Genetic And Chromosomal Disorders Question and Answers

Common Genetic And Chromosomal Disorders

Question 1. Write a short essay/note on various types (classification) of chromosomal disorders/aberrations.
Answer:

Classification of Chromosomal Disorders

Numerical Chromosomal Aberrations

Normal cells are diploid containing 46 chromosomes, 22 pairs of autosomes, and 1 pair of sex chromosomes.

The 23 chromosomes (22 autosomes and one sex chromosome) constitute a haploid. Any exact multiple of the haploid number is called euploid

Read And Learn More: General Medicine Question And Answers

Types of numerical aberrations

• Aneuploidy: It is defined as a chromosome number that is not a multiple of 23 (the normal haploid number).
• It is caused by either loss or gain of one or more chromosomes. Aneuploidy may result from nondisjunction or anaphase lag.
• Trisomy: Numerical abnormalities with the presence of one extra chromosome are referred to as trisomy (2n + 1). It may involve either sex chromosomes or autosomes.
• Examples: Down syndrome (patients have three copies of chromosome 21, i.e., 47 XX, +21, hence Down syndrome is often known as trisomy 21), Patau syndrome (trisomy 13; 47 XY, +13), and Edwards syndrome (trisomy 18; 47 XY, +18).
• Monosomy: Numerical abnormalities with the absence or loss of one chromosome (2n 1) are referred to as monosomy. It may involve autosomes or sex chromosomes.
• Monosomy of autosomes is almost incompatible with survival. An example of monosomy of sex chromosomes is Turner syndrome (45 XO) instead of normal XX (46 XX).
• Polyploidy: It is chromosome number that is a multiple greater than two of the haploid number (multiples of haploid number 23).
• Triploidy is three times the haploid number (69), and tetraploidy is four times the haploid number (92).
• Polyploidy is incompatible with life and usually results in spontaneous abortion.

Causes of numerical aberrations

• Numerical aberrations can occur during meiosis and/or mitosis. These errors are due to nondisjunction and anaphase lag.
• Nondisjunction: It is the failure of paired chromosomes to separate during meiosis or mitosis. Meiotic nondisjunction is the most common cause.
• Anaphase lag: Anaphase lag results in the loss of a chromosome during meiosis or mitosis.

 

Klinefelter Syndrome

Question 4. Write a short essay/note on Klinefelter syndrome.
Answer: It is an important genetic cause of male hypogonadism and is associated with reduced spermatogenesis and male infertility.

Klinefelter Syndrome Pathogenesis

• Most patients with Klinefelter syndrome have one extra X chromosome (47, XXY karyotype). It is due to the nondisjunction of the X chromosome during meiosis.
• A minority is mosaic (e.g., 46, XY/47, XXY) or has more than two X chromosomes (e.g., 48, XY) and one or more Y chromosomes.

Klinefelter Syndrome Clinical Features

• Klinefelter syndrome is usually diagnosed after puberty.
• Most patients are tall and thin with relatively long legs (eunuchoid body habitus).
• Mental retardation is uncommon, although the average intelligence quotient (IQ) is reduced.
• At puberty, the testes and penis remain small with a lack of secondary male characteristics.
  • Female characteristics develop which include a high-pitched/deep voice, gynecomastia, and a female pattern of public hair. Sparse facial, body, and sexual hair.
  • Azoospermia results in infertility.

All of these changes are due to hypogonadism and reduced levels of testosterone.

Klinefelter Syndrome Diagnosis

• Buccal smear for Barr body: Extra X chromosome may be seen as a Barr body on buccal smears.
• Nuclear sexing of leukocytes: Neutrophils in the peripheral smear may also be examined for nuclear sexing.
• In a normal female (XX), the neutrophils in a peripheral smear show a drumstick which is the counterpart of Barr’s body in buccal smear.
• One extra drumstick is found in males with Klinefelter syndrome (XXY).
• Chromosomal analysis
• Hormonal status:

Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are remarkably high.

