Genetic Study of Infertile Couple | Jindal IVF Chandigarh

1

Genetic study of infertile couple
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 burden1 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

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

6
Human cell

• Types of genetic testing
• Cytogenetic
• Molecular cytogenetics
• Molecular genetics

7
Chromosomes and beads of strings
microarray
Gene sequencing
Karyotype
8
Karyotype
Types of genetic testing
Microarray studies

• NGS-Next generation sequencing
• Clinical exomes
• Gene panels
• Whole exome sequence
• Whole genome sequence

9
Chromosomal DisordersAneuploidy

• 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
Genetic testing techniques
17
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
• Interpretation of reports
• Help in decision making

18
Genetics has a role at every step in reproductive
medicine.
19

• Preconceptional genetics in infertile couple

20
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

21
Male infertility Female infertility
Genetic factors 15-30 Genetic factors10-15
Chromosomal (5 in oligospermia and 15 in azoospermia) Sex chromosomal anomalies e.g. Klinefelter syndrome, XYY, Mixed gonadal dysgenesis Translocation carriers-RPL also, recurrent Downs 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 5 alfa reductase deficiency Single gene Fragile X carrier Galactosemia Congenital adrenal hyperplasia Kalman syndrome Perrault syndrome X-linked genes
Organ mosaicism Spectrum of presentation ART
offers reproductive options Testi sperm, PGT
Best Practice Research Clinical Obstetrics
Gynaecology.2017
22

• 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

Cariati et al. J Transl Med (2019)
23
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
24
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
25
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 syndrome1

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
26
Guidelines for genetic testing in male infertility
Translational Andrology and Urology,2021
27
Balanced Translocations- Can cause infertility in
both male and female
28
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

29
PGT Not indicated

• Feasibility of IVF to be considered
• Pooling of embryos
• high blastulation corner stones of success
• Always an ICSI
• Invasive
• Cost issues

Other Limitations
30
(No Transcript)
31
TEAM
32
Genetic Diseases cant be cures but can be
prevented
33
Thank you