Chapter 21 – Congenital and Genetic Disorders

Chromosomal Basis of Genetic Control

• Genetic information is packaged into chromosomes.

  • Humans possess 23 pairs (total 46 chromosomes).

  • 22 pairs = autosomes.

  • 1 pair = sex chromosomes (XX = genetic female, XY = genetic male).

• Karyotype

  • Laboratory‐generated, visual arrangement of chromosomes by size/shape.

  • Utilized to diagnose numerical or structural chromosomal disorders (e.g., trisomies, translocations).

  • Examples shown in slides A–M illustrate normal vs. abnormal complements.

• Key error mechanisms during meiosis that alter chromosome number/structure:

  • Nondisjunction → unequal separation, leading to trisomy/monosomy.

  • Translocation → segment of one chromosome attaches to another, possibly balanced (no loss) or unbalanced (gene loss/gain).

Genotype vs. Phenotype

• Genotype

  • The complete set of alleles an individual carries (all somatic cells share same genotype; gametes carry only one allele per locus).

  • Not every gene is expressed in every cell—gene regulation & epigenetics create tissue specificity.

• Phenotype

  • Observable expression of genotype (anatomical, biochemical, behavioral traits).

  • Two people with identical genotypes may have different phenotypes due to penetrance, expressivity, or environmental influence.

  • Clinical implication: A mutation may exist (genotype) even if phenotype is silent, complicating screening.

Overview of Congenital Disorders

• Defined: Abnormalities present at birth; may be genetic, epigenetic, or developmental.

• Broad etiologic categories:

  1. Single‐gene defects (monogenic) – mutation in one gene/allelic pair.

  2. Chromosomal defects – numerical/structural anomalies detectable by karyotype.

  3. Polygenic/Multifactorial – interaction of multiple genes plus environment.

  4. Developmental/teratogenic causes – environmental insults during gestation (e.g., drugs, hypoxia, prematurity).

• Incidence note: >6000 single‐gene disorders identified; severe forms frequently result in spontaneous miscarriage (natural negative selection).

Single-Gene Disorders (General Features)

• Classified by pattern of inheritance:

  • Autosomal recessive (AR)

  • Autosomal dominant (AD)

  • X-linked dominant (XD)

  • X-linked recessive (XR)

• A single gene can:

  • Control a limited, localized function (e.g., eye photopigments → color vision deficiency).

  • Produce systemic disease due to widely expressed protein (e.g., CFTR mutations in cystic fibrosis affect lungs, pancreas, reproductive tract).

• Punnett square analysis provides recurrence risk per pregnancy, useful for genetic counseling.

Autosomal Recessive (AR) Disorders

• Genetics

  • Disease manifests only in the homozygous state (aa).

  • Heterozygotes (Aa) = carriers; phenotypically normal but can transmit allele.

  • Sex distribution: equal in males & females.

  • Recurrence risks (carrier × carrier matings):

  • 25\% affected (aa)

  • 50\% carriers (Aa)

  • 25\% unaffected non-carriers (AA)

• Key examples of Autosomal Recessive disorders

  • Cystic fibrosis (CF)

  • Phenylketonuria (PKU)

  • Sickle cell anemia

  • Tay–Sachs disease

• Clinical pearl: Population screening is effective where AR disease prevalence or carrier frequency is high (e.g., Tay–Sachs in Ashkenazi Jewish communities).

Autosomal Dominant (AD) Disorders

• Genetics

  • A single mutated allele (A) is sufficient; genotype Aa or AA produces phenotype. (only one parent needs to carry the allele for it to be portrayed)

  • No true carrier state; unaffected individuals do not transmit mutation (penetrance may affect expression but allele absent).

  • Many AD disorders display delayed age of onset ("delayed lethal genotype"), enabling allele transmission before diagnosis (e.g., Huntington disease onset in mid-life).

