Genetic Study of Infertile Couple | Jindal IVF Chandigarh 
                      
Genetic 
study of 
infeDrr. Utmielshe Jin dal
couJinpdal lIVeF 
Sector 20 Chandigarh 
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
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
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
Prevention of 
Genetic Diseases
1. Primary prevention- Pre-pregnancy 
identification and counselling and PGT
2. Secondary prevention- Prenatal 
diagnosis and TOP
3. Tertiary prevention/care- Management 
after birth
• 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
Human cell
Types of genetic 
testing
1. Cytogenetic
2. Molecular cytogenetics
3. Molecular genetics        
        
Chromosomes 
and beads of 
microarray
strings
Gene sequencing
Karyotype
Karyotype
Types of 
Microarray studies
genetic 
testing
NGS-Next generation 
sequencing
• Clinical exomes
• Gene panels
• Whole exome sequence
• Whole genome 
sequence
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
Structural Rearrangements
Structural
• Microdeletions/ 
microduplications/ copy 
number variants
Types of genetic disorders
Single gene disorders
• Variations in single base 
pair
• Autosomal Dominant/ 
Autosomal Recessive
• X-linked / Y-linked
• Mitochondrial
• Epigenetic
        Autosomal dominant disorders
Examples
• Myotonic dystrophy
• Autosomal dominant 
polycystic kidney 
disease
• Achondroplasia
• Marfan syndrome
• Noonan syndrome
    X-linked recessive 
disorders
Examples
• Duchenne muscular 
dystrophy
• Hemophilia
• Fragile X syndrome
Autosomal recessive 
disorders
Examples
• Thalassemia
• Cystic fibrosis
• Congenital adrenal 
hyperplasia
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)
                Genetic testing techniques
Molecular cytogenetic Molecular
Array CGH(Microarray) Sanger sequence
Cytogenetic QF-PCR(Quantitative          Clinical exome
Karyotype fluorescent PCR)          Whole exome
MLPA(Multiplex ligation probe          Whole genome
dependent amplification)          Mitoexome
What does a geneticist do? 
• 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 15 10 
Interpretation of reports years years
Help in decision making
      Preconceptional genetics in infertile couple
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
Male infertility Female infertility
Genetic factors~ 15-30% Genetic factors~10-15%
Chromosomal Chromosomal
(5% in oligospermia and 15% in azoospermia) • Turner syndrome
• Sex chromosomal anomalies e.g. • Triple X syndrome
Klinefelter syndrome, XYY, Mixed gonadal • Translocation carriers-RPL also
dysgenesis
• Translocation carriers-RPL also, recurrent 
Down’s
• Y chromosomal microdeletions Organ mosaicism
Spectrum of presentation
Single gene disorders like Single gene ART offers reproductive options
• Cystic fibrosis/ CBAVD • Fragile X carrier Testi sperm, PGT
• Kalman syndrome •  Galactosemia
• Bardet-biedel syndrome • Congenital adrenal hyperplasia
• Hemochromatosis •  Kalman syndrome
• Androgen insensitivity syndrome •  Perrault syndrome
• 5 alfa reductase deficiency • X-linked genes
Best Practice & Research Clinical 
Obstetrics & Gynaecology.2017
Identification of infertility 
causes
•genetic testing in clinically 
suspected diseases
•due to phenotype, RIF or Transmission Risk
RPL, BOH • Targeted Carrier 
•Hormone receptor studies screening 
•ERA •No suspected phenotype 
or history but a general 
screening is done for 
Reproductive Choice common diseases, BOH, 
•Reproductive options RPL, previous losses, 
•PGT-A recurrent malformations 
•PGT-SR etc
•PGT-M •Evolving speciality
•Prenatal diagnosis
•Acceptance
Cariati et al. J Transl Med (2019)
•Gamete replacement
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
  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
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
Guidelines for genetic testing in 
male infertility
Translational Andrology and Urology,2021
Balanced Translocations- Can cause 
infertility in both male and female
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
PGT Not indicated
PGT-A PGT-M PGT-SR
• One or two embryos • When genetic • Unbalanced or very 
only diagnosis is large segment 
• Young women