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

Proc Natl Acad Sci U S A
Authors
Keywords
Abstract

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 , 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 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 Eleven of the 43 kindreds affected by sporadic disease (26%) carry mutations, whereas 12 of the 13 multiplex kindreds (92%) carry 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 exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.

Year of Publication
2018
Journal
Proc Natl Acad Sci U S A
Volume
115
Issue
34
Pages
E8007-E8016
Date Published
2018 08 21
ISSN
1091-6490
DOI
10.1073/pnas.1805437115
PubMed ID
30072435
PubMed Central ID
PMC6112730
Links
Grant list
UL1 TR001866 / TR / NCATS NIH HHS / United States
HHMI / Howard Hughes Medical Institute / United States