Genetic Disorders - Basics, Multifactorial/polygenic inheritance 

Terminologies

• Codon: A trinucleotide unit that codes for a single amino acid.
• Locus: site of a particular gene on a chromosome.
• Exon: coding region of DNA.
• Intron: Non-Coding intervening region of DNA.

Basics of genetics

The human genome has about 20,000 genes total. The human genome is comprised of 46 chromosomes, or 23 pairs, of which 1 pair is of sex chromosomes/allosomes (XX/XY) and the other 22 pairs of autosomes. 

Structure of Chromosomes

Chromosomes are made up of two arms: the q arm, which is a long arm, and the p arm, which is a short arm.  Chromosome types determined by centromere location.  Satellite projections are seen on the shorter length of chromosomes in acrocentric chromosomes. 

Denver system of classification

As one moves from group A to group G, chromosomal size reduces.
• Submetacentricity exists on the X chromosome.
• There is an acrocentric Y chromosome.

Also Read: Infections of the Upper Airway- Common Cold and Sinusitis

Classification of genetic disorders

Additional classifications for chromosomal disorders include aberrant numbers and atypical sizes, shapes, and structures. Diseases caused by a single gene exhibit Mendelian inheritance.  X linked recessive  X linked dominant Mendelian inheritance encompasses them all. 
Patients with neural tube abnormalities are susceptible to polygenic/multifactorial diseases.  Among the non-Mendelian genetic illnesses are:  Gonadal mosaicism, also known as germline mosaicism.
Diseases of the mitochondria  Disorders involving trinucleotide repeats o Genetic imprinting 

Chromosomal disorders

Number disorders: Aneuploidy, which comes in two varieties Monosomy, Trisomy.  Structural disorders  Translocations: There are two different ways that genetic material might shift: balanced and inverted translocations.  Inversions: the shifting or 180-degree rotation of a certain genomic region.  Gene deletions: While many microdeletions, such as Williams syndrome, which affects chromosome 7q11, and DiGeorge syndrome, which involves chromosome 22q11, are compatible with life, large gene deletions are not.

Gene duplications where the complete gene is duplicated, such as the APP gene on the 21 chromosomes that cause Alzheimer's. Additionally, it has been shown that some individuals with Down syndrome have three copies of the 21 chromosomes, while other children without the condition experience duplication, resulting in two copies of the APP gene on the 21 chromosome, giving them a total of three copies and an earlier onset of Alzheimer's disease. 
The p and q chromosomes stay together to create a ring when chromosomes are cut, a phenomenon known as "ring chromosomes." 

Image Description 

During a typical cell division, a chromosome with one p and one q arm is generated when the cell splits lengthwise.  The division of chromosomes happens along the transverse axis rather than the longitudinal axis, which can be fatal in utero.

Also Read: Aneuploidies Including Turner And Klinefelter Syndrome

Testing for chromosomal disorders 

• Karyotyping 
• FISH (Fluorescent In Situ Hybridization)
• qPCR q polymerase chain reaction.
• MLPA: Multiple ligation probe amplification 
• CMA: chromosomal microassay 

Karyotyping 

Bone marrow cells and circulating lymphocytes are the cells used in karyotyping.  At the metaphase stage, cells are stopped.  In vitro karyotyping is carried out. Giemsa staining, also referred to as G-staining, is used to stain after metaphase arrest in order to identify any alterations, such as aneuploidy.

Image Description 

XXY is showing Klinefelter syndrome.

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

Fish-fluorescent in Situ Hybridization

Finding a specific gene component and determining whether it is normal or abnormal for this involves creating a probe DNA, attaching a radioactive dye to it, mixing it with genetic material containing that parent DNA, denaturing it, making the strands open, and then hybridizing it. 

The probes are then attached to their corresponding DNA and observed under a polarized microscope, allowing the specific gene loci to be seen. This process is known as FISH. It is a method of molecular cytogenetics that permits the localization of a chromosome or a particular DNA sequence within a cell.

in situ hybridization" class="wp-image-34414" style="object-fit:cover;width:281px;height:153px"/>

in situ hybridization" class="wp-image-34416" style="object-fit:cover;width:188px;height:147px"/>

Image Description

After applying a fluorescent pigment, the probe DNA is joined to the DNA. It is hybridized and denatured.

CMA

A group of tiny DNA patches affixed to a stable surface. It may identify changes in copy number, including gains and losses (deletions and duplications).  The diagnostic yield is superior compared to traditional karyotype.  The resolution is over 50 times higher; it doesn't require cell division; it's widely employed in study on intellectual disability and autism spectrum disorders.

Also Read: Genomic Imprinting, Uniparental Disomy And Related Disorders 

Multifactorial/polygenic inheritance 

It is made up of several gene sets, each of which contributes in an additive way to the development of disease manifestation. Environmental factors and epigenetic mechanisms also play a part.
Found in: Congenital hypertrophic pyloric stenosis (CHPS);  Cleft lip/palate;  Type 2 diabetes mellitus;  Neural Tube abnormalities.
Heart illness at birth.

Trinucleotide repeat disorders

it results from specific trinucleotide repeats expanding. Repeating CAA as "CAACAACAACAACAA" causes DNA instability, which in turn causes mutations and particular symptoms.

FMR-1 Protein is the gene product, CGG is the trinucleotide repeat, and the inheritance pattern is X-linked recessive in fragile X syndrome.  The trinucleotide repeat in Huntington's disease is CAG; the gene product is Huntington; and the inheritance pattern is autosomal dominant. 

Myotonic protein kinase is the gene product, the trinucleotide repeat in myotonic dystrophy is CTG, and inheritance is autosomal dominant.  Friedreich Ataxia is inherited as an autosomal recessive condition with repetitions of GAA, which codes for the frataxin protein.  The trinucleotide repeat in spinocerebellar ataxia types 1, 2, 3, 6, and 7 is CAG; the gene product is ataxin; and the inheritance pattern is autosomal dominant.

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.