Medical Genetics

Genetics plays an important role in the field of medical sciences. There arises a genetic base to a disease, the development, reproduction, and other processes in the body. The gene or a blueprint of life occurs in every cell and is an important inheriting factor. Hence, it is important to understand genes and their role in various diseases, cancers, developmental stages, and interactions with various components. Some of the genes encode for proteins. The genes get passed on from one generation to the next generation. They also carry any minute changes or mutations. The diverse population is a sign of variation. Due to recent advances in health research, more and more diseases showed a genetic base. The science of genetics helps in detecting many diseases. It helps in their treatment or prevention. When you try to understand the molecular intricacies of the genetic material, you will be amazed to see an entirely different world. Thousands of reactions keep occurring at a molecular level.

DNA, the blueprint of life consists of nucleotide base pairs attached to the phosphodiester bonds. Small units of DNA form genes and exhibit specific functions. Various disorders arise due to gene mutations. Hence, they are known as genetic disorders. Detection of genetic disorders involves modern genetic diagnostic techniques. There involves the tremendous importance of genetics in medical sciences. To understand its role in health and disease, we must know the basic concept of genetics. 

The review covers the following topics in detail:

1.     What are genes and various branches of genetics?

2.     Chromosomes and disorders associated with the genes

3.     Disorders inherited due to faulty genes

4.     The role of gene mutations in biochemical disorders

5.     Detection of genetic disorders

6.     Genetic counseling

7.     Gene Cloning and DNA analysis

8.     Gene therapy

Image 1: Medical genetics

Various branches of genetics:

Human genetics involves several branches such as cytogenetics, molecular genetics, biochemical genetics, cancer genetics, Immunogenetics, and developmental genetics. Cytogenetics is the study of chromosomes and various disorders associated with the same. A chromosome is a specialized structure consisting of DNA-protein complex packed in a condensed manner. Cytogenetic techniques help in studying these structures. Molecular genetics involves the study of genes at the molecular levels such as single base pair changes, mutations, and other studies. Biochemical genetics involves genes controlling the enzyme production. Cancer genetics involves studying cancer genes and mutations associated with cell cycle control. Different antigen-antibody interactions studies involve immunogenetics. Developmental genetics helps to study the genetic control of the development. Hence there are many such branches of genetics. The field of genetic science is very vast. Half the rate of first trimester abortions involves chromosomal abnormalities. Congenital malformations, childhood blindness, deafness, and mental retardation mostly occur due to gene mutations.

Chromosomes and disorders associated with the same:

Every cell in the human body constitutes chromosomes. The chromosome complement in humans consists of autosomes and sex chromosomes. There are 22 pairs of autosomes and a pair of sex chromosomes. They are known as X and Y chromosomes respectively. A normal male has 22 pairs of autosomes, an X, and a Y chromosome. A normal female has 22 pairs of autosomes and two X chromosomes. Karyotyping involves arranging the chromosomes as per the groups resulting in a photomicrograph. This photomicrograph or a karyotype consists of autosomes and sex chromosomes arranged in groups. Structural and numerical abnormalities in the chromosomes result in genetic disorders. They are known as chromosomal anomalies or chromosomal abnormalities.

Disorders due to an abnormal number of chromosomes are known as numerical anomalies. They arise due to non-disjunction of chromosomes. Monosomies (one chromosome less), trisomies (one chromosome extra), and many other conditions consist of chromosomal anomalies. Down’s syndrome is an example of trisomy. It occurs due to trisomy of the 21^st chromosome. Disorders associated with the structural abnormalities of chromosomes are known as structural anomalies. Deletions, duplications, inversions, and translocations arise due to the structural anomalies of the chromosomes. They also result in conditions such as mosaicism.

