MRCOG Part 1 · Genetics · Gene Abnormalities and Principles of Inheritance

Types of Gene Abnormalities: MRCOG Part 1 questions and key facts

This topic covers the classes of mutation—including point mutations, triplet repeat expansions, and collagen gene defects—and the single-gene disorders that illustrate them. Complete androgen insensitivity syndrome, an androgen receptor gene defect, serves as the classic X-linked endocrine example. Key autosomal conditions examined include sickle cell disease, cystic fibrosis, osteogenesis imperfecta, spinal muscular atrophy, and phenylketonuria. Candidates are expected to recognise clinical triggers and inheritance in X-linked conditions such as glucose-6-phosphate dehydrogenase deficiency and haemophilia B. Triplet repeat disorders, notably fragile X syndrome and Huntington's disease, illustrate dynamic mutational mechanisms with reproductive and clinical implications across generations.

The Uterio bank has 27 questions on this topic. 3 arebelow in full; the syllabus detail is in the Genetics study guide.

How the exam tests Types of Gene Abnormalities

  • Identifying specific mutation classes, including point mutations in beta-globin, collagen gene defects in osteogenesis imperfecta, and triplet repeat expansions.
  • Recognising triggers of acute haemolysis in G6PD deficiency and distinguishing Factor IX deficiency in haemophilia B from Factor VIII in haemophilia A.
  • Identifying complete androgen insensitivity syndrome by its 46,XY karyotype, female external phenotype, normal breast development, sparse pubic hair, and absent uterus.
  • Recognising clinical manifestations of single-gene disorders, including neonatal meconium ileus and adult congenital bilateral absence of the vas deferens in cystic fibrosis.

High-yield facts

  1. Missense mutations alter single amino acids, nonsense mutations create premature stop codons, frameshifts alter reading frames, splice-site defects disrupt splicing, and triplet repeat expansions cause dynamic gene elongation.
  2. Sickle cell disease is caused by an adenine to thymine point mutation in the beta-globin gene, substituting glutamic acid with valine at position six.
  3. Cystic fibrosis causes congenital bilateral absence of the vas deferens in about 95 to 98 per cent of affected males, resulting in obstructive azoospermia.
  4. Neonatal meconium ileus results from distal ileal obstruction by tenacious secretions and is a classic presentation of cystic fibrosis.
  5. Complete androgen insensitivity syndrome is caused by an X-linked recessive mutation of the androgen receptor gene; 46,XY individuals have a female phenotype with normal breasts, sparse pubic hair, usually undescended testes and no uterus.
  6. Müllerian-inhibiting factor from testes in complete androgen insensitivity causes Müllerian duct regression, leaving a short, blind-ending vaginal pouch.
  7. Huntington's disease and fragile X syndrome are triplet repeat expansions displaying anticipation; HTT CAG expansions often advance onset, while FMR1 CGG expansion beyond 200 copies causes silencing.
  8. Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive disorder where fava beans, infection, or oxidant drugs cause acute haemolytic anaemia.
  9. Haemophilia B is an X-linked recessive bleeding disorder caused by Factor IX deficiency, distinguishing it from Factor VIII deficiency in haemophilia A.
  10. Osteogenesis imperfecta results from COL1A1 or COL1A2 mutations that disrupt type I collagen triple-helical structure, causing bone fragility.
  11. Spinal muscular atrophy causes proximal muscle weakness via lower motor neurone loss, unlike myotonic dystrophy which features myotonia and frontal balding.
  12. Phenylketonuria management requires a low-phenylalanine diet and avoidance of aspartame; normal life-span and fertility are expected with early, well-controlled treatment.

Common pitfalls

  • Growth in fragile X syndrome is accelerated in childhood with near-normal adult height; short stature is not a recognised feature to expect.
  • Attributing frontal balding or myotonia to spinal muscular atrophy; these features indicate myotonic dystrophy, whereas spinal muscular atrophy produces proximal muscle weakness.
  • Confusing haemophilia A with haemophilia B; haemophilia A is Factor VIII deficiency, whereas haemophilia B is Factor IX deficiency.
  • Expecting ambiguous genitalia in complete androgen insensitivity syndrome; external genitalia are entirely female, whereas partial androgen insensitivity produces ambiguous genitalia.

Practice questions: Types of Gene Abnormalities

Single best answer, exactly as the exam asks. Commit to an option before opening the explanation.

Question 1

Genetics

When phenylketonuria is swiftly diagnosed and managed, what outcome is typical?

  1. ANormal life-span and fertility
  2. BUsual life expectancy but compromised reproductive ability
  3. CShortened fertility duration and decreased longevity
  4. DDecreased life-span while retaining reproductive capacity
  5. ELower life expectancy and fertility despite preserved cognitive function
Show answer and explanation

Correct answer: A. Normal life-span and fertility

Key takeaway

With early diagnosis and proper management, individuals with phenylketonuria (PKU) can expect a normal life-span and fertility.

