ESPE Yearbook of Paediatric Endocrinology

Pediatrics. 2021 Jul;148(1):e2020019000. doi: 10.1542/peds.2020-019000.

Brief Summary: This case report of an infant with dysgenesis of the corpus callosum, whose whole genome sequencing (WGS) revealed variants of unknown significance (VUS) in ROBO1, demonstrates the potential of VUS in guiding clinical decisions.

Next-generation sequencing (NGS) is increasingly applied in investigations of suspected genetic diseases (1). Only a subset of the interesting variants identified by NGS are further evaluated and classified as pathogenic, likely pathogenic, likely benign, or benign according to the American College of Medical Genetics (ACMG) classification (2, 3). In fact, in as many as 70% of cases, NGS cannot identify a pathogenic variant for diagnosis (4). However, when genetic disease is highly suspected, careful evaluation of the available evidence might show that VUS are relevant for the case in question.

Here, the authors present a male infant who presented with small size for gestational age, dysmorphic face, hypospadias, and retractile testes. Head ultrasound revealed hydrocephalus, absent septum pellucidum, dysgenesis of the corpus callosum, and a finding suggestive of Probst bundles, aberrant bundles of axons running in an anterior-posterior direction between the cerebral hemispheres. These notions raised the suspicion of a genetic axon guidance disorder. He underwent rapid WGS, which revealed 2 rare VUS at conserved sites in the axon guidance receptor gene, ROBO1.

Due to the previous reported associations of ROBO1 variants with dysgenesis of midline structures, renal abnormalities, and hypopituitarism, the patient was further examined. The subsequent workup confirmed the callosal defect and uncovered kidney anomalies, as well as pituitary dysfunction. Finally, to support other investigators in critical evaluation of VUS, the paper presents a set of online resources for this purpose.

To conclude, this case report exemplifies how individualized interpretation of VUS as pathogenic may lead to early detection of accompanying anomalies and guide treatment. The paper also shows that the clinical judgment of variant pathogenicity can differ from and replace the ACMG classification. Importantly, this report sets a reminder of updating the variant interpretation as evidence accumulates.

References: 1. Clark MM, Stark Z, Farnaes L, Tan TY, White SM, Dimmock D, Kingsmore SF. Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases. NPJ Genom Med 2018 3:16. 2. Lappalainen T, Scott AJ, Brandt M, Hall IM. Genomic Analysis in the Age of Human Genome Sequencing. Cell 2019 177(1):70–84. 3. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015 17(5):405–24. 4. Friedman JM, Bombard Y, Cornel MC, Fernandez CV, Junker AK, Plon SE, Stark Z, Knoppers BM; Paediatric Task Team of the Global Alliance for Genomics and Health Regulatory and Ethics Work Stream. Genome-wide sequencing in acutely ill infants: genomic medicine’s critical application? Genet Med 2019 21(2):498–504.