  • Recurrence risks (affected heterozygote × normal): 50\% affected, 50\% normal per pregnancy.

• Representative conditions for Dominant

  • Adult polycystic kidney disease (PKD)

  • Huntington chorea/disease

  • Familial hypercholesterolemia (LDL receptor defect → premature atherosclerosis)

  • Marfan syndrome (fibrillin-1 mutation → connective tissue fragility; see slide image showing long limbs, arachnodactyly).

  • includes sickle cell

X-Linked Dominant (XD) Disorders

• Inheritance nuances

  • Mutation on X chromosome expressed dominantly.

  • Heterozygous females: variable penetrance due to random X-inactivation.

  • Hemizygous males: typically fully affected because only one X.

  • Affected father transmits allele to all daughters and no sons; affected mother passes to 50\% of children of either sex.

• Example: Fragile X syndrome

  • Trinucleotide repeat expansion (CGG) in FMR1 gene.

  • Most common heritable intellectual disability in North America; presents with learning disorders, elongated face, macroorchidism in males.

X-Linked Recessive (XR) Disorders

• Genetics

  • Allele on X; manifests in hemizygous males because Y lacks a matching allele.

  • Females usually carriers; homozygous affected state is rare but possible.

  • Pedigree often shows "skipped" generations via female carriers.

• Risk patterns

  • Carrier mother × normal father → sons: 50\% affected; daughters: 50\% carriers.

  • Affected father × normal mother → daughters: all carriers; sons: none affected (no paternal X to sons).

• Hallmark disorders

  • Duchenne muscular dystrophy (DMD) – dystrophin absence → progressive muscle weakness.

  • Classic hemophilia A – Factor VIII deficiency → bleeding diathesis.

  • Red-green color blindness.

Chromosomal Disorders

• Result from numeric or structural chromosome abnormalities detectable by karyotyping. Triosmy 21 means the extra chromosome is added to the 21st set

• Common entities

  1. Down syndrome (Trisomy 21)

  • Etiology: nondisjunction in meiosis I/II; occasionally Robertsonian translocation.

  • Incidence strongly correlates with increased maternal age.

  1. Turner syndrome (Monosomy X, karyotype 45,XO)

  • Phenotype: short stature, webbed neck, streak ovaries → infertility.

  1. Klinefelter syndrome (Polysomy X, karyotype 47,XXY)

  • Tall stature, gynecomastia, small testes, infertility.

  1. Trisomy 18 (Edwards) – severe, high neonatal mortality. cleft pallete (incompatible with life)

• Clinical paradigm: chromosomal analysis is crucial in neonates with multiple congenital anomalies.

Multifactorial & Developmental Disorders

• Multifactorial inheritance

  • Polygenic predisposition + environmental trigger.

  • Threshold model: disease manifests after cumulative liability exceeds threshold.

  • Examples: anencephaly, cleft lip/palate, congenital heart disease, clubfoot, myelomeningocele, type 2 diabetes, schizophrenia.

• Developmental disorders

  • Caused by non-genetic events before, during, or shortly after birth (e.g., prematurity, hypoxia, difficult labor leading to cerebral palsy).

Teratogenic Agents & Critical Periods

• Teratogens = substances/events that induce fetal malformations.

  • Drugs (e.g., thalidomide), chemicals, radiation.

  • TORCH infections (Toxoplasma, Other [syphilis, varicella, HIV], Rubella, Cytomegalovirus, Herpes) – screened routinely.

• Critical window: first 8 weeks (organogenesis); severity/time relationship depicted in slide chart:

  • Early exposure (0–2 wk) → "all-or-none" (embryonic death or no effect).

  • Weeks 3–8 → major structural anomalies of CNS, heart, limbs, eyes, ears, teeth, palate.

  • After 8 wk → functional minor abnormalities, growth deficits.

Diagnostic Tools & Prenatal Screening -Tests will be done if disease are suspected

• Preconception & Prenatal testing indications:

  • Positive family history.

