Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons
Bolze A., Boisson B., Bosch B., Antipenko A., Bouaziz M., Sackstein P., Chaker-Margot M., Barlogis V., Briggs T., Colino E., Elmore AC., Fischer A., Genel F., Hewlett A., Jedidi M., Kelecic J., Krüger R., Ku C-L., Kumararatne D., Lefevre-Utile A., Loughlin S., Mahlaoui N., Markus S., Garcia J-M., Nizon M., Oleastro M., Pac M., Picard C., Pollard AJ., Rodriguez-Gallego C., Thomas C., Von Bernuth H., Worth A., Meyts I., Risolino M., Selleri L., Puel A., Klinge S., Abel L., Casanova J-L.
<jats:p>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 <jats:italic>RPSA</jats:italic>, 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 <jats:italic>RPSA</jats:italic> 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 <jats:italic>RPSA.</jats:italic> Eleven of the 43 kindreds affected by sporadic disease (26%) carry <jats:italic>RPSA</jats:italic> mutations, whereas 12 of the 13 multiplex kindreds (92%) carry <jats:italic>RPSA</jats:italic> 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 <jats:italic>RPSA</jats:italic> exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.</jats:p>