Testosterone: Low to low-normal level.

The ratio of estrogen and testosterone determines the degree of feminization.

Complications of Klinefelter syndrome 

Klinefelter Syndrome Management

• Testosterone: It should be started at puberty (around 12 years ago) and increasing its dosage sufficient to maintain serum concentrations of testosterone, estradiol, FSH, and LH appropriate to the age.
• It promotes normal body proportions and the development of normal secondary sex characteristics. However, it does not affect infertility, gynecomastia, and atrophy of the testis.
• It decreases long-term complications such as breast cancer, autoimmune disease, and osteoporosis.
• Speech therapy.
• Physiotherapy for hypotonia or delayed motor skills.

Turner Syndrome

Question 5. Write a short essay/note on Turner syndrome.
Answer:

• Turner syndrome is a sex chromosomal abnormality. Turner syndrome is characterized by a spectrum of abnormalities due to complete or partial monosomy of the X chromosome in a phenotypic female.
• It is characterized by hypogonadism and is the most common sex chromosome abnormality in females.

Turner Syndrome Karyotypic Abnormalities

• Missing of an entire X chromosome: This results in a 45, X karyotype due to nondisjunction of X chromosomes during meiosis. Genetic constitution hence becomes 45 XO.
• Structural abnormalities of the X chromosomes: These includes isochromosome of the long arm, translocations, ring chromosome, and deletions (Xp/Xq).
• Mosaics: The mosaic patients have a combination of a 45, X cell the population along with one or more karyotypically normal or abnormal cell types.

Examples: (1) 45, X/46, XX; (2) 45, X/46, XY. It is known as mosaic Turner syndrome.

Turner Syndrome Clinical Features

• Turner syndrome is usually not discovered before puberty. It presents with failure to develop normal secondary sex characteristics. Important diagnostic features are:
• Adult women with short stature (<5 feet tall) primary amenorrhea and sterility. Raised FSH levels are noted.

Turner Syndrome Other features are:

• Webbed neck, and low posterior hairline, wide/increased carrying angle at the elbows (cubitus valgus), Madelung deformity of the forearm and wrist, broad chest (shield chest) with widely spaced nipples and hyperconvex fingernails.
• The genitalia remains infantile, and breast development is inadequate, and there is little pubic hair. The ovaries are converted to fibrous streaks. Lack of secondary sexual characteristics.

Complications of Klinefelter syndrome.

• Increased risk of breast carcinoma in 47, XXY (relative risk exceeding 200 times).
• Endocrine complications: Diabetes mellitus, hypothyroidism, and hypoparathyroidism.
• Autoimmune diseases: Systemic lupus erythematosus, Sjogren’s syndrome and rheumatoid arthritis.

Turner Syndrome Decreased bone density:

• Increased risk of ischemic heart disease, mitral valve prolapse, lower extremity varicose veins, venous stasis ulcers, and deep venous thrombosis and pulmonary embolism
• Extragonadal germ cell cancer and non-Hodgkin lymphoma occur in more frequency
• Pigmented nevi and pilomatrixoma as the age advances.
• Congenital lymphedema, short fourth metacarpals and/or metatarsals, horseshoe kidney, osteoporosis.
• Cardiovascular anomalies such as congenital heart disease particularly coarctation of the aorta or bicuspid aortic valve may be present.
• Aortic dissection or rupture is a common cause of death. Systemic hypertension is seen in 30%of cases. No mental retardation.

Intellectual Disability

Question 6. Write a short note on mental retardation and its causes.
Answer:

Definition: It is a neurodevelopmental disorder that begins in childhood and is characterized by limitations in both intelligence and adaptive skills, affecting at least one of three adaptive domains (conceptual, social, and practical), with varying severity.

Earlier was termed mental retardation.

