Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons

Alexandre Bolze, Bertrand Boisson, Barbara Bosch, Alexander Antipenko, Matthieu Bouaziz, Paul Sackstein, Malik Chaker-Margot, Vincent Barlogis, Tracy Briggs, Elena Colino, Aurora C. Elmore, Alain Fischer, Ferah Genel, Angela Hewlett, Maher Jedidi, Jadranka Kelecic, Renate Krüger, Cheng Lung Ku, Dinakantha Kumararatne, Alain Lefevre-UtileSam Loughlin, Nizar Mahlaoui, Susanne Markus, Juan Miguel Garcia, Mathilde Nizon, Matias Oleastro, Malgorzata Pac, Capucine Picard, Andrew J. Pollard, Carlos Rodriguez-Gallego, Caroline Thomas, Horst Von Bernuth, Austen Worth, Isabelle Meyts, Maurizio Risolino, Licia Selleri, Anne Puel, Sebastian Klinge, Laurent Abel, Jean Laurent Casanova

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here 11 new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 5′-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that 6 of 18 (33%) protein-coding mutations and the two (100%) 5′-UTR mutations display incomplete penetrance. Three mutations were identified in two independent kindreds, due to a hotspot or a founder effect. Finally, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.

Original languageEnglish (US)
Pages (from-to)E8007-E8016
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number34
StatePublished - Aug 21 2018


  • Incomplete penetrance
  • Isolated congenital asplenia
  • RPSA
  • Ribosomopathy
  • Spleen

ASJC Scopus subject areas

  • General


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