Genetic Disorders — Causes, Inheritance, Examples

Genetic disorders arise from mutations — changes in DNA sequence — that disrupt normal gene function. Some mutations are inherited from parents; others arise spontaneously during cell division. Understanding the inheritance patterns of these disorders is central to CBSE Class 12 and NEET genetics.

This guide covers the major types of genetic disorders, their inheritance patterns, and the examples that are most tested in Indian board exams and NEET.

Key Terms

Mutation: A change in the DNA sequence. Can affect a single nucleotide (point mutation), a larger chromosomal segment, or the entire chromosome number.

Autosomal disorder: Caused by a mutation in a non-sex chromosome (chromosomes 1–22).

Sex-linked disorder: Caused by a mutation on the X or Y chromosome. Most sex-linked disorders are X-linked.

Dominant disorder: Only one copy of the mutant allele is needed for the disorder to manifest. Affected parent → 50% chance of passing to each offspring.

Recessive disorder: Two copies of the mutant allele are needed. A person with one copy is a carrier — phenotypically normal but can pass the allele to offspring. Two carriers → 25% chance of affected offspring.

Chromosomal disorder: Not a gene mutation but an abnormal chromosome number (aneuploidy) or structure. Results from errors in meiosis.

Major Genetic Disorders in CBSE Class 12 and NEET

Mendelian Disorders (Single Gene)

Sickle Cell Anaemia (Autosomal Recessive)

Cause: Point mutation in the β-globin gene — single nucleotide change (A→T in codon 6) causing glutamic acid to be replaced by valine in the β-globin chain.

Effect: Haemoglobin S (HbS) polymerises under low oxygen conditions, causing red blood cells to sickle (crescent shape). Sickled cells:

Block capillaries (pain crises)
Are destroyed rapidly (haemolytic anaemia)

Inheritance: Autosomal recessive.

HbA/HbA: Normal
HbA/HbS: Carrier (sickle cell trait) — mild protective effect against malaria
HbS/HbS: Sickle cell disease

Indian context: High prevalence in tribal populations in Odisha, Chhattisgarh, and Maharashtra — historically correlated with malaria-endemic regions (heterozygous advantage).

Phenylketonuria (PKU) (Autosomal Recessive)

Cause: Mutation in the gene encoding phenylalanine hydroxylase (PAH) — the enzyme that converts phenylalanine to tyrosine.

Effect: Phenylalanine accumulates in blood and brain, causing intellectual disability, seizures, and lighter skin/hair (tyrosine is a melanin precursor).

Treatment: Low-phenylalanine diet begun in infancy prevents brain damage. This is one of the success stories of newborn genetic screening.

Haemophilia (X-linked Recessive)

Cause: Mutations in Factor VIII gene (Haemophilia A) or Factor IX gene (Haemophilia B) on the X chromosome. The factors are clotting proteins.

Effect: Inability to form blood clots → prolonged bleeding from minor injuries, internal bleeding in joints.

Inheritance:

Affected males: $X^h Y$ (only one X, so one mutant allele is enough)
Carrier females: $X^H X^h$ (phenotypically normal, but 50% of sons will be affected)
Affected females: $X^h X^h$ (rare — requires father to be affected and mother to be carrier)

Historical note: Called the “Royal disease” — Queen Victoria was a carrier and passed haemophilia to several European royal families.

NEET question type: Draw pedigree for haemophilia; determine which individuals are carriers, affected, or normal from phenotype information.

Colour Blindness (X-linked Recessive)

Cause: Mutations in opsin genes on the X chromosome — red–green colour blindness is most common.

Inheritance: Same pattern as haemophilia. Sons of carrier mothers have a 50% chance of being colour blind.

Prevalence: About 8% of males and 0.4% of females are colour blind (the female frequency is much lower because two X chromosomes must both carry the mutation).