Causes of Intellectual Disability

Assessment of Degree of Intellectual Disability

Adaptive function: Impaired functioning in at least one of the following three domains, affecting participation in multiple everyday settings: conceptual domain, social domain, and
practical domain.

The American Psychiatric Association’s DSM-5 categorizes adaptive impairment from mild to profound.

Intellectual function: It is assessed by IQ testing.

IQ = Mental age/Chronological age

Intellectual Disability Inheritance

Inheritance patterns are classified as either monogenic (Mendelian and non-Mendelian) or polygenic.

Single-Gene or Monogenic Disorders/Mendelian Disorders

Genetic disorders that result from mutations in a single gene are called single-gene or monogenic (Mendelian) disorders.

This type of inheritance is called Mendelian inheritance.

Intellectual Disability Polygenic

Examples: Hypertension, diabetes—caused by the cumulative and interactive effects of genetic variation in more than one
gene.

Question 7. List the characteristics of autosomal dominant inheritance with examples. What do you mean by penetrance and variable expressivity?
Answer:

Autosomal Dominant Pattern of Inheritance

• It is determined by the presence of one abnormal gene on one of the autosomes (chromosomes 1–22)
• The disease is in heterozygotes (These disorders generally manifest when one of the two homologous (paired) chromosomes carries a mutant gene).

The general characteristics of autosomal dominant inheritance:

• Location of mutant gene: These are found on autosomes.
• Required number of defective genes: Only one copy of the mutant (abnormal) gene is required for effects.
• The disorder is transmitted in a vertical (parent to child) pattern, appearing in multiple generations.
• Sex affected: Males and females are equally affected.
• Pattern of inheritance: Every affected individual has one affected parent.
• Unaffected individuals (family members who do not manifest the trait) do not pass the disorder to their children.
• Risks of transmission to children (offspring): Affected males and females have an equal risk of passing on the disorder to children.

Causes of intellectual disability.

• Genetic and chromosomal disorders, For Example, Down syndrome and Fragile X syndrome
• CNS lesions:
  • Hydrocephalus
  • Microcephaly
  • Cerebral palsy
  • Post-traumatic, postmeningitic, and postencephalitic states
• Birth trauma, kernicterus

Environmental causes:

• • Associated intrauterine infections: Congenital infections, congenital rubella syndrome, cytomegalovirus, and other viruses
  • Intrauterine exposure to toxins and other insults: Alcohol, hypoxia or malnutrition
  • Postnatal causes: Exposure to toxins, infection, and heavy metals
• Metabolic disease, e.g., cretinism, phenylketonuria, mucopolysaccharides, inborn errors of metabolism (e.g., glycogen storage diseases)

When only one parent is affected and other is normal: An affected individual has a 50% (1 in 2) chance of passing on the deleterious genes for each pregnancy, and therefore of having a child affected by the disorder.

This is called as the recurrence risk for the disorder.

When both parents are affected: It has 75% chance of children being affected and a 25% chance to be normal.

Finding of male-to-male transmission essentially confirms autosomal dominant inheritance.

Examples of autosomal dominant and autosomal recessive disorders are listed.

Additional properties:

• Penetrance: Penetrance is the percentage of individuals with the mutation who present with clinical symptoms.
• With complete penetrance, all individuals show clinical symptoms.
• With incomplete penetrance or reduced penetrance, only some individuals show disease and in nonpenetrance (gene is not expressed at all) individuals may not show any symptoms.
• For example, retinoblastoma: AD malignant eye tumor is a good example of reduced penetrance. About 10% of the obligate carriers of the RB susceptibility gene (affected parent and affected child or children) do not have the disease.
• Variable expressivity: It refers to variations in expression (qualitatively or quantitatively) of the severity of the same
  disorder among individuals (even within the same family), who have the abnormal gene. In some, the disorder may be mild and in others, it may show significant symptoms. Penetrance may be complete, but the severity of the disease can vary greatly. A well-studied example is neurofibromatosis type 1, or von Recklinghausen disease.

