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RECESSIVE YET MOSAIC CBL DEFICIENCY BY SEGMENTAL UPD IN IDENTICAL TRIPLETS WITH PULMONARY DISEASE
Abstract
Background and Aims
Rare missense variants are frequently detected by next-generation DNA sequencing but the deleterious functional consequence of these is often difficult or impossible to establish with computational means.
Methods
We utilize a database of regulatory post-translational modifications, accumulated from thousands of scientific papers, to search missense variants that affect post-translational modification sites known to regulate the protein activity.
Results
Using this approach, we identified three patients, monochorionic triamniotic identical triplets, with a homozygous variant, p.Y371C, in CBL. The patients suffer from recurrent pneumonia and emphysema associated with an excess of transitional B cells and moncytosis. The variant is loss-of-function affecting the phosphorylation site required for CBL function . The triplets have inherited the CBL mutation from their father by segmental uniparental disomy (UPD) mosaicism. Surprisingly, the mosaic distribution of the mutant allele is exactly identical between the three siblings, affecting bone marrow and peripheral blood, oral mucosa but not hair and fingernails. The homozygosity rate in whole blood is above 95%, explaining the homogeneity of the immunological phenotype between the three siblings.
Conclusions
In summary we discovered and described a novel inborn error of immunity (IEI): autosomal recessive, yet mosaic CBL deficiency, causing recurrent pneumonia, myeloproliferation and a B-cell defect. To date, this report represents the first IEI in monozygotic triplets.