Genomic Imprinting, Uniparental Disomy And Related Disorders 

UPD(Uniparental Disomy) 

• It occurs when both chromosomes of a pair or area from one chromosome in any individual have been inherited from a single parent. E.g., in a normal chromosome. Two copies of the same chromosome of a cell go under gamete formation. It has two copies of chromosomes, one copy of each subsequent gametes. This is called haploid formation. The sperm enters with its haploid pair of chromosomes and fuses with the gamete. It becomes diploid again, which has two copies of chromosomes. One is maternal, and one is paternal.

If there is a meiotic nondisjunction in a chromosome. Two copies of chromosomes go under gamete formation, producing two gametes, but there was a nondisjunction of chromosomes. The two gametes produced - one has both the chromosome, and another has no copy of the chromosome. Both chromosomes went to the single gamete. The sperm enters with its haploid pair and fuses with the gamete. During the fusion - one cell has three sets of chromosomes, i.e., two maternal and one paternal set of chromosomes, i.e., Trisomy of chromosomes occurs. And one cell has only one pair of chromosomes, i.e., Monosomy occurs. 

Rescue Phenomenon

• The rescue phenomenon is restoring the diploid number of chromosomes. It occurs in two ways: 

• The image shows trisomy.  In case of Trisomy, trisomy rescue occurs and diploid / disomy is restored. There are 2 possibilities. 

If extra maternal chromosome is deleted, then the child born is normal. If only the paternal chromosome gets deleted, then it’s called as UPD (Uniparental Heterodisomy).

The image shows monosomy. In case of Monosomy, Monosomy rescue takes place and duplication of same chromosome occurs. As the chromosome is derived from same parent it is called as Uniparental disomy.

• Uniparental Isodomy -The chromosomes or chromosomal regions are identical.
• Uniparental Heterodisomy- Both chromosomes are different members of a pair but inherited from the same parent. 
• UPD can result in three scenarios - 
  • It can uncover and produce diseases related to genetic imprinting. 
  • It can uncover and express autosomal recessive disorders.
• It can result in mosaicism.

Also Read: Marfan Syndrome : Signs, Diagnosis, Management and Prognosis

Genomic Imprinting 

• In the image - Pink - maternal allele, Blue - paternal allele, E – expressing, S - silenced 

What Is Genomic Imprinting?

• A phenomenon characterized by selective inactivation of either the maternal or paternal allele. This means that the phenotypic expression of a gene entirely depends upon the parent of origin. It is a normal phenomenon arising from- MATERNAL IMPRINTING - Transcriptional silencing of the maternal allele. PATERNAL IMPRINTING - Transcriptional silencing of the paternal allele.
• Genomic imprinting occurs in the ovum or the sperm before fertilization and then is stably transmitted to all the somatic cells through mitosis. It occurs via epigenetic modification, e.g., DNA methylation at CG nucleotides. The number of genes that are imprinted is >60 (Nelson) or 200-300 (Robbin).

Imprinting Disorder

• It arises due to abnormal phenomena affecting certain genes - showing genomic imprinting. It occurs due to - Deletion, UPD (Uniparental Disomy), Other e.g. Point mutation, epigenetic aberrant methylation pattern.

Also Read: Aneuploidies Including Turner And Klinefelter Syndrome

Common Imprinting Disorders

• Some common imprinting disorders are - 
  • Prader -Willi syndrome 
  • Angelman syndrome 
  • Silver - Russel syndrome 
  • Beckwith- Weidmann syndrome 
  • Pseudohypoparathyroidism type 1B
  • Wang syndrome 
  • Temple syndrome 
  • Transient neonatal diabetes mellitus 

Prader - Willi Syndrome 

• On 15q, there are genes for the SNOPR family -code for smaller nucleolar RNAs (snoRNAs) are involved in modifying rRNA. Normally, this cluster is maternal imprinted. This means only the paternal allele is expressed and is functional. The loss of the paternal contribution results in Prader - Willi syndrome. So, one mechanism for Prader - Willi syndrome to occur is Paternal deletion in the presence of maternal imprinting. The second mechanism can be the UPD of maternal chromosome 15. SNORP gene on 15q is normally maternally imprinted and is silent. If both genes get derived due to maternal UPD, it will produce a scenario where both alleles are silent, producing the disease.

Molecular Summary 

It can occur due to two phenomena. 70% of cases arise due to deletion - Paternal deletion + Maternal deletion. 30% of cases arise from UPD - Maternal disomy + Maternal imprinting.

Diagnostic Criteria 

The following image shows the diagnostic criteria for Prader-Willi Syndrome:

Interpretation 

Any child of age </= 3 years - Total 5 points with minimum 4 major criteria. Age >3 years - Total 8 points with minimum 5 major criteria.

Nutritional Phases

The following image shows the nutritional phases of Prader-Willi syndrome:

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Angelman Syndrome

On 15q, there is a maternal derived UBE 3A gene, which codes for a ubiquitin ligase involved in protein targeting. Normally, this cluster is paternally imprinted. This means only the maternal allele is expressed and functional. The loss of maternal contribution results in Angelman syndrome.

Molecular Summary

It occurs due to 3 phenomena - 70% of cases arise due to deletion - Maternal deletion + Paternal imprinting. 11% of cases arise due to single gene mutation in E6-AP ubiquitin-protein ligase, mainly in familial cases. 5% of cases arise due to UPD - Paternal disomy + Maternal imprinting. 10-15% of cases arise due to unknown or unidentified mechanisms.

Key Clinical Manifestations

• The main clinical manifestation is severe intellectual dysfunction, Ataxia, Impaired or absent speech, Epilepsy with EEG abnormalities with large amplitude, slow-spike waves, atypically happy, Tremulousness (fine tremors) in the limbs, Microcephaly, Strabismus and short attention span.
• Obesity can be present in Angelman syndrome, but it is not a defined feature. Obesity is a defined feature of Prader - Willi syndrome. Prader - Willi syndrome can have intellectual dysfunction but is not severe as Angelman syndrome.

Also Read: KEY POINTS AND RECOMMENDATIONS IN PEDIATRIC ADVANCED LIFE SUPPORT

Hope you found this blog helpful for your NEET SS Genetic Disorders preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.