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<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>

Original publication

DOI

10.1073/pnas.1805437115

Type

Journal article

Journal

Proceedings of the National Academy of Sciences

Publisher

Proceedings of the National Academy of Sciences

Publication Date

21/08/2018

Volume

115

Pages

E8007 - E8016