Congenital and Genetic Disorders

Genetic information is in chromosomes: $23$ pairs in total ( $22$ autosomes, $1$ sex chromosome pair: XX female, XY male).
Genotype: Actual genetic information in an individual's cells (except gametes).
Phenotype: Expression of genes, observable characteristics.

Disorders present at birth, including inherited or developmental.
Inherited disorders may be due to: single gene expression, polygenic expression, or chromosomal defects.
Single-gene disorders: Trait controlled by one set of alleles, transmitted across generations.
Chromosomal anomalies: Errors during meiosis, such as non-disjunction (failure of chromosome separation) or translocation (rearrangement between non-homologous chromosomes).
Teratogenic agents: Agents causing damage during embryonic/fetal development.
Multifactorial disorders: Involve both genetic and environmental factors (e.g., cleft palate, Type $2$ diabetes mellitus).
Other developmental disorders: Can stem from premature birth, difficult labor/delivery (e.g., Cerebral Palsy, a group of brain/nervous system disorders).

Classified by inheritance patterns: Autosomal Recessive, Autosomal Dominant, X-linked Recessive, X-linked Dominant.

Requires inheritance of two abnormal alleles (one from each parent) for the disorder to manifest.
Parents can be heterozygous carriers (unaffected), or homozygous affected.
Males and females are affected equally.
Examples:
- Cystic Fibrosis (CF): Affects secretory glands; causes thick mucus in lungs (leading to infections) and blockages in pancreatic ducts.
- Tay-Sachs: Lack of hexos-amin-i-dase enzyme, leading to toxic ganglioside accumulation (primarily in brain nerve cells).
- Phenylketonuria (PKU): Lack of phenylalanine hydroxylase (PAH), causing accumulation of phenylalanine (converted to neurotoxic phenylketone). Screened in newborns; requires strict dietary management.

Requires inheritance of only one abnormal allele for the disorder to manifest.
Only one parent needs to carry the allele.
No carriers; an unaffected person does not transmit the disorder.
Examples:
- Adult Polycystic Kidney Disease: Slow, progressive, irreversible disease with multiple renal cysts.
- Huntington's Disease (Chorea): Progressive atrophy of cerebral cortex and basal ganglia, leading to involuntary movements, cognitive decline, and personality changes.
- Familial Hypercholesterolemia: Defect on chromosome $19$ (LDL-R gene mutations) leading to high serum LDL and increased risk of early atherosclerosis.
- Marfan Syndrome: Connective tissue disorder (defects in Fibrillin-1 gene on chromosome $15$ ), causing excessive height, long limbs, and soft tissue issues (e.g., aortic problems, pneumothorax, eye lens dislocation).

Dominant disorder, affecting both heterozygous males and females.
Only one allele needed.
Reduced penetrance in females, often leading to less severe symptoms.
Example:
- Fragile X Syndrome: Most common genetic cause of cognitive deficits; affects males more severely than females. Symptoms include behavioral (aggression, hyperactivity), developmental (learning/speech delays), and musculoskeletal issues.

Down Syndrome (Trisomy $21$ ): Most common chromosomal disorder ( $1$ in $700$ births or $0.14\%$ ); caused by non-disjunction or translocation. Characterized by distinct facial features, short stature, hypotonia, and cognitive impairment. Risk increases with maternal age.
Turner Syndrome (XO): Affects females ( $1:2,500$ births or $0.04\%$ ); missing or incomplete X chromosome. Causes short stature and infertility.
Klinefelter Syndrome (XXY): Affects males ( $1:500-1,000$ births or $0.1\%$ ); extra X chromosome. Causes infertility and developmental delays.

Result from interplay of genetic influences and environmental factors (e.g., hazardous substances, occupational hazards).
Examples: Cleft palate, congenital hip dislocation, congenital heart disease, Type $2$ diabetes mellitus.

Teratogen exposure (drugs, chemicals, radiation) during the first $2$ months of pregnancy can impair organogenesis.

Timing: Prior to conception, during first trimester, or in a newborn.
Recommendations: Family history, previous abnormal child, high-risk ethnic groups, pregnant women over $35$ .
Methods:
- Maternal Blood Tests: Alpha FetoProtein (AFP) testing (e.g., Triple/Quad screen) to detect spinal defects or chromosomal abnormalities.
- In Utero Testing: Amniocentesis ( $15-20$ weeks) and Chorionic Villus Sampling ( $10-13$ weeks) for direct confirmation (carry miscarriage risk). Cell-free DNA (cfDNA) test ( $10$ weeks) is non-invasive.
- Neonatal Testing: Heel stick for excreted metabolites (e.g., PKU).

Screening "at-risk" populations for specific alleles is costly, with privacy concerns.
DNA testing for paternity or forensics.
Legislation exists to protect genetic rights (healthcare, employment, insurance).

Research identifies and quantifies total protein content resulting from gene expression.
Aims to link abnormal proteins to specific harmful genes to develop tailored drugs.

Gestational age often calculated from the first day of the Last Menstrual Period (LMP) for an estimated delivery date (EDD). Ultrasound age is considered more accurate.