Genetic study of infertile couple by Dr. Umesh N Jindal

1. Dr. Umesh Jindal
Jindal IVF
Sector 20 Chandigarh

2. Objectives
• Disease Burden
• Few basics the OBGYN should know
• When to suspect genetic disorders and role of clinical
geneticist
• What to expect and not to expect from genetic work up
and counselling and avoid misuse
• Reproductive options

3. Why there is concern for genetic disorders???
• Most of the disorders are lethal or lead to mental or physical handicap
• No curative treatment or the treatment is costly, with side effects
• Concerns of family
• “Why did this happen to me?”
• “Will it recur in my family or what are the chances of recurrence?”
• “Can we prevent recurrence?”
• Important to Identify red flag signs of genetic disorders, counsel them
and refer them to a geneticist for appropriate investigations and advice
where available

4. Genetic disease burden
• Genetic disease burden:1% of all
live births; 20% of infant mortality,
and 20% of paediatric hospital
admissions
• 20-30% of Autism spectrum
disorders and IDs
• More than 50% miscarriages
related to genetic causes
• Almost 25-30% of unexplained still
births and neonatal deaths
• Many cases of birth asphyxia could
be of genetic aetiology ICMR2018

5. Prevention of
Genetic Diseases
• ASRM has recommended PGT-M with IVF as
a significant advance over post-conception
invasive prenatal diagnosis (ASRM Practice
Committee guidelines 2018)
• PGT- being ultimate kind of prevention which
has potential to eliminate the offending
gene from family tree
1. Primary prevention- Pre-pregnancy
identification and counselling and PGT
2. Secondary prevention- Prenatal
diagnosis and TOP
3. Tertiary prevention/care- Management
after birth

6. Human cell
Types of genetic
testing
1. Cytogenetic
2. Molecular cytogenetics
3. Molecular genetics

7. Chromosomes and
beads of strings
Karyotype
microarray
Gene sequencing

8. Types
of
genetic
testing
Karyotype
Microarray studies
NGS-Next generation
sequencing
• Clinical exomes
• Gene panels
• Whole exome sequence
• Whole genome
sequence

9. Chromosomal Disorders
Aneuploidy
Numerical
• Full aneuploidies
(Trisomy/ Monosomy)
• Inversions/Translocations
• Partial aneuploidies
(Deletions/ Duplications of
sufficient size that they
can be seen on
Microscope)
• Phenotype practically
always abnormal

10. Structural Rearrangements
Structural
• Microdeletions/
microduplications/ copy
number variants

11. Types of genetic disorders
Single gene disorders
• Variations in single base
pair
• Autosomal Dominant/
Autosomal Recessive
• X-linked / Y-linked
• Mitochondrial
• Epigenetic

12. Autosomal dominant disorders
Examples
• Myotonic dystrophy
• Autosomal dominant
polycystic kidney
disease
• Achondroplasia
• Marfan syndrome
• Noonan syndrome

13. X-linked recessive disorders
Examples
• Duchenne muscular
dystrophy
• Hemophilia
• Fragile X syndrome

14. Autosomal recessive disorders
Examples
• Thalassemia
• Cystic fibrosis
• Congenital adrenal
hyperplasia

15. Mitochondrial Inheritance
Examples
• Leigh disease
• Mitochondrial encephalopathy,
lactic acidosis and stroke-like
episodes (MELAS) syndrome
• Leber hereditary optic neuropathy
(LHON)
• Kearns-Sayre syndrome (KSS)
• Myoclonic epilepsy and ragged-
red fiber disease (MERRF)

16. Cytogenetic
Karyotype
Molecular cytogenetic
Array CGH(Microarray)
QF-PCR(Quantitative
fluorescent PCR)
MLPA(Multiplex ligation probe
dependent amplification)
Molecular
Sanger sequence
Clinical exome
Whole exome
Whole genome
Mitoexome
Genetic testing techniques

17. • History, Pedigree, clinical exam and lab tests
• Counselling to patient to understand
Nature of disorder
Prognosis and management
Inheritance and risk of recurrence
Reproductive options
Psychosocial support
• Part of PGT team
Pre-PGT workup
Interpretation of reports
Help in decision making
What does a geneticist do?
15
years
10
years