Phenylketonuria (PKU) is an autosomal recessive deficiency of phenylalanine hydroxylase. In the UK it is detected by newborn bloodspot screening, and the European PKU guidelines recommend starting treatment as early as possible, ideally before 10 days of age. Management consists of a low-phenylalanine diet with phenylalanine-free protein substitutes (plus the cofactor sapropterin in responsive patients), avoidance of aspartame, and lifelong monitoring of blood phenylalanine.

Normal life-span and fertility are the typical outcomes of PKU when treatment starts early and control is maintained. Early-treated PKU does not shorten life, so decreased life-span while retaining reproductive capacity, shortened fertility duration and decreased longevity and lower life expectancy and fertility despite preserved cognitive function are all wrong. PKU does not impair gonadal function either, so usual life expectancy but compromised reproductive ability is also incorrect.

Because fertility is normal, preconception care matters: a woman with PKU needs strict phenylalanine control before conception and throughout pregnancy, because high maternal phenylalanine is teratogenic (maternal PKU syndrome, with microcephaly, intellectual disability, congenital heart disease and growth restriction in the baby).

Question 2

Genetics

What is the underlying genetic defect in sickle cell disease?

  1. AMutation in the alpha-globin gene
  2. BMutation in the beta-globin gene
  3. CDeletion of a large segment of a chromosome
  4. DExpansion of a trinucleotide repeat
  5. EMutation in a mitochondrial gene
Show answer and explanation

Correct answer: B. Mutation in the beta-globin gene

Key takeaway

Sickle cell disease results from a point mutation in the beta-globin gene, leading to abnormal haemoglobin S (HbS) production and subsequent red blood cell sickling.

Sickle cell disease is an autosomal recessive disorder characterised by a point mutation in the beta-globin gene on chromosome 11. This single nucleotide substitution (adenine to thymine) leads to the substitution of glutamic acid with valine at the sixth position of the beta-globin chain.

This seemingly minor change has a profound effect on haemoglobin structure. The abnormal haemoglobin, known as haemoglobin S (HbS), polymerises under deoxygenated conditions. This polymerisation distorts the red blood cell shape, leading to the characteristic 'sickle' appearance. These sickled red blood cells are rigid and less deformable, causing vaso-occlusion, haemolysis, and the wide range of clinical manifestations associated with sickle cell disease.

Mutations in the alpha-globin gene cause alpha-thalassaemia, not sickle cell disease. Alpha-thalassaemia affects the production of alpha-globin chains, leading to an imbalance in globin chain synthesis and subsequent anaemia.

A deletion of a large segment of a chromosome represents a different class of genetic abnormality and isn't the specific defect in sickle cell disease. Similarly, expansion of a trinucleotide repeat is associated with conditions like Huntington's disease and fragile X syndrome. Finally, mitochondrial gene mutations are linked to mitochondrial disorders with maternal inheritance.

Question 3

Genetics

Which of the following is a characteristic feature of G6PD deficiency?

  1. AIncreased risk of bleeding
  2. BFava bean-induced haemolysis
  3. CThrombocytopenia
  4. DProlonged clotting time
  5. ESkeletal abnormalities
Show answer and explanation

Correct answer: B. Fava bean-induced haemolysis

Key takeaway

G6PD deficiency causes haemolysis induced by eating fava beans, along with medications and infections, due to the red blood cells' inability to handle oxidative stress.

Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is an X-linked recessive genetic disorder that affects red blood cells.

Fava bean-induced haemolysis (favism) is the classic feature of G6PD deficiency. G6PD is an enzyme crucial for the pentose phosphate pathway, which produces NADPH. NADPH is essential for reducing oxidative stress within red blood cells. In individuals with G6PD deficiency, certain triggers, such as fava beans (broad beans), certain medications (like antimalarials), and infections, lead to increased oxidative stress. This overwhelms the red blood cells' limited capacity to deal with the stress, causing them to break down (haemolysis). This haemolysis manifests clinically as haemolytic anaemia.

Increased risk of bleeding and prolonged clotting time are not typical features of G6PD deficiency. These are more associated with disorders of coagulation factors or platelets.

Thrombocytopenia (low platelet count) is also not a characteristic feature of G6PD deficiency. G6PD deficiency primarily affects red blood cells, not platelets.

Skeletal abnormalities are not associated with G6PD deficiency. They are a feature of other inherited disorders, such as thalassaemia major, in which marrow expansion deforms the skull and facial bones.

24 more types of gene abnormalities questions in the bank

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What the syllabus covers under types of gene abnormalities

  • Mutations

Read the full section in the Genetics guide, or check the next exam dates.