Disorders inherited due to faulty genes:

Monogenic or single gene disorders are the genetic disorders arising due to the inheritance of a mutated gene. Two main types of inheritance include autosomal inheritance and sex-linked inheritance. Autosomal inheritance involves autosome related disorders or traits. Inheritance of the traits due to the expression of genes present on the sex chromosomes is known as a sex-linked inheritance. Autosomal dominant inheritance manifests the trait even if the mutant gene occurs in a single dose. For example, Huntington’s disease arises due to abnormal CAG nucleotide repeat. Autosomal recessive inheritance manifests the trait even if the gene is present in the double dose (homozygous). An example includes sickle-cell anemia. Sex-linked inheritance is either X-linked or Y-linked. The X-linked inheritance occurs in a dominant or a recessive form. Very few cases report Y-linked inheritance.

Polygenic or multifactorial inheritance depends on many genes. The traits are known as quantitative traits and depend on many factors. Abnormalities in mitochondrial DNA (mtDNA) occur due to mitochondrial inheritance. The genes do not behave as dominant or recessive in polygenic inheritance. They exhibit an additive effect on the trait.

Biochemical genetics:

This area of genetics deals with the genetic control of the metabolic pathways. According to the one gene-one enzyme hypothesis proposed by Beadle and Tatum, metabolic processes occur in various steps controlled by enzymes. Each enzyme gets coded by one gene. Inborn error of metabolism arises due to enzyme unavailability or insufficiency occurring as a result of related gene mutations. The inborn error of metabolism follows Mendelian inheritance pattern. PKU, a classic example of the inborn error of metabolism, arises due to the deficiency of phenylalanine hydroxylase.

Image 2: The role of genetics in medicine

Detection of genetic disorders:

Cytogenetic and molecular genetic studies or tests detect various anomalies. The prenatal diagnosis helps to detect abnormalities in the fetus before birth. Examples of prenatal tests include Amniocentesis, chorionic villus sampling, fetoscopy, ultrasonography, maternal serum screening, and fetal blood sampling. Non-invasive prenatal tests also help in detecting the fetal DNA through maternal serum testing. Karyotyping helps to detect chromosomal abnormalities. FISH and other hybridization techniques detect minute changes in the DNA. SNP genotyping involves PCR, agarose gel electrophoresis, and gel documentation systems.

Genetic counseling:

It is a specialized session with a genetic counselor. The genetic counselor is an expert in genetics and a trained professional who guides the couples and patients suspected with the genetic disorders. Genetic counseling helps in the risk assessment of hereditary diseases, repeated abortions, and stillbirth cases. It also helps in reducing the risk of having a baby with the genetic and other ailments including the inborn errors of metabolism.

Gene cloning and DNA analysis:

Gene cloning involves cloning the gene of interest for incorporation into the desired vector. It has a wide range of applications in recombinant DNA technology. It helps in expressing the desired products such as proteins, vitamins, and other molecules. Peptide vaccines and hormones get developed using gene cloning. DNA analysis using techniques such as DNA fingerprinting help to solve parental issues. Analyzing DNA and genotyping techniques help in detecting gene mutations.

Gene therapy:

It helps in replacing the gene that has lost its function. The first step involves defective gene identification and cloning the normal gene in place of the defective gene. The normal gene insertion includes a vector. The first gene therapy gained success in case of a child having ADA deficiency associated with severe combined immunodeficiency syndrome (SCID). 

References:

[1] Emery’s elements of Medical Genetics, Peter D. Turnpenny

[2] Chromosome Abnormalities and Genetic Counseling,  R.J. MKinlay Gardner, Grant R Sutherland, Lisa G. Shaffer
[3] Medical Genetics, G. Bradley Schaefer, James N. Thompson

Copyright, 2018 All Rights Reserved

Prenatal diagnosis

Genetic disorders are difficult to treat.  It is very important to diagnose a genetic disorder. The prenatal diagnosis helps to detect genetic abnormalities before birth. Prenatal diagnosis involves various techniques such as ultrasonography, fetal blood sampling, fetoscopy, maternal serum screening, testing cell-free DNA, amniocentesis, and chorionic villus sampling.

What is the prenatal diagnosis?

The prenatal diagnosis serves in detecting the genetic abnormalities in a child before birth. Thus, it helps the parents in decision making.

