leukocytes.
PRENATAL SCREENING AND DIAGNOSIS
Prenatal diagnosis must be considered in the contest of
Fig.2. Commonly used pedigree symbols

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255 Apollo Medicine, Vol. 6, No. 3, September 2009
the entire situation – the risk of disease in the baby,
confirmed diagnosis in affected child/carrier status in
parents, availability of treatment for the disease in question
and above all the wish of the couple. Ideally the discussion
and planning should start pre-pregnancy which is
invariably not the case in our situation. Prenatal diagnostic
techniques are shown in Table 1 & 2.
Prenatal screening for common chromosomal
disorders has good sensitivity using maternal serum
biochemical markers and ultrasonography.
Maternal serum screening should be a routine
prenatal test to determine the risk of anenploidies and
certain malformations like neural tube defects. Earlier,
maternal serum screening was classically done in the
second trimester but now first trimester screen has been
found to be more effective and useful.
Second trimester screen can be done between 15-22
weeks of pregnancy, however, it is best preferred at 16 -18
Table 1. Prenatal Screening/ Diagnostic Techniques
(i) Noninvasive techniques : Timing
(a) Maternal serum screening
– First trimester (PAPP-A& free BetaHCG) 11-13+6wk
– Second Trimester
Triple test (AFP, HCG, unconjugated estriol) 16-18weeks
Quadruple screen (AFP, HCG, unconjugated estriol &inhibinA) 16-18weeks
(b) Fetal inspection by
– Fetal ultrasonography (USG)
First trimester (NT& Newer markers) 11-13+6wk
Second Trimester (Anomaly scan) 18-20weeks
– Fetal echocardiography 18-20weeks
– Fetal MRI >26weeks
(ii) Invasive techniques
– Chorionic villus sampling (CVS) 11-13weeks
– Amniocentesis 16-18weeks
– Cord blood sampling >18weeks
– Fetal skin, liver or muscle biopsy 18-20weeks
Table 2 Compares various invasive techniques
Procedure Risk Timings Indications*
Amniocentesis Fetal loss 0.5-1% 16-18 weeks Cytogenetic
Amniotic fluid leak Molecular
Respiratory problem Biochemical
TORCH infections
CVS Fetal loss 1.5-2% 11-13 weeks Molecular
Fetomaternal hemorrhage Biochemical Cytogenetic
Cordocentsis Fetal loss 2-3% after 18 weeks Hematological
Infections
Cytogenetics
Molecular
* Any of the samples obtained by fetal sampling can be used for cytogenetic, molecular or biochemical tests but CVS
sample is a desired sample for DNAbased tests where as amniotic fluid is preferred for cytogenetic analysis.