Question 8. Discuss autosomal recessive inheritance with examples.
Answer:

• Autosomal Recessive Pattern of Inheritance
• Autosomal recessive inheritance involves mutations in both copies of a gene.

These disorders generally manifest when both the homologous chromosomes carry mutant genes (homozygous state).

The general features of these disorders are:

Location of mutant gene: These genes are located on autosomes.

Required number of defective gene: Symptoms of the disease appear only when an individual has two copies of the mutant gene.

The heterozygote state is called as a carrier. In the carrier state, the product of the normal gene is able to compensate for the mutant allele and is hence the patients are asymptomatic.

Horizontal transmission: The observation of multiple affected members of kindred in the same generation, but no affected family members in other generations.

Pattern of inheritance: For a child to be at risk, both parents must be having at least one copy of the mutant gene.

Almost all inborn errors of metabolism are autosomal recessive disorders.

• Sex affected: Males and females being equally affected, though some traits exhibit different expression in males and females (ovarian cancer, hypospadias).
• Consanguineous marriage: It is common predisposing factor. Recurrence risk of 25% for parents with a previous affected child.
• Risks of transmission to children (offspring):
  • When both parents are heterozygous for the condition: Heterozygous parents carry one mutated gene and normal gene.
  • When two heterozygotes mate, 25% of the children will be affected, 50% will be unaffected heterozygotes and 25% will be normal.
  • When one parent is affected and the other is normal: All the children will be unaffected heterozygote.
  • When one parent is affected and the other is heterozygote: The chances are that 50% of children will be unaffected heterozygote and 50% homozygous affected.
  • When one parent is normal and the other is heterozygote: This may result in 50% unaffected heterozygote carriers and 50% normal children.
• If the frequency of an autosomal recessive disease is known, then frequency of the heterozygote or carrier state can be calculated from the Hardy-Weinberg formula: p2 + 2pq + q2 = 1, where p is the frequency of one of a pair of alleles and q is the frequency of the other.

Examples of autosomal dominant and autosomal recessive disorders.

X-Linked Pattern of Inheritance

Question 9. Discuss X-linked inheritance with examples.
Answer:

Almost all sex-linked Mendelian disorders are X-linked. Males with mutations affecting the Y-linked genes are usually infertile.

Expression of an X-linked disorder is different in males and females. Though X-linked disorders may be inherited either as dominant or recessive, almost all X-linked disorders have recessive pattern of inheritance.

Characteristics of X-linked inheritance:

• Males are more commonly and more severely affected than females.
• Female carriers are generally unaffected, or if affected, they are affected more mildly than males.
• Affected males will have only carrier daughters.
• Carrier women have a 25% risk for having an affected son, a 25% risk for a carrier daughter, and a 50% chance for a child that does not inherit the mutated X-linked gene.

X-linked Recessive Traits

• Location of mutant gene: Mutant gene is on the X chromosome and there is no male-to-male transmission.
• Required number of defective gene: One copy of mutant gene is required for the manifestation of disease in males, but
  two copies of the mutant gene are needed in females.
• Sex affected: Males are more frequently affected and manifest disease than females; daughters of affected male are all asymptomatic carriers. In many diseases, males do not survive.
• Pattern of inheritance: Transmission is through female carrier (heterozygous). Mothers are always carriers and all their sons are affected. The disease is never passed from father to son.

• Very rarely, a female can develop the disease due to:
  • Female having Turner syndrome (XO) with only one X chromosome.
  • Presence of testicular feminization syndrome.
  • Father with mutation in X chromosome and a carrier female.
  • Affected father and carrier mother.
  • Inactivation of normal X chromosome in most cells (Lyon hypothesis).

Examples of X-linked recessive disorders

X-linked Dominant Conditions.

