Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance

Paola Prandini, Samuel Deutsch, Robert Lyle, Maryline Gagnebin, Celine Delucinge Vivier, Mauro Delorenzi, Corinne Gehrig, Patrick Descombes, Stephanie Sherman, Franca Dagna Bricarelli, Chiara Baldo, Antonio Novelli, Bruno Dallapiccola, Stylianos E. Antonarakis

Research output: Contribution to journalArticlepeer-review


Down syndrome (DS) is characterized by extensive phenotypic variability, with most traits occurring in only a fraction of affected individuals. Substantial gene-expression variation is present among unaffected individuals, and this variation has a strong genetic component. Since DS is caused by genomic-dosage imbalance, we hypothesize that gene-expression variation of human chromosome 21 (HSA21) genes in individuals with DS has an impact on the phenotypic variability among affected individuals. We studied gene-expression variation in 14 lymphoblastoid and 17 fibroblast cell lines from individuals with DS and an equal number of controls. Gene expression was assayed using quantitative real-time polymerase chain reaction on 100 and 106 HSA21 genes and 23 and 26 non-HSA21 genes in lymphoblastoid and fibroblast cell lines, respectively. Surprisingly, only 39% and 62% of HSA21 genes in lymphoblastoid and fibroblast cells, respectively, showed a statistically significant difference between DS and normal samples, although the average up-regulation of HSA21 genes was close to the expected 1.5-fold in both cell types. Gene-expression variation in DS and normal samples was evaluated using the Kolmogorov-Smirnov test. According to the degree of overlap in expression levels, we classified all genes into 3 groups: (A) nonoverlapping, (B) partially overlapping, and (C) extensively overlapping expression distributions between normal and DS samples. We hypothesize that, in each cell type, group A genes are the most dosage sensitive and are most likely involved in the constant DS traits, group B genes might be involved in variable DS traits, and group C genes are not dosage sensitive and are least likely to participate in DS pathological phenotypes. This study provides the first extensive data set on HSA21 gene-expression variation in DS and underscores its role in modulating the outcome of gene-dosage imbalance.

Original languageEnglish
Pages (from-to)252-263
Number of pages12
JournalAmerican Journal of Human Genetics
Issue number2
Publication statusPublished - Aug 2007

ASJC Scopus subject areas

  • Genetics


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