  • Previous affected child.

  • Ethnic high-risk groups (e.g., sickle cell in African descent).

  • Maternal age >35 yr (risk of non-disjunction).

• Maternal blood assays

  • Alpha-fetoprotein (AFP) – elevated in neural tube defects, decreased in Down syndrome.

  • Triple/quad screen integrates AFP, hCG, estriol, inhibin A.

• Imaging & sampling

  • First-trimester nuchal translucency ultrasound.

  • Amniocentesis (2nd trimester, sample amniotic fluid cells). -big long needle

  • Chorionic villus sampling (CVS, earlier sampling of placental tissue).

• Neonatal testing

  • Heel-stick blood for metabolic errors (e.g., PKU, hypothyroidism).

  • Urinary metabolite screens.

Genetic Engineering, Gene Therapy & Designer Drugs

• Genetic engineering

  • Isolation, cloning, and insertion of genes into various organisms → production of recombinant proteins or GMO foods.

  • Ultimate medical goal: germline or somatic insertion of a healthy allele to cure disease (still experimental; ethical debates ongoing).

• Gene therapy workflow

  1. Identify pathogenic gene & protein product.

  2. Clarify regulation of its expression.

  3. Develop vectors (viral/non-viral) to deliver corrective gene OR drugs to silence expression (e.g., antisense oligos).

  4. Cancer therapeutics leading area: targeting oncogene expression.

• Genetic screening & DNA testing

  • Used for at-risk population screening, prenatal diagnosis, paternity, forensics.

  • U.S. legislation (e.g., GINA – Genetic Information Nondiscrimination Act) protects privacy & guards against insurance/employment discrimination.

  • AI algorithms facilitate rapid genomic analysis in critically ill neonates.

• Proteomics & designer drugs

  • Mapping of protein networks downstream of gene expression.

  • Enables pharmacogenomics: tailoring medications to patient genotype to enhance efficacy and reduce adverse events.

  • Example: variable CYP450 isoenzyme expression impacts warfarin dosing.

Down Syndrome (Trisomy 21) – Detailed Case Study

• Epidemiology & Risk

  • Most prevalent live-born chromosomal disorder.

  • Maternal age relationship: risk climbs from 1/1500 at age 20 → 1/100 at 40.

• Screening & Diagnosis

  • First-trimester combined screen (NT ultrasound + maternal serum biomarkers) or 2nd trimester triple/quad test; positive screens prompt confirmatory karyotype via amniocentesis/CVS.

• Characteristic phenotype

  • Craniofacial: small brachycephalic head, flat facial profile, slanted palpebral fissures, epicanthic folds.

  • Oral: macroglossia, high-arched palate → feeding/speech issues.

  • Hands/feet: single transverse palmar crease, short broad fingers, sandal‐gap toes.

  • Growth: short stature; hypotonia & ligamentous laxity cause motor delay.

• Developmental & Medical complications

  • Intellectual disability ranges mild → severe.

  • Congenital heart disease (AV canal) in ≈40\% of infants.

  • GI anomalies (duodenal atresia, Hirschsprung).

  • Endocrine: high prevalence of hypothyroidism, type 1 DM.

  • Hematologic malignancies: 10–20× risk of acute lymphoblastic leukemia (ALL).

  • Life expectancy improved (≈60 yr) with medical management.

• Reproductive aspects

  • Males generally infertile; females ovulate but have ↓ fertility and ↑ risk of trisomic offspring.

Ethical / Practical Implications Summary

• Genetic testing offers preventive & therapeutic opportunities but raises concerns about informed consent, psychological impact, discrimination, and access equity.

• Prenatal diagnosis enables reproductive choices; however, societal implications regarding selective termination warrant sensitive counseling.

• Emerging gene-editing platforms (e.g., CRISPR-Cas9) blur line between therapy and enhancement, demanding robust ethical frameworks.