Human Genetic Disorders - Mendelian Disorders in Humans

Mendelian disorders are genetic disorders caused by mutations or alterations in a single gene (monogenic disorders). They follow the classical Mendelian patterns of inheritance - autosomal dominant, autosomal recessive, or sex-linked - and can be traced through family pedigrees.​

Key Characteristics:

• Caused by alteration/mutation in one gene locus​
• Can be identified by pedigree analysis of family history​
• Either inherited from one or both parents or arises due to new mutations​
• Relatively rare - may affect one in every thousand or a million individuals​

An autosomal recessive blood disorder caused by a point mutation in the β-globin gene, leading to structurally abnormal haemoglobin (HbS) and sickle-shaped red blood cells.

Micrograph of the red blood cells and the amino acid composition of the relevant portion of the β-chain of haemoglobin: (a) From a normal individual; (b) From an individual with sickle-cell anaemia

Gene & Chromosome:

• Gene: HBB (β-globin gene) on Chromosome 11 (short arm)​
• Alleles: HbA (normal) and HbS (mutant)

Molecular Mechanism:

An autosomal recessive inborn error of metabolism caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH), leading to the accumulation of phenylalanine and its toxic derivatives.

Gene & Chromosome:

• Gene: PAH on Chromosome 12q (long arm)​
• PAH enzyme deficiency accounts for ~95% of PKU cases​

Mechanism:

Key Features:

• Mental retardation, if untreated
• Reduced hair and skin pigmentation (less tyrosine → less melanin)​
• Phenylpyruvate and phenylacetate are excreted in urine​
• Ferric chloride test → green discolouration of urine (diagnostic)​
• Newborn screening (Guthrie test / Tandem Mass Spectrometry within 24–48 hours of birth) allows early dietary intervention​

An autosomal recessive blood disorder characterised by reduced synthesis (quantitative defect) of α- or β-globin chains of haemoglobin, resulting in severe anaemia.​

Gene & Chromosome:

• α-Thalassaemia → mutations in HBA1 and HBA2 genes on Chromosome 16​
• β-Thalassaemia → mutations in HBB gene on Chromosome 11​

Types Comparison:

Symptoms: Severe anaemia, bone deformities, facial deformities, enlarged spleen/liver, jaundice, poor growth.
Treatment: Regular blood transfusions, bone marrow transplant in severe cases.

An autosomal recessive disorder characterised by the absence of melanin in skin, hair, and eyes due to a non-functional or absent tyrosinase enzyme.

Gene & Chromosome:

• TYR gene on Chromosome 11q14 (tyrosinase gene) for OCA type 1​
• Inheritance: Autosomal recessive - the sex of individual does NOT affect occurrence

Mechanism:

Key Features:

• Very pale/white skin, hair, and eyes​
• Photosensitivity - high risk of sunburn and skin cancer​
• Vision problems - lack of melanin in the retina​
• Carriers (Aa) are normal in appearance; only aa individuals are affected​
• Real-Life Note: Approximately 1 in 20,000 people globally are affected by oculocutaneous albinism (OCA)

An X-linked recessive disorder in which blood clotting is impaired due to a deficiency of clotting factors (Factor VIII in Haemophilia A; Factor IX in Haemophilia B).​

Gene & Chromosome:

• Gene located on the X chromosome (sex chromosome)
• Males (XY): Only one X → if defective, disease manifests (hemizygous)
• Females (XX): Need two defective copies to be affected; one copy = carrier

Genotype Table:

Key Features:

• Prolonged/uncontrolled bleeding even from minor cuts​
• Internal bleeding in joints (haemarthrosis) is common​
• Transmitted from carrier mother to son (criss-cross inheritance)​
• Haemophilic father → all daughters are carriers; all sons are normal (if mother is normal)

An X-linked recessive disorder in which the individual cannot distinguish between red and green colours, due to defective or absent cone pigments in the retina.​

Gene & Chromosome:

• Genes for red-sensitive (OPN1LW) and green-sensitive (OPN1MW) cone pigments on the X chromosome​
• Dominant allele X^c → normal vision; Recessive allele X^c → colour blind

Key Features:

• Affected individuals see red and green as shades of grey​
• Approximately 8% of males and 0.4% of females are colour blind (higher in males because males are hemizygous)​
• Shows criss-cross inheritance: colour-blind father passes the trait to all daughters (as carriers), not to sons​

Cross: Carrier Female × Normal Male