How do you identify the mode of inheritance from a pedigree tree in medical genetics?

How to Identify Mode of Inheritance from a Pedigree Tree

To identify the mode of inheritance from a pedigree, systematically analyze the pattern of affected individuals across generations, looking for key features that distinguish autosomal dominant, autosomal recessive, X-linked, and mitochondrial inheritance patterns.

Step-by-Step Approach to Pedigree Analysis

1. Assess Vertical vs. Horizontal Transmission

• Vertical transmission (disease appears in every generation) strongly suggests autosomal dominant inheritance 1
• Horizontal transmission (disease skips generations, appearing in siblings but not parents) suggests autosomal recessive inheritance 1
• If the pattern shows affected individuals in multiple generations with approximately 50% of offspring affected, this confirms autosomal dominant inheritance 1

2. Evaluate Male-to-Male Transmission

• Direct father-to-son transmission rules out X-linked inheritance entirely, as fathers pass only their Y chromosome to sons 2
• If you observe father-to-son transmission, the inheritance must be autosomal (either dominant or recessive) 2
• Absence of male-to-male transmission does not confirm X-linked inheritance but keeps it as a possibility 2

3. Analyze Sex Distribution of Affected Individuals

• Predominantly or exclusively affected males with unaffected carrier females suggests X-linked recessive inheritance 3
• Equal distribution between males and females indicates autosomal inheritance (dominant or recessive) 4
• If affected males have unaffected parents but affected maternal uncles or male cousins through maternal aunts, this confirms X-linked recessive 3

4. Determine Parental Consanguinity

• Consanguinity in parents (marriage between relatives) strongly suggests autosomal recessive inheritance 1
• Autosomal recessive conditions are more likely to appear when both parents carry the same rare mutation, which is more probable in related individuals 1

5. Calculate Affected Offspring Ratios

• Approximately 50% of offspring affected from an affected parent suggests autosomal dominant 1
• Approximately 25% of offspring affected from two unaffected carrier parents suggests autosomal recessive 1
• For X-linked recessive: affected males typically have unaffected parents, with 50% of male offspring of carrier mothers being affected 3

6. Look for Specific X-Linked Patterns

• Carrier females may show mild manifestations due to X-inactivation, while affected males show full disease expression 3
• The disease "skips" from affected grandfather through carrier daughter to affected grandson (diagonal pattern) 3
• No affected females appear unless the father is affected AND the mother is a carrier (extremely rare) 3

7. Consider Maternal-Only Transmission

• If all offspring of affected mothers are affected regardless of sex, but affected fathers never transmit the condition, consider mitochondrial inheritance 4
• Mitochondrial inheritance shows no male transmission because sperm contribute negligible mitochondria to offspring 4

Common Pitfalls to Avoid

• Incomplete penetrance can make autosomal dominant inheritance appear recessive because some individuals with the mutation don't express the phenotype 1
• Variable expressivity means affected individuals may have different severity levels, potentially causing you to miss mildly affected individuals 1
• Small pedigrees may not show clear patterns; larger multigenerational pedigrees provide more reliable information 5
• New mutations in autosomal dominant conditions can appear as isolated cases without family history 1
• Compound heterozygosity in autosomal recessive conditions means affected individuals may have two different mutations rather than two copies of the same mutation 1

Special Considerations

• X-linked dominant inheritance (rare) shows affected males and females, but affected males have all affected daughters and no affected sons 4
• Y-linked inheritance (extremely rare) shows only male-to-male transmission affecting all sons of affected fathers 4
• Genetic heterogeneity means the same phenotype can result from different inheritance patterns in different families 2
• Always confirm the diagnosis and relationship information through medical records when possible, as family reporting can be inaccurate 1