Somatic variation as an incidental finding in the pediatric next-generation sequencing era

• Published in: Cold Spring Harbor molecular case studies 2021-12, Vol.7 (6), p.a006135
• Main Authors: Melas, Marilena, Mathew, Mariam T, Mori, Mari, Jayaraman, Vijayakumar, Wilson, Sarah A, Martin, Cortlandt, Jacobson-Kelly, Amanda E, Kelly, Ben J, Magrini, Vincent, Mardis, Elaine R, Cottrell, Catherine E, Lee, Kristy
• Format: Article
• Language: English
• Subjects: Child; Cranial sutures; Craniosynostosis; Epithelial cells; Epithelium; Genomic analysis; Genomics; High-Throughput Nucleotide Sequencing; Humans; Incidental Findings; Intellectual disabilities; Intellectual Disability; Leukemia; Leukocytes; Male; Microencephaly; Myelomonocytic leukemia; Next-generation sequencing; Noonan's syndrome; Pediatrics; Peripheral blood; Phenotype; Phenotypes; Population studies; Research Report; Tissue analysis; Variation
• ISSN: 2373-2865; 2373-2873
• DOI: 10.1101/mcs.a006135

The methodologic approach used in next-generation sequencing (NGS) affords a high depth of coverage in genomic analysis. Inherent in the nature of genomic testing, there exists potential for identifying genomic findings that are incidental or secondary to the indication for clinical testing, with the frequency dependent on the breadth of analysis and the tissue sample under study. The interpretation and management of clinically meaningful incidental genomic findings is a pressing issue particularly in the pediatric population. Our study describes a 16-mo-old male who presented with profound global delays, brain abnormality, progressive microcephaly, and growth deficiency, as well as metopic craniosynostosis. Clinical exome sequencing (ES) trio analysis revealed the presence of two variants in the proband. The first was a de novo variant in the gene (c.773G > A, p.Arg258His), which is associated with autosomal dominant (AD) intellectual disability, accounting for the proband's clinical phenotype. The second was a recurrent hotspot variant in the gene (c.1111T > C, p.Tyr371His), which was present at a variant allele fraction of 11%, consistent with somatic variation in the peripheral blood sample. Germline pathogenic variants in are associated with AD Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia. Molecular analyses using a different tissue source, buccal epithelial cells, suggest that the alteration may represent a clonal population of cells restricted to leukocytes. This report highlights the laboratory methodologic and interpretative processes and clinical considerations in the setting of acquired variation detected during clinical ES in a pediatric patient.