Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

<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