The high-risk couples get a chance to decide.  Following couples get the benefit of prenatal diagnosis:

1.     The family history of genetic disorders

2.     Women above 35 years expecting a baby

3.     The family history of neural tube defects

4.     The first child has chromosomal abnormalities or any genetic condition

5.     Couples having a first child with Down's syndrome

6.     Diabetics

7.     Carrier mothers

Period of screening	Prenatal screening tests	Estimation of risk
First trimester	Blood tests	·        Estimate the level of pregnancy-associated placental protein A ·        Beta-human chorionic gonadotropin ·        Help in estimating the risk of Down’s syndrome
	Ultrasonography	·        Detection of the abnormalities associated with the neck and back of the fetus.
	Cell-free fetal DNA (cfDNA testing)	·        Determine chromosomal abnormalities.
	Chorionic villus sampling, amniocentesis	·        Amniocentesis helps in estimating the alpha-fetoprotein. ·        Help in the detection of chromosomal abnormalities.
Second trimester	Blood tests	·        Alpha-fetoprotein ·        Estriol ·        HCG ·        Inhibin A ·        Detection of neural tube defects ·     Complications associated with miscarriages
	Ultrasonography Amniocentesis Triple screening	·        Determine the presence of more than one fetus ·        Determine  defects

Table: Estimation of risk using prenatal diagnosis

Amniocentesis:

Amniocentesis involves chromosomal abnormalities to get detected by a collection of the amniotic fluid. It involves obtaining the cells of the developing fetus for analysis. The procedure gets performed between 14-16 weeks of pregnancy.

The amniotic fluid analysis helps in detecting neural tube defects by estimating alpha-fetoprotein with a raised level in the amniotic fluid. The amniotic fluid is a protective fluid that surrounds the developing fetus. It serves as a cushion against shock. The amniotic sac provides a favorable environment for fetal development. Amniocentesis is a very specialized procedure that requires an expert. The procedure is extremely risky and needs proper concentration and careful examination. The amniotic fluid is collected using a syringe needle injection through the uterine wall and amniotic sac. This fluid consists of fetal cells. These cells are analyzed further for the chromosome studies. The fetal cells are cultured in the laboratory. Various tests such as DNA tests and biochemical tests for enzyme deficiencies are carried out.

Image: Amniocentesis

Chorionic villus sampling:

Chorionic villus sampling is a form of biopsy. It involves sampling of the fetal tissue which contains a large number of fetal cells. It detects chromosomal disorders as well as single gene disorders. The procedure is carried out during 10 to 11 weeks of the gestation period. The risk of abortions reduces with this type of detection. This procedure is carried out at early stages of pregnancy. Chorionic villus sampling between the 8^th and 12^th weeks of pregnancy is ideal. The amniocentesis is ideal after the 12^th week of gestation. A membrane layer surrounding the fetus is known as a chorion.

Non-Invasive Prenatal Testing:

The reason for conducting a genetic test involves the detection of any mutations occurring in the fetus before birth. Prenatal diagnosis is an important application of genetic testing. Hence, we check whether the fetus is at risk. Two main procedures such as prenatal diagnosis and chorionic villus sampling involve a lot of risk for the mother and the baby. They are very painful too. Hence, it led to the development of non-invasive prenatal testing (NIPT). The maternal plasma shows the presence of fetal DNA. It is a cell-free DNA floating in the plasma of the expected mother. The abbreviation of cell-free DNA is known as cfDNA. Hence, it is possible to collect plasma samples of the expected mothers for analyzing cfDNA. NIPT is a simple, harmless, and painless procedure. It detects gene mutations and chromosomal abnormalities. The embryos with chances of serious genetic disorders get removed before the implantation stage.

Fetoscopy:

It is a kind of endoscopy that enables to visualize the fetus.  A fetoscope is a fibro-optic self-illuminated instrument that gets inserted in the amniotic cavity under local anesthesia. Cleft lip, cleft palate, facial malformations, limb defects, and skin disorders get detected with the help of fetoscopy.

