Genetics, Cousin Marriages & Inherited Disorders

What Medical Science Tells Us?

This information is intended for educational purposes only.

MUTATIONS

Speaker:�Umm-e-Habiba (BS Biotechnology Student)

Mutation

A mutation is a permanent alteration in the DNA sequence of an organism's genome.

Abnormal protein cannot perform its normal role → leads to cellular dysfunction.

Example pathways:

• Metabolic disorders
• Structural disorders
• Blood disorders

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Causes of Gene Mutation

Inherited Genetic Disorders

• Inherited genetic disorders are diseases caused by mutations in genes or chromosomes that are passed from parents to offspring through heredity.

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How many genes do I share with my relatives?

Sometimes people carry hidden recessive mutations.

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Rr × Rr

RR : Rr : Rr : rr

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If two cousins carry the same mutation, their child has a higher chance of inheriting that mutation from both parents.

Common Genetic Disorders Resulting from Cousin Marriages: Thalassemia

Speaker:�Miss Ruba Shahid (Lecturer Biotechnology & Biochemistry)

What Are Consanguineous Marriages?

• Cousin marriage, the union of individuals with common grandparents, is common in Middle Eastern, North African, and South Asian cultures, often chosen to strengthen family ties, preserve wealth, and maintain cultural traditions.
• While socially supported in some communities, it poses increased risks of recessive genetic disorders and high infant mortality due to close blood relations.

Thalassemia: What Actually Happens?

Thalassemia: A Genetic Blood Disorder

Healthy Individual

Efficient Oxygen Transport

Thalassemia Patient

Normal Hemoglobin

Reduced Oxygen Transport

Defective Hemoglobin

Healthy RBC

Abnormal RBC

Molecular Mechanisms Behind Thalassemia

Prevalence in Pakistan

• 5-7% β-thalassemia cases
• 10 million carriers
• ~5000 children diagnosed each year

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Regional prevalence of thalassemia in Pakistan, highlighting variations among Sindh, Baluchistan, and Punjab provinces.

The ratio of carrier to disease cases is disproportionately high because of consanguinous marriages

Pakistan: ~5,500 to 6,600 births/year

Global: ~40,000 births/year

~13.75-16.5% of cases = Pakistan (a hotspot)

Autosomal Recessive Inheritance

A = Normal Gene

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a = Mutated Gene Responsible For Thalassemia

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25%

25%

50%

A Case Study of a Large Family Using Cascade Testing

• Conducted in 2008 in a remote rural area.
• Goal: to demonstrate that genetic counseling can reduce the risk of B-Th cases.

SELECTED FAMILY

27 LIVING MEMBERS

SINGLE

1 INDEX CHILD WITH TH-MAJOR

8 AFFECTED CHILDREN DIED

A Case Study of a Large Family Using Cascade Testing

Amplification Refractory Mutation System Polymerase Chain Reaction

12 = carriers (44.4% frequency; general frequency in Pakistani population ~5%)

Pedigree of a family identified through a transfusion-dependent proband (V-16) indicated by an arrow. Circles represent female family members, squares symbolize male family members. Half solid symbols are heterozygotes (carriers) for -thalassemia, symbols with a slash stand for dead family members and NA represents members not available for testing. Twenty-eight members of this family, including the index case, were available for testing.

Results

• The family was initially reluctant.
• Elders and couples hesitant about prenatal testing.
• Unwilling to marry out of ‘BIRADRI’.
• Cooperative after genetic counseling.
• Later agreed to premarital testing and avoiding marrying carriers.
• Authors emphasize that cascade testing is more effective than general screening in a landscape like Pakistan.

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Complications of Thalassemia

Overview of systemic complications in thalassemia, including endocrine, hematologic, and organ-specific manifestations

Symptoms of Thalassemia

Treatments: Conventional

1. Blood Transfusion.
2. Iron chelation therapy (❌ iron overload).
3. Splenectomy (in selected patients).
4. Hydroxyurea (to induce fetal Hb).
5. Allogenic hematopoietic stem cell transplantation (improved outcomes but limited donor availability and transplantation risks present).

Treatments: Emerging Therapies

Molecular Agents that aim to reduce transfusion dependence:

1. Luspatercept
2. Pyruvate Kinase Activators
3. Ferroportin Inhibitors

Molecular Agent: Luspatercept

Insights from History and Data

Speaker:�Miss Falak Sajjad (Lecturer Biotechnology & Biochemistry)

Historical Perspective

• The practice of endogamy was common in the subcontinent.
• The case of Manu tribe (power and family consolidation).
• Prevalence in Mughal Empire (Akbar, and Shah Jahan).
• In “The Wonder That Was India” A. L. Basham explains the caste system marriages.

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Prevalence

Data Insights

• 100 lakh women above the age of 35 are unmarried; reason: endogamy practices (UN).
• Population-wide: 5th largest country.
• 64% marriages are among first cousins.
• Labeled as a Silent Pandemic by German neurologist Prof. Dr. Arnold Rolfs.
• 160 lac rare genetic disorders.

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Survey Analysis

Survey

(Gallup Pakistan)

1990

~50% cousin marriages

2020

~49% cousin marriages

Possible Implications of Cousin Marriages

• Autosomal recessive genetic disorders, e.g., night blindness, thalassemia, and sickle cell anemia.
• Birth defects (a total of 59%).
• For every 1000 births, 15 children die.

