Discuss Patterns of Inheritance — its causes, clinical features and management.

Introduction

Genetic disorders are inherited in Mendelian (single-gene) and non-Mendelian patterns. Recognising the pattern from the pedigree allows diagnosis, recurrence-risk estimation and counselling.

Autosomal Dominant (ad)

• Vertical transmission — affected individuals in every generation; males and females equally affected.
• An affected parent has a 50% risk in each child; features include variable expression and incomplete penetrance.
• Examples — achondroplasia, Marfan syndrome, neurofibromatosis, Huntington disease.

Autosomal Recessive (ar)

• Horizontal pattern — usually affected siblings with unaffected (carrier) parents; associated with consanguinity.
• Two carrier parents have a 25% risk per child.
• Examples — thalassaemia, cystic fibrosis, sickle cell disease, most inborn errors of metabolism, PKU.

X-linked Recessive

• Males affected, females are carriers; no male-to-male transmission.
• A carrier mother transmits to 50% of sons (affected) and 50% of daughters (carriers).
• Examples — haemophilia, Duchenne muscular dystrophy, G6PD deficiency, red-green colour blindness.

X-linked Dominant

• Affected males and females; no male-to-male transmission; may be lethal in males.
• Examples — Rett syndrome, X-linked (vitamin D-resistant) hypophosphataemic rickets.

Non-mendelian Inheritance

Key Concepts / Terminology

Pedigree Analysis

• Squares = males, circles = females; a horizontal line = mating; shaded = affected.
• A three-generation pedigree with consanguinity loops and affected relatives reveals the pattern.

WHY Pattern Matters

Identifying the inheritance pattern gives the recurrence risk and guides carrier testing, prenatal diagnosis and counselling for the family.

Consanguinity & Community

Consanguineous marriage increases the risk of autosomal recessive disorders (both partners more likely to carry the same rare allele); this is relevant in many Indian communities and informs premarital counselling.

Representative Disorders

Sex-limited & Sex-influenced Traits

• Sex-limited — expressed in one sex only (e.g. Features confined to one sex despite autosomal inheritance).
• Sex-influenced — expressed differently in the two sexes (e.g. Pattern baldness).

Mosaicism & New Mutations

A new (de novo) mutation explains an affected child with no family history (common in achondroplasia); germline mosaicism in a parent can cause recurrence despite apparently unaffected parents — an important counselling point.

Application to Counselling

• The pattern gives the numerical recurrence risk quoted to families (AR 25%, AD 50%, X-linked risks by sex).
• It also identifies at-risk relatives who may benefit from carrier testing and reproductive counselling.

WHY Some Patterns Do Not Obey the Rules

• Understanding why real pedigrees so often fail to look like the textbook prevents serious errors in counselling.
• Several phenomena confound the simple patterns.
• Reduced penetrance: a person carries the dominant gene but shows NO features at all — so the disease appears to 'skip' a generation.
• Variable expressivity: the same mutation produces disease of very different severity in different family members — so a mildly affected parent may be overlooked entirely, while their child is severely affected (as in neurofibromatosis).
• Anticipation: a triplet-repeat expansion grows as it passes down the generations — so the disease becomes progressively earlier and more severe in each generation (Huntington's, myotonic dystrophy, fragile X).
• Genomic imprinting: the effect of a gene depends on which parent it came from — so an identical deletion of 15q11-13 causes PRADER-WILLI if inherited from the father and angelman if from the mother.
• And mosaicism, new mutations (which is why a dominant disease can appear with no family history), and multifactorial inheritance (most common diseases and malformations) complete the picture.