Whole-Genome Sequencing and Integrative Genomic Analysis Approach on Two 22q11.2 Deletion Syndrome Family Trios for Genotype to Phenotype Correlations

Jonathan H. Chung, Jinlu Cai, Barrie G. Suskin, Zhengdong Zhang, Karlene Coleman, Bernice E. Morrow

Research output: Contribution to journalArticle

10 Scopus citations


The 22q11.2 deletion syndrome (22q11DS) affects 1:4,000 live births and presents with highly variable phenotype expressivity. In this study, we developed an analytical approach utilizing whole-genome sequencing (WGS) and integrative analysis to discover genetic modifiers. Our pipeline combined available tools in order to prioritize rare, predicted deleterious, coding and noncoding single-nucleotide variants (SNVs), and insertion/deletions from WGS. We sequenced two unrelated probands with 22q11DS, with contrasting clinical findings, and their unaffected parents. Proband P1 had cognitive impairment, psychotic episodes, anxiety, and tetralogy of Fallot (TOF), whereas proband P2 had juvenile rheumatoid arthritis but no other major clinical findings. In P1, we identified common variants in COMT and PRODH on 22q11.2 as well as rare potentially deleterious DNA variants in other behavioral/neurocognitive genes. We also identified a de novo SNV in ADNP2 (NM_014913.3:c.2243G>C), encoding a neuroprotective protein that may be involved in behavioral disorders. In P2, we identified a novel nonsynonymous SNV in ZFPM2 (NM_012082.3:c.1576C>T), a known causative gene for TOF, which may act as a protective variant downstream of TBX1, haploinsufficiency of which is responsible for congenital heart disease in individuals with 22q11DS. Circos plot showing coding (red) and noncoding (green) genetic variants and their affected genes in an individual with 22q11.2 deletion syndrome. Whole genome sequencing and integrative analysis were used to prioritize genetic variants and identify a small subset of genes (blue labels) that may influence the phenotypes seen in this individual.

Original languageEnglish (US)
Pages (from-to)797-807
Number of pages11
JournalHuman Mutation
Issue number8
StatePublished - Aug 1 2015



  • 22q11.2 deletion syndrome
  • Integrative analysis
  • Juvenile rheumatoid arthritis
  • Schizophrenia psychosis
  • Tetralogy of Fallot

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this