GENETIC DISORDERS

Genetic disorders are health problems caused by alterations in a person's genetic material,
specifically the DNA or chromosomes. These alterations can result in a wide range of health issues,
some evident at birth and others manifesting later in life. They are caused by single gene defects,
chromosomal abnormalities, or multifactorial inheritance (a combination of genes and
environmental factors). Genetic diseases arise from mutations in the DNA the hereditary material
located in chromosomes that encodes approximately 20,000 to 25,000 genes essential for protein
synthesis and cellular function. These mutations can impair the normal function of genes, often
leading to enzyme deficiencies and a wide range of diseases. To date, over 5,000 genetic disorders
have been identified. It is estimated that about 3% to 6% of all newborns are affected by congenital
disorders, roughly half of which have a genetic origin.

Genetic abnormalities are also a major contributor to miscarriages, infant mortality, and hospital
admissions across all age groups. Furthermore, around 10% of adults may carry mild genetic
defects that can remain undetected. Genetic disorders can be broadly classified into chromosomal
abnormalities and single-gene (Mendelian) disorders. Chromosomal abnormalities are relatively
common, occurring in approximately 1 in every 150 live births. They are responsible for nearly
50% of first-trimester and 20% of second-trimester miscarriages. These abnormalities can be
numerical, such as in cases of nondisjunction where entire chromosomes fail to separate properly
(e.g., Trisomy 21, or Down syndrome, which occurs in about 1 in 800 births), or structural,
involving deletions, insertions, or translocations. Unbalanced structural abnormalities, such as the
deletion on chromosome 5 that leads to Cri du chat syndrome, often result in severe consequences,
while balanced abnormalities may go unnoticed but can be inherited. Sex chromosome
aneuploidies are another form of chromosomal disorders, found in roughly 1 in 400 males and 1
in 650 females. Examples include Turner syndrome (45,X), which results in short stature and
infertility; Klinefelter syndrome (47,XXY), characterized by tall stature and reduced fertility; and
other mild forms like 47,XXX and 47,XYY.

Mendelian disorders result from mutations in single genes and are inherited in distinct patterns.
Autosomal dominant (AD) disorders require only one mutated allele for disease manifestation and
typically show vertical transmission across generations. Achondroplasia, caused by a mutation in
the FGFR3 gene, is a well-known example, with affected individuals exhibiting dwarfism, a large
head, and shortened limbs. Other examples include Huntington disease, osteogenesis imperfecta,
Marfan syndrome, and neurofibromatosis. These disorders often exhibit phenomena such as de
novo mutations, pleiotropy (where one gene affects multiple systems), allelic and genetic
heterogeneity, variable expressivity, and incomplete penetrance. Autosomal recessive (AR)
disorders, on the other hand, require mutations in both alleles of a gene. Carriers, who have one
normal and one mutated allele, are typically asymptomatic. If both parents are carriers, each child
has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being
unaffected. AR disorders are more common in consanguineous families and display horizontal
inheritance in pedigrees. Instances include Tay-Sachs disease, albinism, cystic fibrosis,
phenylketonuria (PKU), thalassemia, and sickle cell anemia. X-linked recessive disorders
predominantly affect males, as they have only one X chromosome. Females may be carriers
without symptoms. Disorders such as hemophilia A and Duchenne muscular dystrophy are classic
examples, often skipping generations in family histories.

It is important to distinguish between congenital and genetic conditions. Congenital anomalies are
present at birth and can be structural, biochemical, or functional. While many are genetic,
congenital defects can also result from environmental factors or a combination of both. For
example, congenital heart defects may be caused by maternal rubella infection during pregnancy
and are not necessarily genetic.Genetic injuries and mutagenic factors further complicate the
landscape of inherited disease. Biological influences such as advanced maternal age increase the
likelihood of chromosomal nondisjunction, and roughly a quarter of chromosomal abnormalities
originate from paternal sperm. Physical and biological mutagens also play a role. Radiation
exposure, such as that experienced by atomic bomb survivors, increases chromosomal
abnormalities and cancer risks. Viruses such as Epstein–Barr virus (EBV), human papillomavirus
(HPV), hepatitis B and C, and retroviruses can integrate into the genome and drive mutations.
Chemical mutagens, particularly those found in industrial settings and pharmaceuticals, often
require metabolic activation to become harmful. Tools like the Ames test help identify mutagenic
properties in bacterial models, although their relevance to humans may vary.
Combustion products, especially those from fossil fuels and tobacco smoke, contain numerous
DNA-damaging agents such as dioxins and nitrogen oxides. Alcohol, especially its metabolite
acetaldehyde, has mutagenic effects and is linked to increased cancer risk with chronic exposure.
Prenatal exposure to alcohol can lead to fetal alcohol syndrome, a serious congenital disorder.
Different types of radiation have distinct mutagenic properties. Ultraviolet (UV) radiation causes
thymine dimers in DNA, and individuals with xeroderma pigmentosum lack the ability to repair
this damage. Ionizing radiation, including X-rays and gamma rays, can break DNA strands and
stems from sources like cosmic rays, medical imaging, and nuclear fallout. Reactive oxygen
species (ROS), byproducts of normal metabolism, also damage DNA. The body’s defense
mechanisms such as superoxide dismutase, catalase, and peroxidases help mitigate this damage.
Certain genetic diseases, including chronic granulomatous disease and familial forms of
amyotrophic lateral sclerosis (ALS), are associated with ROS dysfunction.

Mutations leading to disease can occur at different levels from large chromosomal alterations to
single nucleotide changes. While somatic mutations are acquired and not inherited (e.g., in cancer),
germline mutations are passed on to offspring. The mode of inheritance autosomal dominant,
autosomal recessive, or X-linked affects how a disease presents and spreads in a family. Pleiotropy,
variable expressivity, and incomplete penetrance can all influence the severity and range of
symptoms seen in individuals with the same genetic mutation.Diagnosis and management of
genetic diseases rely on a range of tools and strategies. Genetic counseling helps families
understand inheritance risks. Diagnostic options include prenatal and postnatal testing, enzyme
assays, and metabolic screenings. Management strategies may involve dietary interventions, as
seen in PKU, enzyme replacement therapy, or symptom-targeted care. Advances in research,
particularly in molecular diagnostics and gene therapy, are paving the way for more personalized
and effective treatments. Molecular medicine continues to expand our understanding and ability
to intervene in genetic disorders.

Ultimately, human disease exists along a spectrum influenced by both genetic and environmental
factors. Many conditions labeled as "familial" including certain cancers, hypertension, and obesity
result from the interplay between genetic predispositions and environmental exposures. It is crucial
to distinguish between genetic and congenital disorders, as not all inherited conditions are evident
at birth, and not all birth defects are genetic. A clear understanding of genetic disease
classifications, mutagenic influences, inheritance patterns, and gene-environment interactions is
essential for effective diagnosis, treatment, and public health interventions. Accurate terminology
and conceptual clarity are foundational for advancing genetic medicine and improving patient
outcomes.