• Disorders are relatively uncommon (very rare). For example, vitamin D resistance rickets, Alport’s syndrome, Rett syndrome.
• Location of mutant gene: It is located on the X chromosome and there is no transmission from affected male to son. This is because the son’s “normal” X chromosome is from mother.
• Required number of defective gene: One copy of mutant gene is required for its effect.
  • Often lethal in males and so may be transmitted only in the female line.
  • Often lethal in affected males and they have affected mothers.
  • There is no carrier state as the disease will manifest, even if single chromosome has abnormal gene.
  • These are more frequent in females than in males.

Risks of transmission to children (offspring):

• When female is affected and the male is normal: They transmit the disorder to 50% of their sons and 50% of their daughters.
• When male is affected and the female is normal: They transmit to all their daughters but none to their sons.
• All daughters of an affected father develop disease because the daughter gets abnormal X from the father.
• When both male and female are affected: All the females will be affected and half of males will be affected.

Y-linked Diseases

Y-linked Diseases Characterized by:

• Only males are affected.
• An affected male transmits the disorder to all his sons but not to his daughters.
• Most Y-linked genes are related to male sex determination and reproduction, and are associated with infertility.
• Therefore,it is rare to see familial transmission of a Y-linked disorder.
• For example, Leri-Weill dyschondrosteosis, Langer mesomelic dwarfism, Hairy ears.

Y-linked Diseases Digenic Inheritance

• Digenic inheritance explains the occurrence of retinitis pigmentosa (RP) in children of parents who each carry a different RP-associated gene.
• Both parents have normal vision, but the offspring who were double heterozygotes developed RP.
• Digenic pedigrees exhibit characteristics of both autosomal dominant (vertical transmission) and autosomal recessive inheritance (1 in 4 recurrence risk).
• Other disorders with digenic inheritance—Bardet-Biedl syndrome, Hirschsprung disease, Long QT syndrome.

Y-linked Diseases Mitochondrial Inheritance

• An individual’s mitochondrial genome is entirely derived from the mother.
• Examples include Leber optic atrophy, MELAS (myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), MERRF (myoclonic epilepsy associated with ragged red fibers), and Kearns-Sayre syndrome (ophthalmoplegia, pigmentary retinopathy, and cardiomyopathy).

Y-linked Diseases Pseudodominant Inheritance

Pseudodominant inheritance of a recessive trait in two generations of a family without consanguinity mimics a dominant pattern.

Pseudodominant inheritance of hereditary hemochromatosis (HH), an autosomal recessive disorder, can be attributed to the high carrier frequency of HFE alleles in individuals of European descent.

In this case, the father is homozygous for the mutated alleles and the mother is the carrier of the genetic mutation; therefore, there are 50% chances that the offspring will
inherit mutated genes from both the parents and will have hemochromatosis.

Y-linked Diseases Triplet Repeat Expansion Disorders

• Caused by expansion in the number of three-basepair repeats.
• An error in replication can result in expansion of that number, referred to as premutation.
• There is a clinical correlation to the size of the expansion, with a greater expansion causing more severe and/or earlier age of onset for the disease.

The observation of increasing severity of disease and early age of onset in subsequent generations is termed genetic anticipation and is a defining characteristic of triplet repeat expansion disorders.

Examples of triplet repeat expansion disorders are listed.

Simple Tandem Repeat Mutation

• Variations in the length of simple tandem repeats of DNA are thought to arise as the result of slippage of DNA during meiosis and are termed microsatellite (small) or minisatellite (larger) repeats.
• These repeats are unstable and can expand or contract in different generations. This instability is related to the size of the original repeat, in that longer repeats tend to be more unstable.
• For example, Huntington disease, sickle cell anemia, MJD, Fragile X, myotonic dystrophy.

Y-linked Diseases Genetic Imprinting

• The two copies of most genes are functionally equivalent. In a small number, only one of the pair is transcribed.
• The active gene will be that inherited from a specific parent, and the other copy is silenced associated with methylation of DNA (epigenetic modification of a gene not due to a DNA mutation).

