Genetic Disorders

Genetic variation can confer increased fitness in an organism or population because the variants may be more adaptive to an environment or certain circumstances. Genetic variations and mutations can lead to pleasing visual and aesthetic differences so that not all flowers, puppies, or humans look the same. However, genetic variation can also lead to unfortunate outcomes when these variants or mutations reduce fitness due to causing a disease or genetic disorders.

Genetic Disorder Definition

Sometimes genetic disorders are syndromic - and you may see disorders referred to as syndromes, such as Down's Syndrome or Turner Syndrome - and sometimes genetic disorders are referred to as diseases - such as maple syrup urine disease or sickle cell disease.

Regardless, the important thing to know is that there are many of these genetic diseases, disorders, and syndromes.

Tools for Determining Genetic Disorders and Genetic Disorder Testing

Before we get into detail about the many types and examples of genetic disorders, let's first analyze how we could determine if an individual has one. This is through a process called genetic testing, and there are many possibilities at different stages of life and different levels of technology.

• Pedigree analysis:
  • Pedigrees look like family trees, where the emphasis is not just on keeping a lovely reminder of your genealogy but on determining the health status (carrier, non-carrier, has a disorder, etc.) of members of an extended family.
  • This is best used for an existing family when everyone has already expressed their traits, and we can determine their status.
  • Pedigrees are also used to determine inheritance patterns of existing disorders. For example, we can tell in the image below that this disorder has recessive inheritance because two healthy individuals gave birth to a child who has the disorder (Fig. 1). This would be impossible for a dominantly inherited allele.

Recessively Inherited Genetic Disease Pedigree

• Amniocentesis
  • Amniocentesis involves taking a small amount of amniotic fluid from the uterus of a pregnant woman and using it to analyze the genetic material of her baby.
  • Abnormal or defective cells may be swimming around in amniotic fluid
  • This method is used only to analyze fetuses. Down Syndrome and other trisomies are checked in this manner.
• Chorionic Villus Sampling (CVS)
  • The chorionic villus is the placenta. CVS involves taking a sample of the placenta and testing it for genetic abnormalities
  • It is invasive, just like amniocentesis. Its benefit over amniocentesis is that it can be done a few weeks earlier in pregnancy.
• Karyotyping
  • Karyotyping involves visualizing the full set of chromosomes under a microscope. The chromosomes are best visualized in the metaphase of mitosis (Fig. 2).
  • This is done to analyze the size, shape, and number of chromosomes and any abnormalities like breakage.
  • Karyotyping is done at any age and merely requires a DNA sample.

Human Karyotype

Genetic Disorders List

We can examine a subset of important genetic disorders and divide them into categories based on their inheritance pattern.

Autosomal recessive genetic disorders:

1. Sickle cell anemia
2. Cystic Fibrosis
3. Tay Sachs Disease
4. Alpha Thalassemia
5. Beta Thalassemia
6. Wilson's Disease
7. Neimann-Pick Disease
8. Hemochromatosis
9. Hurler's Syndrome
10. Phenylketonuria

Autosomal dominant genetic disorders:

1. Achondroplasia (Dwarfism)
2. Familial Hypercholesterolemia
3. Marfan Syndrome
4. Huntington's Disease
5. Hypertrophic Cardiomyopathy
6. Romano-Ward Syndrome
7. Diamond-Blackfan Anemia
8. Aniridia
9. Ehler's Danlos Syndrome (some forms)
10. Osteogenesis Imperfecta (some forms)

X-linked dominant genetic disorders:

1. Aicardi Syndrome
2. Goltz Syndrome
3. Alport Syndrome
4. Hypophosphatemic Rickets
5. Rett Syndrome

X-linked recessive genetic disorders:

1. Hemophilia A
2. Hemophilia B
3. Duchenne Muscular Dystrophy
4. Becker's Muscular Dystrophy
5. Ocular Albinism
6. Fabry's Disease
7. Lesch-Nyhan Syndrome
8. G6PD Deficiency
9. Sideroblastic Anemia
10. Bruton Agammaglobulinemia

Chromosomal disorders

1. Kleinfelter Syndrome
2. Turner's Syndrome
3. Cri du chat Syndrome
4. Down's Syndrome (Trisomy 21)
5. Edward's Syndrome (Trisomy 18)
6. Patau Syndrome (Trisomy 13)

Mitochondrial inheritance disorders

1. MELAS Syndrome
2. Leber's Hereditary Optic Neuropathy (LHON)
3. Diabetes and Deafness (DAD syndrome)

Select Examples of Genetic Disorders

Let's examine one disorder of each category, starting with sickle cell disease (also known as sickle cell anemia or SCD). Sickle cell is an autosomal recessive disorder, meaning you must have two copies of this allele to have the disorder. It occurs most frequently in people of West African descent.