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Case Study I

Case Example – North Balochistan (Brohi family)

A family from North Balochistan (Brohi tribe) had children affected by genetic disorders

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Case Study II: Ghafoor Hussain Shah Family

Research in Pakistan shows that about 70% of hearing impairment cases occur in children born to cousin marriages

Ghafoor Hussain Shah (teacher)�

Son’s brain did not develop normally (intellectual disability).�

One daughter has a speech disorder (mute / difficulty speaking)�

Another daughter has hearing impairment (deaf)

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A Comprehensive Genetic Landscape of Inherited Retinal Diseases in a Large Pakistani Cohort

Visual Impairment

• Any loss or limitation of vision not corrected by glasses
• Can range from mild to complete blindness
• Affects daily life: reading, mobility, education

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Causes

• Non-genetic / acquired: cataract (age-related), trauma, infections, vitamin A deficiency
• Genetic / inherited: inherited retinal diseases (IRDs), congenital cataract, other syndromic conditions

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Introduction to Inherited Retinal Diseases (IRDs)

Genetic disorders affecting the retina → progressive vision loss

Examples:

1. Retinitis Pigmentosa (RP) – most common
2. Leber Congenital Amaurosis (LCA)
3. Stargardt disease
4. Cone-Rod Dystrophies
5. Can be syndromic (Usher, Bardet-Biedl) or non-syndromic
6. Cause progressive vision loss

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Introduction to Inherited Retinal Diseases (IRDs)

IRDs and Cousin Marriages in Pakistan

1. ~92% of IRD cases in Pakistan linked to consanguineous marriages
2. High inbreeding → recessive gene mutations manifest
3. Gene pool transfer across generations

Retinitis Pigmentosa

1. Progressive degeneration of photoreceptors.
2. Early symptom: night blindness → tunnel vision → complete blindness.
3. Usually autosomal recessive, sometimes dominant or X-linked.
4. Onset: childhood to early adulthood.
5. Prevalence in Pakistan is high due to consanguinity.

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My Research (An Overview)

Goal: Identify IRD-causing genes in Pakistani families

Regions sampled: Sialkot, Daska, Lahore, Multan, Gujranwala, Gujrat 213 unrelated families, totaling 722 affected individuals

1. Collected blood samples from affected individuals
2. DNA extraction
3. Gel electrophoresis for quality check
4. Quantification using Nanodrop

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Gel Electrophoresis

Nanodrop

Sequencing and Analysis

1. Samples sent to Spain for Next Generation Sequencing
2. Whole Exome Sequencing (WES) performed.

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Inheritance Patterns

1. 96% autosomal recessive.
2. Few X-linked or dominant.
3. Explains high prevalence in consanguineous marriages.

Treatments & Future Outlook

1. Gene therapy available in the US for RPE65 mutations.
2. Currently, no gene therapy is available in Pakistan.
3. Importance of early diagnosis & genetic counseling.

PROBABILITY VS. DENSITY INBREEDING COEFFICIENT

Speaker:�Asma Abbas (Biotechnology graduate & Researcher)

Inbreeding Coefficient (F): What It Really Means?​

"probability that a child inherits two identical alleles

from a common ancestor."​

Formula:​� F = Σ (1/2)ⁿ​​

• First cousins who share grandparents have F = 0.0625 (1/16)​

​Key stats:​

• General population risk of congenital disorders: ~2–3%​
• First-cousin unions: ~4–7%​

Risk roughly doubles, but does not become extreme.

Probability: Individual-Level Genetics​

"chance a child is affected given parental genetics."​

• If both parents are carriers (Aa × Aa):​

• In unrelated couples: low chance both carry same rare allele​​
• In cousins: shared ancestry increases carrier overlap​​

Chance that both cousins carry the same allele ∝ shared lineage (F)​​

Inbreeding increases carrier pairing probability, not mutation rate.

Density: Population Genetics Perspective​

“Density = frequency of a deleterious allele in a population​”

• Represented as q (allele frequency) in Hardy–Weinberg​

Normal population:​

Disease frequency = q²​

With inbreeding:​

Frequency becomes:​� q² + Fq (1 − q)​

Even if q is small, F increases homozygosity​

Real-world stats:​

In populations with high consanguinity:​

• Autosomal recessive disorders increase by 2–3x

Example:​

Thalassemia prevalence significantly higher in consanguineous population

Inbreeding shifts genotype distribution → more homozygotes​

Probability vs Density: The Complete Picture​

Short-term:

F increases risk per child​

�Long-term:

F reshapes population genetics​

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Final stat-based takeaway:​

First-cousin marriage:​

• ~2x increase in disorder risk​

but impact compounds over generations via density.

Current landscape of Diseases and Awareness in Pakistan

Speaker:

Rida Zainab (Biotechnology Student)

Survey on Awareness of Genetic Risks(Cousin Marriages)

Attitudes of Patients Supporting Testing

Concerns of Patients NOT Supporting Testing

Conclusion

Speaker:

Tooba Noor (Biochemistry Student & Researcher | Science Outreach Organizer)

Building a Healthier Future

Building a Healthier Future

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Thank you for your participation in the event!

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Q/A Segment