Conditions Associated with Genetic Imprinting

• Prader-Willi syndrome with paternal chromosome deletion.
• Angelman syndrome with maternal chromosome deletion.
• Uniparental disomy (UPD): Rare occurrence of a child inheriting both copies of a chromosome from the same parent is another genetic mechanism that can cause Prader-Willi and Angelman syndromes.
• Other conditions associated with imprinting are Beckwith-Wiedemann syndrome and Russell-Silver syndrome, Duchenne muscular dystrophy (DMD) in females and epigenetic silencing in oncogenesis, For Example, colon cancer 3p21 MLH1.

Y-linked Diseases Pleiotropy

• Genes that exert effects on multiple aspects of physiology or anatomy are pleiotropic.
• For example: Marfan syndrome (affects eye, the skeleton, and the cardiovascular system), cystic fibrosis (affects sweat glands, lungs, pancreas, and genitourinary system), osteogenesis imperfecta (affects bones, teeth, and sclera), sickle cell anemia (affects RBCs, bone, and spleen).

Y-linked Diseases Locus Heterogeneity

• Disease that can be caused by mutations at different loci in different families is said to exhibit locus heterogeneity.
• Osteogenesis imperfecta (OI): Subunits of procollagen triple helix are encoded by two genes, one on chromosome 17 and the other on chromosome 7. Mutation in either of these genes can alter the structure of the collagen molecules and lead to OI, disease states are often indistinguishable.

Y-linked Diseases Polymorphisms

• A polymorphism is defined as one that exists with a population frequency of >1%.
• Most common polymorphisms are neutral but some cause subtle changes in gene expression or in protein structure and function.
• For example, cystic fibrosis, hemochromatosis, alpha-1 antitrypsin deficiency, spinomuscular dystrophy.

 

Question 12. Write a short note on gene mutations.
Answer:

Gene mutations

Types of gene mutations include:

• Point mutation: alteration of a single DNA base pair, e.g., sickle-cell disease
• Deletion: loss of one or more base pairs, e.g., cystic fibrosis
• Insertion: addition of one or more base pairs, e.g., beta-thalassemia
• Substitution: one or more base pairs are replaced by different base pairs
• Trinucleotide repeat expansion:
  • Increased repetition of base triplets that leads to faulty protein synthesis or folding
  • Examples: fragile X syndrome, Huntington disease, myotonic dystrophy.

Gene mutations can be classified based on the outcome:

Frameshift mutation:

• Shift in the reading frame caused by insertion or deletion of a number of nucleotides not divisible by 3, which leads to modified amino acid coding in the gene segments downstream.
• It results in the synthesis of shorter or longer proteins that have a modified function or are dysfunctional.
• Examples: Tay-Sachs disease, Duchenne muscular dystrophy

In-frame deletion or insertion:

Deletion or insertion of three, six, nine, or more base pairs (always in triplets!), without a shift in the reading frame, but with deletion or insertion of one, two, three, or more amino acids in the protein during translation.

Silent mutation:

• Altered codon, which codes for the identical amino acid

Nonsense mutation:

• Formation of a stop codon, which leads to alterations in the splicing process and early termination of translation

Missense mutation:

• Altered codon, which codes for a different amino acid
• Example: sickle cell disease (glutamic acid → valine)
• Considered as “conservative” missense mutation when the new amino acid is similar in chemical structure to the original amino acid

Splice mutation:

• Alterations (especially point mutations) in the nucleotide sequences required for splicing (e.g., on the exon-intron border or at the junction) that lead to defective mRNA and shortened proteins
• Examples: some types of β-thalassemia, dementia, cancers, and epilepsy

Dominant negative mutation:

• A gene mutation that results in a nonfunctional protein that impairs the function of protein produced by the wild-type allele in heterozygotes