Ultrasonography:

The 12^th week of pregnancy is an ideal period for performing ultrasonography test. However, the first and the second trimesters may involve the test. It is an ultrasound-based imaging technique involved in the purpose of diagnosis.  The high-frequency sound waves help in generating images. Ultrasounds help in confirming the pregnancy. It helps in checking the fetal heartbeat and help in detecting any abnormality in the fetus. It detects an ectopic pregnancy. It is a condition in which the fetus does not attach to the uterus. It is possible to determine the sex of the baby using ultrasonography. During the second trimester, it helps to determine the possible characteristics of the Down’s syndrome or any other physical abnormalities in the baby.

Maternal serum screening:

The indication of the level of alpha-fetoprotein uses maternal serum screening. The raised level of alpha-fetoprotein indicates neural tube defects, including spina bifida and anencephaly.

Fetal blood sampling:

It involves a prenatal diagnosis of hemophilia, thalassemia, sickle cell disease, immune deficiency disorders, and chromosomal analysis. It requires a small amount of blood from the fetus or the unborn baby.

Conclusion:

Although prenatal testing serves for the detection of many genetic conditions, still many babies are born with the genetic conditions every year. The reason involves the lack of proper knowledge regarding familial disorders, pregnancy risks, and many other environmental conditions. It is important for the physicians to be familiar with the risks associated with the genetic disorders and the genetic tests available for the same. The knowledge of prenatal testing and genetic counseling helps to prevent the birth of the babies with the defects and help in decision making.

References:
[1] Human Genetics, 3/e, Gangane
[2] Chromosome Abnormalities and Genetic Counseling, R.J. McKinlay Gardner, Grant R Sutherland, Lisa G. Shaffer
[3] Essential Medical Genetics, Edward S. Tobias, Michael Connor, Malcolm Ferguson-Smith
[4] Thompson & Thompson Genetics in Medicine, Robert L. Nussbaum, Roderick R. McInnes, Huntington F. Willard

                                     © Copyright, 2018 All Rights Reserved.

Genetic Counseling

Genetic counseling involves counseling of a patient regarding the risk of disease inheritance. A genetic disorder is a condition with a problem in the genome. Genetic disorders may be inherited. Treatment of genetic disorders is difficult. Genetic counseling helps prevent the disease. It involves a discussion about the risk factors of genetic disorders and their management. Genetic counseling gives an idea of the possible risks of giving birth to a child with a genetic defect.

Indications for Genetic Counseling:

People with the following conditions require a genetic counseling session:

·        The family history of genetic disorders.

·        Women who are above age 35 and wish to conceive.

·        People who have a child with genetic defects.

·        Women with repeated spontaneous abortions.

·        Issues of disputed paternity.

·        Cousins marriage.

Who is a Genetic Counselor?

Genetic counselors are specified counselors with genetics background. They are certified to practice genetic diagnosis, counseling, and management of genetic disorders. Genetic counselors help patients in decision making. They are professionals in medical genetics. The patients first fix an appointment with the genetic counselor. The genetic counselor may choose a specific genetic test based on the careful examination of the individual. After the test result, the genetic counselor interprets it and explains it to the patient. In the case of patients with repeated abortions, prenatal diagnosis may be adviced.

Diagnosing a genetic disorder is extremely important. The patient and his relatives must be well informed. They must know the prognosis and treatment. A genetic counselor may diagnose genetic disorder based on the three important parameters such as family history, careful examination of the patient and laboratory investigations.

Carrier detection and fetal analysis are helpful in detecting genetic disorders. Carrier detection identifies heterozygosity for a recessive gene mutation. Thus it helps in the risk assessment. An example of heterozygosity is a sickle cell trait. People having a sickle cell trait possess HbA/HbS genotype. Hence, these individuals are known as heterozygotes. The fetal analysis involves two main procedures such as amniocentesis and chorionic villus sampling.

Image 1: Genetic counseling

Prenatal and Postnatal Genetic Counseling:

About 3% of babies are born with defects per year. Prenatal genetic counseling is not useful for those who are about to deliver the baby. It helps before pregnancy or during the initial stages of pregnancy. Cleft lip, cleft palate, and club feet are the most common defects that can be corrected by surgery. Postnatal genetic counseling is helpful for an inborn error of metabolism.

