35. Mosaicism as incidental finding in the pediatric next generation sequencing era

      Rapidly emerging high throughput sequencing technology with higher depths of coverage increases the potential for unraveling genomic findings that are incidental to the initial indication for clinical testing. The interpretation and management of clinically meaningful incidental genomic findings is a pressing issue particularly in the pediatric population due to the impact of genetic information on the family and potential for additional clinical investigation. Our study describes a 16-month-old male with notable brain abnormalities, delayed visual maturation, microcephaly, global delay, growth deficiency, metopic craniosynostosis and severe scoliosis. Clinical Trio Exome Sequencing revealed two de novo pathogenic missense alterations in the proband. First was in the PPP2R1A gene (c.773G>A, p.Arg258His), known to cause severe intellectual disability and epilepsy accounting for his clinical phenotype. The second variant occurred in a mutational hotspot of CBL gene (c.1111T>C, p.Tyr371His), at a reduced allelic frequency (11%), consistent with mosaicism. Germline variants in CBL are associated with AD Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (JMML). Targeted sequence analysis on buccal epithelial cells was negative for the CBL variant, indicating that the alteration may represent a clonal population of cells restricted to leukocytes. JMML can be caused by somatic and/or germline alterations in CBL. The proband is currently asymptomatic for features of JMML and is under hematological surveillance. To the best of our knowledge this is the first report of a concomitant pathogenic germline PPP2R1A variant and tissue-restricted mosaicism for a CBL variant.
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