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

Isolated congenital asplenia (ICA) is characterized by the absence of spleen (undetectable by ultra sound) at birth without any other developmental defect. ICA predisposes to severe bacterial infections early in childhood. In 2013, we showed that deleterious mutations, absent from the worldwide population in the protein-coding region of RPSA, which encodes a ribosomal protein, caused ICA in 8 of 23 kindreds. We have since enrolled 33 new kindreds. We identified 11 new ICA-causing RPSA protein-coding mutations, as well as the first 2 ICA-causing mutations in the 5'-UTR of this gene. A few individuals carrying one of the new RPSA mutations had a detectable and seemingly functional spleen, indicating that very rare mutations in RPSA can cause ICA with incomplete penetrance. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry very rare, heterozygous, ICA-causing mutations in RPSA exons.