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

Abstract

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-month old male who presented with Dandy-Walker malformation, metopic craniosynostosis and developmental delay. Clinical exome sequencing (ES) trio analysis revealed the presence of two variants in the proband. The first was a de novo variant in the PPP2R1A 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 CBL 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 CBL are associated with AD Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (JMML). Molecular analyses using a different tissue source, buccal epithelial cells, suggest that the CBL 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.

Novel Variants of PPP2R1A in Catalytic Subunit Binding Domain and Genotype–Phenotype Analysis in Neurodevelopmentally Delayed Patients

“…These patients showed different clinical manifestations such as opposite abnormal head circumference types, and microcephaly and macrocephaly. To identify the correlations between the different variations of PPP2R1A with clinical features, we collected and reviewed the clinical and genetic information of 64 NDD patients (2 reported fetuses were excluded, and 4 patients in our study were included) [ 7 , 10 , 13 , 14 , 15 , 22 ]. We found that patients with microcephaly often had brain structure abnormalities and severe epilepsy; patients with Met180Thr/Val variants displayed macrocephaly and severe ID, but did not suffer from epilepsy; patients with Arg258His/Ser variants all had microcephaly but rarely suffered from epilepsy.…”

PPP2R1A neurodevelopmental disorder is associated with congenital heart defects

“…A genetic syndrome caused by pathogenic heterozygous variants in the PP2A subunits was first described in 2015, when 3 de novo PPP2R1A variants and 4 de novo PPP2R5D variants were identified among 1133 proband‐parent trio exomes in the United Kingdom's Deciphering Developmental Disorders project (Deciphering Developmental Disorders, 2015). Since that time, 39 patients have been reported with 19 different de novo PPP2R1A variants (Deciphering Developmental Disorders, 2015; Houge et al, 2015; Lenaerts et al, 2021; Melas et al, 2021; Ruxmohan et al, 2021; Wallace et al, 2019; Zhang et al, 2020). The associated phenotype is variable and includes intellectual disability, developmental delay, epilepsy, agenesis/dysgenesis of the corpus callosum, and dysmorphic facial features.…”