Chromosomal Disorders

Down Syndrome (Trisomy 21)

Cause: Presence of three copies of chromosome 21 instead of two. Most often due to non-disjunction during meiosis I in the mother.

Karyotype: 47, XX (or XY), +21

Features: Characteristic facial features (flat nasal bridge, epicanthal folds), intellectual disability (variable), heart defects (40–50%), hypotonia (low muscle tone).

Maternal age effect: Risk increases significantly with maternal age because oocytes complete meiosis I only at fertilisation — older oocytes have been arrested longer and are more prone to non-disjunction.

Risk: ~1 in 700–800 live births overall; ~1 in 25 for mothers over 45.

Klinefelter Syndrome (XXY)

Cause: Extra X chromosome in males. Karyotype: 47, XXY.

Features: Tall stature, small testes, infertility, gynaecomastia (breast development), learning difficulties (often mild).

Note: The extra X chromosome is usually inactivated (as in normal females), but not completely — some X-linked genes escape inactivation, contributing to the phenotype.

Turner Syndrome (Monosomy X)

Cause: Only one X chromosome in females. Karyotype: 45, X0.

Features: Short stature, webbed neck, primary amenorrhoea (absence of menstruation), infertility, cardiovascular defects (coarctation of aorta).

Note: This is the only viable monosomy in humans — most other monosomies are lethal in utero.

Inheritance Patterns — Summary Table

Disorder	Chromosome	Inheritance	Indian/NEET Relevance
Sickle cell anaemia	Autosome (chr 11)	Recessive	High in tribals; malarial correlation
PKU	Autosome (chr 12)	Recessive	Neonatal screening
Haemophilia A	X chromosome	X-linked recessive	PYQ staple
Colour blindness	X chromosome	X-linked recessive	PYQ staple
Down syndrome	Chromosome 21	Trisomy (non-disjunction)	PYQ staple
Klinefelter	X chromosome	Trisomy (XXY)	Often confused with Turner
Turner	X chromosome	Monosomy (X0)	Often confused with Klinefelter

Reading Pedigree Charts

Pedigree analysis is a core NEET skill. Key rules for reading pedigrees:

Autosomal recessive:

Affected individuals (shaded) in every generation is unlikely — often skips generations
Two unaffected parents can have an affected child (both are carriers)
Equal frequency in males and females

Autosomal dominant:

At least one affected parent for every affected child (usually)
Appears in every generation (no “skip”)
Equal in males and females

X-linked recessive:

Predominantly affects males
Carrier females are phenotypically normal
Affected father cannot pass to sons (passes Y chromosome to sons)
All daughters of affected father are carriers (they get his X with mutation)

X-linked dominant:

Affected father passes to ALL daughters (but no sons)
Affected mother passes to ~50% of sons and ~50% of daughters

Exam-Specific Tips

NEET: Pedigree analysis questions appear in almost every paper (1–2 marks each). Practice drawing pedigree charts and determining: (1) is the trait dominant or recessive? (2) is it autosomal or sex-linked? Work from “is it common in males only?” (sex-linked) and “can two unaffected parents have affected children?” (recessive). NEET 2023 had a pedigree question about colour blindness inheritance.

CBSE Class 12: Board papers consistently ask “Distinguish between Klinefelter and Turner syndrome” (3–4 marks). Always include karyotype (47,XXY vs 45,X0), phenotype, and mechanism (non-disjunction in Klinefelter vs typically missing X in Turner). Do not confuse: Klinefelter = extra X in males = infertile males; Turner = missing X in females = infertile females.

Common Mistakes to Avoid

Mistake 1 — Confusing Klinefelter and Turner: Klinefelter = XXY = phenotypically male (extra X). Turner = X0 = phenotypically female (missing X). The memory hook: “Klinefelter has a Knee too many chromosomes” (extra one). Turner is the only monosomy that is viable.