Risk of Abnormalities in Normal Population:

Risks	Ratio
Risks of congenital abnormality	1 in 30
Risk of a serious mental or physical handicap	1 in 50
Risk of spontaneous abortion	1 in 8
Risk of perinatal death	1 in 30 to 1 in 100
Risk of infertility	1 in 10

Table: It mentions the risk of abnormalities and their corresponding ratios.

Family History and Pedigree Analysis:

Mode of inheritance is studied using pedigree analysis. A pedigree represents the presentation of family information in the form of charts. A family tree is constructed using standardized symbols. Pedigree analysis helps to study the inheritance of the genes.

There are two types of pedigree:

1.Dominant pedigree: It involves studying traits that exhibit dominant gene action. There are two conditions for assessing this. Individuals have an affected parent. Sometimes both the parents may be affected. A phenotype appears in every generation.

2.Recessive pedigree: It exhibits a trait with a recessive gene. In this, an unaffected parent can have an affected offspring. Affected progeny are both male and female.

Image 2: Pedigree analysis of dominant and recessive types of inheritance

Laboratory Investigations:

Genetic tests are performed using a sample of blood, hair, amniotic fluid, skin or any other part. The samples are analyzed further. Laboratory investigations may include biochemical analysis, chromosomal analysis, and molecular studies. Prenatal diagnosis detects abnormalities in the fetus before birth.

Techniques for prenatal diagnosis include:

·        Amniocentesis

·        Chorionic villus sampling

·        Fetoscopy

·        Ultrasonography

·        Maternal serum screening

·        Fetal blood sampling

Determination of Mode of Inheritance:

There are five modes of inheritance such as Autosomal dominant, autosomal recessive, sex-linked, mitochondrial and multifactorial inheritances. Couples with an affected first child must know the status of the next pregnancy. The study of the mode of inheritance may help to detect the presence or absence of abnormalities in the second child. It may help to assess the risk of disability.

Decision Making:                       

Genetic counseling helps in decision making. After diagnosing the disease and assessing the risk factors, parents are advised to take a decision. The high-risk factor may indicate termination of the pregnancy. However, the decision lies with the couple. In cases of repeated abortions, the couple may be advised to adopt a baby. Parents who are suffering from the autosomal dominant disorder may require artificial insemination by a healthy donor.

Genetic Counseling in Disputed Paternity:

Genetic counseling may help to deal with disputed paternity. In such cases, a genetic counselor may ask for the blood groups of the child, the mother, and the putative father. Matching blood groups may help to decide the paternity. Genetic fingerprinting may also be useful.

Cousins Marriage:

Marriages between close relatives may increase the risk of genetic diseases. If the offspring are from mating between first degree relatives, there are 50% chances of inheriting the disease. If the offspring are from mating between second-degree relatives, there are 5-10% chances of inheriting the disease. Marriage between third-degree relatives possesses the risk of 3-5%.

Genetic Counseling and Adoption:

Couples with the problem of conceiving or repeated abortions may be advised to go for adoption. In the case of consanguineous marriages, genetic counseling may be helpful.

Genetic Counseling for Congenital Heart Defects:

Genetic testing during pregnancy may help to find out the genetic cause of heart disease. Genetic counseling for congenital heart defects involves studying genetic test reports and fetal echocardiogram.

Cancer Genetic Counseling:

Genetic counseling is also helpful for people who have a family history of cancer. Hereditary cancers are passed on from generations to generations.

Cancer genetic counseling is useful for:

·        Individuals with a family history of cancer.

·        People with cancer genetic mutations.

·        People with genetic disorders along with cancer.

·       Rare or unusual cancers.

 References:
[1] A Guide to Genetic Counseling, Wendy R. Uhlmann, Jane L. Schuette, Beverly Yashar
[2] Genetic counseling-UNESCO 
[3] Counseling About Cancer: Strategies for Genetic Counseling, Katherine A.      Schneider
[4] Genetic Counseling Practice: Advanced Concepts and Skills, Bonnie S. LeRoy

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