Correct Answer: A. Cystic fibrosis
Cystic fibrosis (CF) is caused by mutations in the CFTR gene (cystic fibrosis transmembrane conductance regulator) located on chromosome 7q31.2. It follows autosomal recessive inheritance, meaning an affected individual must inherit two mutant alleles—one from each parent. Both parents are typically heterozygous carriers (phenotypically normal) with a 25% risk of an affected child in each pregnancy. CF is the most common lethal autosomal recessive disorder in Caucasian populations, though increasingly recognized in Indian populations. The disease manifests with pancreatic insufficiency, chronic lung infections (due to thick mucus), meconium ileus in neonates, and elevated sweat chloride (>60 mEq/L on sweat chloride test—the gold standard diagnostic test). In India, CF prevalence is lower but rising, particularly in North Indian populations. The carrier frequency is approximately 1 in 25–30 in Caucasians but lower in Indian populations. Understanding CF's recessive pattern is critical for genetic counseling: two carrier parents have a 25% chance of affected offspring, and all children of two affected parents will be affected.
Why the other options are wrong
B. Achondroplasia — Achondroplasia follows autosomal dominant inheritance. It is caused by mutations in the FGFR3 gene (fibroblast growth factor receptor 3) on chromosome 4p16.3. Affected individuals need only one mutant allele to manifest the phenotype (short stature, rhizomelic dwarfism, genu varum). About 80% of cases arise from de novo mutations, particularly in paternal germline (advanced paternal age is a risk factor). This is a common trap: students may confuse it with recessive inheritance because it is a skeletal dysplasia. C. Treacher Collins syndrome — Treacher Collins syndrome follows autosomal dominant inheritance. It is caused by mutations in the TCOF1 gene on chromosome 5q32-q33, affecting craniofacial development (malar hypoplasia, micrognathia, conductive hearing loss, cleft palate). Affected individuals have one mutant allele and manifest the phenotype. About 40% of cases are de novo mutations. The craniofacial presentation may mislead students into thinking it is recessive, but it is definitively dominant. D. Huntington's disease — Huntington's disease follows autosomal dominant inheritance with complete penetrance. It is caused by CAG trinucleotide repeat expansions (>36 repeats) in the HTT gene on chromosome 4p16.3, leading to progressive neurodegeneration (chorea, cognitive decline, psychiatric symptoms) typically manifesting in the 4th–5th decade. Affected individuals need only one mutant allele. Genetic anticipation occurs (earlier onset and severity in successive generations, especially with paternal transmission). This is a classic dominant disorder often tested in genetics.
High-Yield Facts
- Cystic fibrosis (CF) is autosomal recessive; CFTR gene on chromosome 7q31.2; two mutant alleles required for disease manifestation.
- Sweat chloride test (>60 mEq/L) is the gold standard diagnostic test for CF; elevated sweat sodium and chloride due to CFTR dysfunction.
- Achondroplasia is autosomal dominant (FGFR3 gene); 80% de novo mutations; advanced paternal age is a risk factor.
- Treacher Collins syndrome is autosomal dominant (TCOF1 gene); craniofacial dysostosis with malar hypoplasia and conductive hearing loss.
- Huntington's disease is autosomal dominant with CAG repeat expansion (>36 repeats); genetic anticipation occurs; progressive chorea and dementia.
- In autosomal recessive disorders, two carrier parents have 25% risk of affected child per pregnancy; all children of two affected parents are affected.
Mnemonics
Recessive Respiratory Rule CF (Cystic Fibrosis) = Carrier parents, Chloride in sweat, Chromic lung disease. Remember: Recessive = Respiratory (CF is the classic recessive respiratory-pancreatic disorder). Dominant Disorders (Skeletal & Neuro) ADH = Achondroplasia (Dominant), Dwarfism, Huntington's (Dominant). Treacher Collins also Dominant. Use: "Achondroplasia and Huntington's are Dominant; CF is Recessive."
NBE Trap
NBE may pair cystic fibrosis with "carrier parents" or "two affected parents" scenarios to test understanding of recessive inheritance risk calculations. Students who confuse CF with dominant skeletal dysplasias (achondroplasia) or dominant craniofacial syndromes (Treacher Collins) will select wrong options.
Clinical Pearl
In Indian clinical practice, CF is increasingly recognized in North Indian populations and among consanguineous families. Neonatal screening for CF (elevated immunoreactive trypsinogen) is now part of some state newborn screening programs. Genetic counseling for CF carrier parents is critical: offering prenatal diagnosis (chorionic villus sampling or amniocentesis with CFTR gene sequencing) and preimplantation genetic diagnosis (PGD) for at-risk families.
_Reference: Robbins & Cotran Pathologic Basis of Disease, Ch. 5 (Genetic Disorders); Harrison's Principles of Internal Medicine, Ch. 394 (Cystic Fibrosis); KD Tripathi Essentials of Medical Genetics, Ch. 3 (Inheritance Patterns)_