Genetic Disorders: Sickle Cell Disease (SCD)

A point mutation causes SCD on the β-globin gene on chromosome 13. The normal gene codes for glutamate, but this point mutation codes for valine.

This single amino acid substitution leads to a defective hemoglobin protein, known as Hemoglobin S. Red blood cells with HbS are less elastic and have a sickled shape, instead of the normal biconcave-disc shape, under stressful or low oxygen conditions (Fig. 3). This shape also causes anemia because these sickled, abnormal red blood cells get destroyed by the body, and the rate of creating new ones cannot compensate.

Beyond anemia, SCD has a wide range of difficult symptoms: extreme pain, swelling in the limbs, predisposition to strokes, predisposition to infections, and recurrent lung disease.

Genetic Disorders, Sickle Cell and Normal RBC IDPH, StudySmarter

Genetic Disorders: Marfan Syndrome

Marfan syndrome is an autosomal dominant disorder due to a mutation on chromosome 15. Normally, this chromosome should code for fibrillin, which helps strengthen the elastic fibers in our connective tissues. When this mutation occurs, connective tissues are abnormal. People with this syndrome are usually very lanky and thin. They're also very flexible but tend to have scoliosis and back problems. Even the elastic fibers in their blood vessels and heart are affected, so they tend to have heart problems and aneurysms.

Genetic Disorders: Rett Syndrome

Rett syndrome is an X-linked dominant disorder that causes severe developmental regression and premature death. A highly lethal mutation causes this disorder, and because of its lethality, boys (XY) who have this gene don't survive till birth.

Girls (XX) who have one normal X chromosome can survive until their 20s. The symptoms of this disorder usually start in girls around ages 2 - 5, with hand flapping, seizures, and loss of ability to walk and talk.

Genetic Disorders: Hemophilia A

Hemophilia is the classic X-linked recessive disorder. Famously, Alexander Romanov had this, and his symptoms of severe bleeding from minor wounds or painful hemarthroses (bleeding between the joints) are tell-tale of this disease. Because Hemophilia A is X-linked recessive, it occurs most often in boys, while girls tend only to be carriers. For a female to actually have Hemophilia A disease, the mutation would need to be on both of their X chromosomes.

Genetic Disorders: Down Syndrome

Down Syndrome is both a trisomy and a chromosomal disorder. A chromosomal disorder means that the genetic error is at the level of the chromosome, not a single gene on a chromosome. Trisomy tells us that the specific chromosomal error, in this case, is three copies (instead of the normal 2) of a particular chromosome. That is why Down Syndrome is also called Trisomy 21, three copies of chromosome 21.

Individuals with Down Syndrome have certain characteristics, like up-slanted eyes, a flat facial profile, and one crease (instead of several) in their palms (Fig. 4). Other effects like intellectual disability, and increased risk of Alzheimer's, are also seen.

Down Syndrome features

Genetic Disorders: MELAS Syndrome

MELAS stands for Myopathy, Encephalopathy, Lactic Acidosis, and Strokes. These four features are the classic features of MELAS syndrome. This disorder is unique in that it is mitochondrially inherited, and the genes and mutations for this disorder occur on the circular mitochondrial chromosome (not one of the 46 nuclear chromosomes). Mitochondrial DNA is only maternally inherited, so a mother passes down this disorder to her children. Typically, MELAS presents with muscular symptoms, like weakness, temporary paralysis, loss of coordination, and neurological symptoms like seizures, vision loss, and headaches.

Common Genetic Disorders

Which genetic disorders are considered common? In genetics, common is relative. Cystic Fibrosis occurs commonly in people of North European ancestry, so it is common to this group. But to people with solely West African ancestry, cystic fibrosis incidence is extremely rare. The reverse could be said about sickle cell disease, which is rather common in people with West African ancestry, but very rare in people with solely North European ancestry.

Remember that common genetic diseases are usually common to a particular population or ethnicity.

Nevertheless, genetic disorders typically classified as common include cystic fibrosis, sickle cell anemia, Tay-Sachs (in Ashkenazi Jewish people), alpha and beta-thalassemia (in people of Mediterranean and Asian ancestry), Down Syndrome, and Huntington's disease.

Rare Genetic Disorders

Thankfully, the vast majority of genetic disorders are uncommon. But which are considered especially rare?

Heritable mitochondrial disorders, like DAD syndrome or LHON, are very rare. Disorders that lead to dangerously decreased immunity to viruses and bacteria, like SCID and Agammaglobulinemia, are quite rare. Heritable polydactyly, a genetic condition that leads an individual to have more than the normal number of fingers or toes, is an example of a spectrum of phenotype and rareness. An extra digit on the pinky finger, for example, is relatively common, while polydactyly of the thumb is rare, and polydactyly of the middle finger is extremely rare!