Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated exons.
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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
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Journal | Proc Natl Acad Sci U S A
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Volume | 115
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Issue | 34
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Pages | E8007-E8016
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Date Published | 2018 08 21
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ISSN | 1091-6490
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DOI | 10.1073/pnas.1805437115
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PubMed ID | 30072435
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PubMed Central ID | PMC6112730
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Grant list | UL1 TR001866 / TR / NCATS NIH HHS / United States
HHMI / Howard Hughes Medical Institute / United States
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