Miscellaneous

Question 13. Write short note on proteomics/proteome.
Answer:

Miscellaneous Proteome

• The term proteome is derived from proteins expressed by a genome. It refers to all the proteins produced by an organism and proteins are the functional units.
• Thus, the proteome represents full sets of proteins produced by the body and is similar to the term genome for the entire set of genes.
• Human body contains more than 2 million different proteins, each having different functions.
• Proteomics is the study of the proteome (full set/entire library of proteins in a cell type or tissue) and its variation/ relationship to disease.
• Amino acids are the basic units of proteins and are very small. Each amino acid consists of atoms ranging from 7 to 24 and cannot be identified under even the powerful microscopes.

Uses: Proteomic technologies play an important role in drug discovery, diagnostics, and molecular medicine.

When a defective protein-causing particular diseases are found, new drugs can be developed to either alter the shape of a defective protein or mimic a missing one.

Epigenetics

Question 14. Write a short note on epigenetics.
Answer:

Epigenetics Definition: Epigenetics is a reversible, heritable change/alteration in gene expression which occurs without mutation and is unrelated to gene nucleotide sequence.

Epigenomics is the study of epigenetics. Epigenetic alterations are associated with cancers and other diseases.

Unlike genetic changes in cancer, epigenetic changes are reversible.

• In normal cells, the majority of the genome is not expressed. Some portions of the genome are silenced by DNA methylation and histone modifications.
• In some tumors, epigenetic changes may directly contribute to tumor development.
• Epigenetic changes involve posttranslational modifications of histones and DNA methylation, both of which affect gene expression.
• In cancer cells, there is global DNA hypomethylation and selective promoter-localized hypermethylation.

Epigenetics Examples

1. Silencing genes by hypermethylation (epigenetic mechanism)

1. Tumor suppressor genes: Examples: p53 can be indirectly inactivated through silencing ARF by hypermethylation. Ths hypermethylated ARF prevents inhibition of the MDM2 oncogenic protein and the enhancement of p53 degradation; BRCA1 in breast cancer and VHL in renal cell carcinomas.
2. DNA repair genes: Mismatch-repair gene MLH1 in colorectal cancer.

2. Hypomethylation: The genome of cancer cells may also undergo global DNA hypomethylation.

Gene hypomethylation can cause chromosomal instability, derepression of growth regulatory genes, and overexpression of antiapoptotic genes, which may induce tumors.

Epigenetics Clinical Applications

• Use of epigenetic tumor markers.
• Use of epigenetic therapeutic agents (e.g., azacitidine, decitabine, vorinostat) in the treatment of myelodysplastic syndromes (MDS) and lymphoma.

Pharmacogenomics

Question 15. Write short note on pharmacogenomics and pharmacogenetics.
Pharmacogenetics or pharmacogenomics is the study of interaction between genetics and therapeutic drugs.
Answer:

• Pharmacogenetics is the study of unexpected drug response result and to look for a genetic cause.
• Pharmacogenomics is the study of identifying genetic differences within a population that explain certain observed responses to a drug or susceptibility to a health problem.

Pharmacogenomics Applications

• To develop a drug that has maximum therapeutic effect and produces least damage to adjacent healthy cells.
• To prescribe drugs depending on the patient’s genetic profile so as to reduce the adverse reactions.
• To determine the accurate dosage.
• To determine drug responses in the treatment of cardiac, respiratory, and psychiatric conditions.
• To develop targeted therapy (e.g., psychiatry, dementia, cardiac conditions) and in the treatment of breast cancer (testing for HER2 receptor for response to trastuzumab) and other cancers (e.g., testing for BCR-ABL for response to imatinib in CML; testing for epidermal growth factor receptor response to gefitinib and erlotinib in lung cancer).