Mistake 2 — X-linked recessive in females: Students say affected females are impossible in X-linked recessive. They are rare, not impossible — they require a homozygous condition ( $X^h X^h$ ), which means their father must be affected ( $X^h Y$ ) and their mother must be a carrier ( $X^H X^h$ ). Colour-blind daughters are possible, just rare.

Mistake 3 — Calling Down syndrome a genetic mutation: Down syndrome is a chromosomal disorder (extra chromosome), NOT a gene mutation. The gene sequence of chromosome 21 is normal — there’s just one too many copies. Sickle cell anaemia, by contrast, IS a point mutation.

Mistake 4 — Sex-linked dominant vs recessive: Students confuse these in pedigree analysis. Remember: in X-linked recessive, the father cannot pass it to sons (he gives them Y). So if you see an affected father with an affected son, the trait cannot be X-linked (unless the son got it from a carrier mother).

Mistake 5 — Ignoring the sickle cell heterozygous advantage: Students learn sickle cell is harmful and stop there. The heterozygous advantage (HbAS carriers have reduced malaria severity) explains why a harmful allele persists at high frequency in malaria-endemic populations. This is evolutionary genetics and appears in NEET.

Practice Questions

Q1. A woman with normal vision whose father was colour blind marries a colour-blind man. What proportion of their sons and daughters will be colour blind?

Mother’s father was colour blind: $X^h Y$ . So mother got $X^h$ from father → she is carrier $X^H X^h$ . Father: $X^h Y$ . Sons get Y from father, X from mother: 50% $X^H Y$ (normal), 50% $X^h Y$ (colour blind). Daughters get $X^h$ from father, X from mother: 50% $X^H X^h$ (carrier), 50% $X^h X^h$ (colour blind). Answer: 50% of sons colour blind; 50% of daughters colour blind.

Q2. In a family, the father is affected with sickle cell anaemia and the mother is a carrier. What is the probability of their child being affected?

Father: HbS/HbS. Mother: HbA/HbS. Cross: all children get HbS from father; 50% get HbA from mother, 50% get HbS from mother. So: 50% HbA/HbS (carriers), 50% HbS/HbS (affected). Probability of affected child = 50%.

Q3. Non-disjunction during which division produces Klinefelter syndrome more commonly, and why?

Non-disjunction during Meiosis I — the X and X chromosomes (or X and Y) fail to separate, producing an egg (or sperm) with two sex chromosomes. When an XX egg is fertilised by a Y-bearing sperm, the result is XXY (Klinefelter). Meiosis I non-disjunction is more common than Meiosis II. Maternal age increases the risk (similar mechanism to Down syndrome).

FAQs

Is sickle cell anaemia curable? No permanent cure exists for most patients, but gene therapy trials using CRISPR are showing promising results. Bone marrow transplant can be curative if a matched donor is available. Hydroxyurea (a drug) reduces crisis frequency by increasing HbF production.

Can a person with Down syndrome reproduce? Females with Down syndrome are occasionally fertile; males are almost always infertile. Offspring of a Down syndrome mother have a ~50% chance of also having Down syndrome.

What is the difference between mutation and chromosomal aberration? A mutation is a change in the DNA sequence — can be a single base change, insertion, deletion, or duplicaton. A chromosomal aberration involves a change in chromosome number (aneuploidy) or chromosome structure (deletion, inversion, translocation) — these are visible in a karyotype.

Why are X-linked recessive disorders more common in males? Males have only one X chromosome. A single copy of the mutant allele on their X is sufficient to cause the disorder (hemizygous condition). Females have two X chromosomes; they need two copies of the mutant allele (homozygous). The probability of inheriting two copies is lower than one copy.

Is colour blindness treatable? Currently, there’s no widely available treatment. Experimental gene therapy in monkeys (delivering the missing opsin gene via viral vector) restored colour vision, and human trials are in early stages. Special EnChroma glasses partially correct some types by filtering certain wavelengths, but they don’t fix the underlying mutation.