18. Preconceptional genetics in infertile couple

19. When to refer for genetic counseling?
• Advanced maternal age
• Consanguineous marriage
• Personal/Family H/O Infertility, recurrent spontaneous abortions,
unexplained still birth, neonatal or infant death, birth asphyxia,
multiple CMF
• Previous child or close relative with developmental
delay/Autism/short stature/malformations/Epilepsy/muscle
disease/Hemophilia/Thalassemia
• History of cancers in multiple family members
• Screen positive for Thalassemia-CBC/HPLC

20. Male infertility Female infertility
Genetic factors~ 15-30% Genetic factors~10-15%
Chromosomal
(5% in oligospermia and 15% in azoospermia)
• Sex chromosomal anomalies e.g.
Klinefelter syndrome, XYY, Mixed gonadal
dysgenesis
• Translocation carriers-RPL also, recurrent
Down’s
• Y chromosomal microdeletions
Chromosomal
• Turner syndrome
• Triple X syndrome
• Translocation carriers-RPL also
Single gene disorders like
• Cystic fibrosis/ CBAVD
• Kalman syndrome
• Bardet-biedel syndrome
• Hemochromatosis
• Androgen insensitivity syndrome
Single gene
• Fragile X carrier
• Galactosemia
• Congenital adrenal hyperplasia
• Kalman syndrome
• Perrault syndrome Best Practice & Research Clinical
Organ mosaicism
Spectrum of presentation
ART offers reproductive options
Testi sperm, PGT

21. Cariati et al. J Transl Med (2019)
Identification of infertility
causes
•genetic testing in clinically
suspected diseases
•due to phenotype, RIF or
RPL, BOH
•Hormone receptor studies
•ERA
Transmission Risk
• Targeted Carrier
screening
•No suspected phenotype
or history but a general
screening is done for
common diseases, BOH,
RPL, previous losses,
recurrent malformations
etc
•Evolving speciality
Reproductive Choice
•Reproductive options
•PGT-A
•PGT-SR
•PGT-M
•Prenatal diagnosis
•Acceptance
•Gamete replacement

22. Carrier screening
Definition of Carrier: Healthy individuals who are heterozygous for a defected gene
copy of an autosomal recessive or X-linked condition
• Most people do not know if they are a carrier for an inherited genetic disease until
they have a child with the disease
• It is a genetic testing used to identify individuals or couples that are at risk to have a
child with such disorders
• Once identified, carriers of these disorders can be guided for their reproductive risks,
reproductive options, and helped to make informed decisions
ACMG carrier screening guidelines,2021

23. Candidates for carrier screen-ACMG guidelines,2021
Includes all common genetic disorders like thalassemia,
Sickle cell anemia, Cystic fibrosis, SMA, CAH, DMD, Fragile
X and disorders with moderate severity

24. Genetic contribution to perinatal deaths
Account for ~ 25% cases
• Chromosomal abnormalities-6% to 17% and higher in malformed
fetuses and lesser in fetuses with normal morphology
• Single gene disorders-??5-10%(Underestimated)
• Single malformations-40%
• Multiple malformations- 40%
• Fetal disruption or dysplasia syndrome~1%
Neonatal sepsis/Birth asphyxia must be the
diagnosis of exclusion after ruling out genetic
disorders especially metabolic ones
Clinical Obstetrics and Gynecology.2010, N ENGL J MED 2020

25. Translational Andrology and Urology,2021
Guidelines for genetic testing in male infertility

26. Balanced Translocations- Can cause infertility in
both male and female

27. How PGT works
• Every Embryo represents one potential pregnancy and PGT gives you
outcome of many pregnancies in one go without going through repeated
transfers, failures, PND and abortions
• Embryo Selection-One can diagnose and prevent imminent IVF failures and
risk of inherited diseases and miscarriages because of embryonic causes
• Reduction in time to pregnancy along with financial, physical and
psychological costs of repeated mishaps

28. PGT Not indicated
PGT-A
• One or two embryos
only
• Young women<35
years
• Poor Quality
embryos
PGT-M
• When genetic
diagnosis is
technically not
feasible
• Reliability of
diagnosis is not high
PGT-SR
• Unbalanced or very
large segment
involvement
• Double or triple
rearrangements
• Feasibility of IVF to be considered
• Pooling of embryos
• high blastulation – corner stones of success
• Always an ICSI
• Invasive
• Cost issues
Other Limitations

30. TEAM
ART
specialist
Geneticist
Counsellor
Embryologist
Genetic lab

31. Genetic Diseases can’t be cures but can be prevented