Chapter 2: Inherited Disease Genomics: Trio Exomes & Mendelian Inheritance
Chapter 2: Inherited Disease Genomics: Trio Exomes & Mendelian Inheritance
Rare Mendelian genetic disorders affect ~300 million individuals globally. While single-proband exome sequencing identifies hundreds of thousands of candidate variants, sequencing the affected child alongside both unaffected parents (Parent-Offspring Trio Sequencing) drastically reduces the diagnostic search space.
Mendelian Segregation Models
- De Novo Mutations (Dominant): Heterozygous variant present in the affected proband (0/1), but completely absent in both biological mother (0/0) and father (0/0). Highly enriched in severe pediatric neurodevelopmental and congenital disorders.
- Autosomal Recessive (Compound Heterozygous): Proband inherits one deleterious variant in Gene X from the mother (0/1) and a distinct deleterious variant in Gene X from the father (0/1).
- Autosomal Recessive (Homozygous by Descent): Proband inherits identical variant alleles from both carrier parents (common in consanguineous pedigrees).
- X-Linked: Hemizygous mutation on chromosome X in an affected male inherited from an asymptomatic carrier mother.
1. Filtering Trio VCFs with Bcftools & Slivar
# Extract candidate de novo variants from a family trio VCF
# Proband: CHILD, Mother: MOM, Father: DAD
bcftools view \\
-i 'GT[CHILD]="0/1" && GT[MOM]="0/0" && GT[DAD]="0/0" && FMT/DP[CHILD]>=20 && FMT/DP[MOM]>=20 && FMT/DP[DAD]>=20 && FMT/AD[CHILD:1]>=8' \\
trio_exome.vcf.gz \\
-Oz -o candidate_denovo.vcf.gz