Uncertain, Not Unimportant: Callosal Dysgenesis and Variants of Uncertain Significance in ROBO1

• Published in: Pediatrics (Evanston) Vol. 148; no. 1
• Main Authors: Woodring, Therese S, Mirza, Mohammed H, Benavides, Valeria, Ellsworth, Katarzyna A, Wright, Meredith S, Javed, M Jawad, Ramiro, Susan
• Format: Journal Article
• Language: English
• Published: United States American Academy of Pediatrics 01.07.2021
• Subjects: Acrocallosal syndrome; Adrenal Insufficiency - genetics; Agenesis of Corpus Callosum - diagnostic imaging; Agenesis of Corpus Callosum - genetics; Axon guidance; Case studies; Clinical Decision-Making; Congenital defects; Corpus callosum; Decision making; Development and progression; Genetic aspects; Genetic diversity; Genetic Variation; Genomes; Health aspects; Heterozygote; Humans; Hypopituitarism - genetics; Infant, Newborn; Infant, Premature; Infants; Kidney Diseases, Cystic - genetics; Magnetic Resonance Imaging; Male; Nerve Tissue Proteins - genetics; Patient outcomes; Patients; Pediatrics; Pituitary; Rare diseases; Receptors, Immunologic - genetics; Renal function; Roundabout Proteins; Ultrasonography; Uncertainty; Uncertainty in illness; Whole Genome Sequencing; United States
• ISSN: 0031-4005; 1098-4275
• DOI: 10.1542/peds.2020-019000

Congenital anomalies affect 3% to 5% of births and remain the leading cause of infant death in the United States. As whole exome and genome sequencing are increasingly used to diagnose underlying genetic disease, the patient's clinical presentation remains the most important context for interpreting sequencing results, including frequently reported variants of uncertain significance (VUS). Classification of a variant as VUS acknowledges limits on evidence to establish whether a variant can be classified as pathogenic or benign according to the American College of Medical Genetics guidelines. Importantly, the VUS designation reflects limits on the breadth of evidence linking the genetic variant to a disease. However, available evidence, although limited, may be surprisingly relevant in an individual patient's case. Accordingly, a VUS result should be approached neither as nondiagnostic genetic result nor as automatically "uncertain" in its potential to guide clinical decision-making. In this article, we discuss a case of an infant born at 29 weeks 4 days without a corpus callosum, whose whole genome sequencing yielded compound heterozygous variants both classified as VUS in , a gene encoding for a receptor involved in a canonical signaling mechanism that guides axons across midline. Approaching the VUS result as potentially pathogenic, we found the infant ultimately had pituitary dysfunction and renal anomalies consistent with other reported variants and basic science literature. Accordingly, we highlight resources for variant interpretation available to clinicians to evaluate VUS results, particularly as they inform the diagnosis of individually rare but collectively common rare diseases.