7. Apollo Medicine, Vol. 6, No. 3, September 2009 256
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weeks. Commonly used 2nd trimester markers are maternal
serum alphafetoprotein (MSAFP), human Chorionic
gonadotropin (hCG) and estriol (the triple screen). MSAFP
and estriol is low and hCG is high in the maternal serum if
the mother is carrying a Down syndrome fetus. A positive
screen is when the risk of Down syndrome is 1 in 250
(which means if 250 women have the given screen
parameters one would have a baby with Down syndrome).
High MSAFP (>2.5 MoM) can identify over 95% of
anencephaly and 75% of open spina bifida cases. Use of
three markers for Down syndrome screening will give a
maximum detection rate of around 70%.This approach will
also result in detection of approx. 50 % of al cases of
trisomy 18.
Quadruple Test
Addition of a 4th biochemical marker, Inhibin-A,
(increased in DS pregnancies) in the second trimester
screen, increases the sensitivity of screening for DS from
60% to 75%.
First Trimester Screening
Although many markers have been studied in the first
trimester two robust markers suggested are free hCG and
pregnancy associated plasma protein A (PAPP-A). Free
hCG has been found to be elevated with the median MoM
values of 2.15, almost similar to the second trimester.
PAPP-A values are low with the median MoM of around
0.45-0.51, this alteration is not seen in the second trimester
.Based on the available data the detection rates using these
two markers varies between 60-67% with a false positive
rate of 5%. Detection of trisomy 18 and 13 has also been
reported by first trimester screening with good detection
rates.
Values of these biochemical tests are to be interpreted in
multiples of median (MoM). Each lab has its own cut offs
and the risk is calculated based on previous history, age,
gestation, number of fetuses, smoking, weight, ethnicity,
gravidity and parity, previous screening results assisted
reproduction, pregnancy complications and diabetes (lower
levels).
When first trimester biochemical screen is combined
with nuchal translucency (combined test), detection rate for
trisomy 21 increases to 85% at a false positive rate of 5%.
Inclusion of various other newer markers such as nasal
bone, tricuspid regurgitation and ductus venosus further
raises the sensitivity to 92% at a false positive rate of 5%.
So first trimester combined screen is clearly has more
sensitivity and specificity and provides early
reassurance [6].
While offering any screening method, one should offer
both pretest as well as posttest counseling. One should
remember that it is not a diagnostic test but is a screening
test to pick up high risk pregnancies and is certainly not a
substitute for fetal karyotyping. Definitive diagnosis can be
provided by chromosomal studies on amniotic fluid,
chorionic villus biopsy or cord blood sample.
Ultrasound scanning in prenatal diagnosis [7]
Fetal anomaly scan is done at 11-14 weeks and 18-20
weeks to look at the major malformations and soft markers.
1st trimester scan
It has been shown that around this time there is strong
association between chromosomal abnormality and
abnormal accumulation of fluid behind baby’s neck,
referred to as increased ‘fetal nuchal translucency.’ This
applies both to DS and other autosomal trisomy syndromes
like trisomy 13 and 18. By combining information on
maternal age with results of fetal nuchal translucency and
thickness measurements, it is possible to detect approx.
80% of fetuses with trisomy 21, if invasive testing is offered
to the 5 % of pregnant women with the highest risk.
2nd trimester scan
Significant sonographic findings are seen in nearly all
fetuses with trisomy 13, 77-100% of trisomy 18. Current
sonographic criteria can identify 65%-75% of fetuses with
Down syndrome with a false positive rate of 4-15% in
second trimester. Presence of multiple abnormalities raises
the risk of any chromosomal abnormality to 35%. With the
combined usage of sonographic markers for Down
syndrome and maternal serum screening, the vast majority
of fetuses with Down syndrome could be potentially
detected.
Perinatal pathology
In case of unexplained fetal deaths or detection of major
congenital malformations on antenatal ultrasound, fetal
autopsy for complete genetic evaluation is of utmost
importance in order to make a specific diagnosis and
ascertain the risk of recurrence.
CONCLUSION
Pediatricians and Gynaecologists are the primary
physicians for the diagnosis, and management of children
and high risk couples with genetic disorders. Also besides
treating the patients, physicians should make the parents or
couple aware of the genetic disorder, risk of recurrence,
prognosis and prenatal diagnosis. The development of
genetic and molecular biology methods has opened up new

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257 Apollo Medicine, Vol. 6, No. 3, September 2009
opportunities in genetic prenatal diagnosis. Genetic
counseling in association with modern prenatal diagnostic
procedures constitutes a basic element of prevention of
congenital anomalies and genetic disorders.
REFERENCES
1. National Center for Biotechnology Information. Online
Mendelian Inheritance in Man (OMIM). Available at:
www.ncbi.nlm.nih.gov/ omim/. Accessibility verified May
21, 2003.
2. Peltonen L, McKusick VA. Genomics and medicine:
dissecting human disease in the postgenomic era.
Science. 2001; 291:1224-1229.
3. Nussbaum RL, McInnes RR, Williard HF. Genetic
APPENDIX-A
HOW TO SEND SAMPLES TOAGENETIC LAB
Genetic lab/Geneticist should be informed before sending the sample.
PRENATALSAMPLES
Amniotic fluid sample-About 20 mL of clear amniotic fluid is sent in sterile tubes (tubes are collected from the lab). It is
required for chromosomal analysis, DNA and biochemical analysis.#
Chorionic villi sample- About 20 -30 mg of chorionic villi should be sent in the transport media. (It can be collected from the
genetic lab).It is required for DNA analysis, enzyme analysis and chromosomal analysis.#
#in the order of preference
POST NATAL sample
Blood
DNAstudies: Collect 3-6 mLblood in EDTA(purple top vacutainer)
Chromosomal analysis: Collect 3 mLof blood in heparin (green top vacutainer)
Enzyme analysis: 3-6 mL blood in heparin(green top vacutainer)
Product of conception/ Skin for chromosomal analysis or DNA can be sent in the culture media (can be collected from the
genetic lab) or normal saline with 2 drops of crystalline penicillin and gentamycin.
counseling and risk assessment. In Thompson and
Thompson Genetics in Medicine. 6th edition by WB
Saunders 2001.
4. Harper PS.Prenatal diagnosis and related reproductive
aspects. In Practical Genetic counseling, 6th Edition,
Arnold Publishers 2004.
5. Muller R F, Young ID. Genetic counseling. In Emery’s
Elements of Medical Genetics. Eleventh edition by
Churchill Livingstone in 2002.
6. Malone FD, et al. FASTER research Consortium.N Engl J
Med 2005; 353:2001-2011.
7. Shipp TD, Benacerraf BR. Second trimester ultrasound
screening for chromosomal abnormalities. Prenatal
diagnosis 2002; 22: 296-307.

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