Intergenerational and intrafamilial phenotypic variability in 22q11.2 Deletion syndrome subjects

Emilia Cirillo, Giuliana Giardino, Vera Gallo, Pamela Puliafito, Chiara Azzari, Rosa Bacchetta, Fabio Cardinale, Maria P. Cicalese, Rita Consolini, Silvana Martino, Baldassarre Martire, Cristina Molinatto, Alessandro Plebani, Gioacchino Scarano, Annarosa Soresina, Caterina Cancrini, Paolo Rossi, Maria C. Digilio, Claudio Pignata

Research output: Contribution to journalArticlepeer-review


Background: 22q11.2 deletion syndrome (22q11.2DS) is a common microdeletion syndrome, which occurs in approximately 1:4000 births. Familial autosomal dominant recurrence of the syndrome is detected in about 8-28% of the cases. Aim of this study is to evaluate the intergenerational and intrafamilial phenotypic variability in a cohort of familial cases carrying a 22q11.2 deletion. Methods: Thirty-two 22q11.2DS subjects among 26 families were enrolled. Results: Second generation subjects showed a significantly higher number of features than their transmitting parents (212 vs 129, P = 0.0015). Congenital heart defect, calcium-phosphorus metabolism abnormalities, developmental and speech delay were more represented in the second generation (P <0.05). Ocular disorders were more frequent in the parent group. No significant difference was observed for the other clinical variables. Intrafamilial phenotypic heterogeneity was identified in the pedigrees. In 23/32 families, a higher number of features were found in individuals from the second generation and a more severe phenotype was observed in almost all of them, indicating the worsening of the phenotype over generations. Both genetic and epigenetic mechanisms may be involved in the phenotypic variability. Conclusions: Second generation subjects showed a more complex phenotype in comparison to those from the first generation. Both ascertainment bias related to patient selection or to the low rate of reproductive fitness of adults with a more severe phenotype, and several not well defined molecular mechanism, could explain intergenerational and intrafamilial phenotypic variability in this syndrome.

Original languageEnglish
Article number1
JournalBMC Medical Genetics
Issue number1
Publication statusPublished - Jan 2 2014


  • 22q11.2 deletion syndrome
  • DiGeorge syndrome
  • Immunodeficiency
  • Phenotypic variability

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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