List of chromosomal disorders are presented

Genetic Testing

Indications of genetic testing

Genome-wide Association Study

• Genome-wide association studies (GWASs) test hundreds of thousands of genes simultaneously and are used in genetics research to associate specific genetic variations with particular diseases.
• It involves scanning the genomes from many different people and looking for genetic markers that can be used to predict the presence of a disease.

Polymerase Chain Reaction And Its Applications

Digeorge Syndrome

Question 17. Write a short note on DiGeorge syndrome.
Answer:

DiGeorge syndrome (DGS) is a constellation of signs and symptoms associated with defective development of the pharyngeal pouch system.

Most cases are caused by a heterozygous chromosomal deletion at 22q11.2.

Chromosome 22q11.2 deletion syndrome (22qDS) includes DGS and other similar syndromes, such as velocardiofacial syndrome.

The classic triad of features of DGS on presentation is conotruncal cardiac anomalies, hypoplastic thymus, and hypocalcemia (resulting from parathyroid hypoplasia).

Digeorge Syndrome Cardiac anomalies

• Interrupted aortic arch
• Truncus arteriosus
• Tetralogy of Fallot
• Atrial or ventricular septal defects

Digeorge Syndrome Hypocalcemia: Hypocalcemia, resulting from underdevelopment of the parathyroid glands and may present with jitteriness, tetany, or seizures, with low serum calcium, elevated serum phosphorus, and very low parathyroid hormone levels.

Hypoplastic/aplastic thymus: The thymus is absent in patients with complete DGS. In patients with partial DGS, the thymus is present, although it is often reported as hypoplastic.

Immunodeficiency: Immunodeficiency is common in patients with DGS and can range from recurrent sinopulmonary infections (termed partial DGS) to severe combined immunodeficiency (SCID)

Genetic Counseling

Question 18. Write a short note on genetic counseling.
Answer:

Genetic counseling is the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease.

This process integrates:

• Collection of a detailed family history, interpretation of the family history with the medical history to assess the chance of disease occurrence or recurrence
• Education of the patient and family regarding the inheritance, testing, management, risk reduction, available resources and research regarding the condition
• Counseling to promote informed choices and appropriate interventions

Genetic counseling can be conducted from preconception to old age.

This includes preconception and prenatal counseling about the potential health of a baby, genetic evaluation of a neonate with birth defects or a toddler with developmental delay.

Family history: The initial step in assessing inherited risk for many chronic conditions is collecting data related to the family history.

Key factors that suggest the presence of a genetic disorder include the following:

• Multiple affected individuals in multiple generations from either side of the individual’s family.
• Occurrence of the disease at an earlier age than usual.
• Close degree of relatedness (i.e., first- or second-degree relative) between affected relatives and the individual.

Once the family history is collected, it is used with the medical history to assess the possibility of an inherited etiology and to identify the chance of disease occurrence or recurrence.

Once an objective risk figure has been determined, the genetic counselor can provide explanations of penetrance and expressivity and apply these to the patient’s family history and assess personal risk.

Risk modification: The genetic counseling session also provides information about risk modification strategies (if available) that may be appropriate for the patient and/or family.

This may involve more aggressive screening (earlier, more frequent), lifestyle or dietary modifications, and medical or surgical interventions.

Examples include:

Familial cancer syndromes: A patient with hereditary breast and ovarian cancer syndrome is at risk for both types of cancers and may have earlier mammography and clinical breast examinations and prophylactic surgeries.

Prenatal counseling: Testing for the partner may be indicated for autosomal recessive conditions when a couple is referred for prenatal counseling.

Question 19. Write a short note on enzyme replacement therapy.
Answer:

Enzyme replacement therapy (ERT) is a type of treament which replaces an enzyme that is deficient or absent in the body.

Enzymes can be made by recombinant DNA technology and can be given by
intravenous injection.

ERT has also been successful in treating SCID caused by an adenosine deaminase (ADA) deficiency.

Enzyme replacement therapy for diseases