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PURPOSE: Genomic test results, regardless of laboratory variant classification, require clinical practitioners to judge the applicability of a variant for medical decisions. Teaching and standardizing clinical interpretation of genomic variation calls for a methodology or tool. METHODS: To generate such a tool, we distilled the Clinical Genome Resource framework of causality and the American College of Medical Genetics/Association of Molecular Pathology and Quest Diagnostic Laboratory scoring of variant deleteriousness into the Clinical Variant Analysis Tool (CVAT). Applying this to 289 clinical exome reports, we compared the performance of junior practitioners with that of experienced medical geneticists and assessed the utility of reported variants. RESULTS: CVAT enabled performance comparable to that of experienced medical geneticists. In total, 124 of 289 (42.9%) exome reports and 146 of 382 (38.2%) reported variants supported a diagnosis. Overall, 10.5% (1 pathogenic [P] or likely pathogenic [LP] variant and 39 variants of uncertain significance [VUS]) of variants were reported in genes without established disease association; 20.2% (23 P/LP and 54 VUS) were in genes without sufficient phenotypic concordance; 7.3% (15 P/LP and 13 VUS) conflicted with the known molecular disease mechanism; and 24% (91 VUS) had insufficient evidence for deleteriousness. CONCLUSION: Implementation of CVAT standardized clinical interpretation of genomic variation and emphasized the need for collaborative and transparent reporting of genomic variation.

Familial hypomagnesemia with secondary hypocalcemia is a rare genetic disorder of magnesium metabolism that presents with refractory seizures during infancy. It is caused by loss-of-function mutations in the gene encoding transient receptor potential cation channel member 6 (TRPM6). Herein we report an infant who presented with refractory seizures that were brought under control by normalizing the magnesium level. Genetic analysis revealed a nonsense variant in the TRPM6 gene. Our case highlights the importance of evaluation for familial hypomagnesemia in any child with recurrent or refractory seizures.

Introduction: Idiopathic intracranial hypertension, also known as pseudotumor cerebri, can be associated with various medications, obesity, systemic conditions, and inherited disorders. To the best of our knowledge, this is the second pediatric case of a GnRH agonist reported to cause pseudotumor cerebri. Case presentation: Our patient, a 12 5/12-year-old transgender male (birth-assigned female), started depot leuprolide acetate to suppress puberty at 11 10/12 years of age (early Tanner 2 breast development). He received Lupron Depot® 7.5 mg intramuscularly for 4 doses, then 22.5 mg intramuscular every 13 weeks thereafter. Five months after his first injection, a routine eye examination revealed bilateral papilledema and enlarged blind spots, which was confirmed by a Pediatric Ophthalmologist. He was asymptomatic. There was no marked weight gain in the previous year with a BMI of 24.5 kg/m2 (+1.85 SD). His blood pressure was 110–123 mmHg systolic and 71–85 mmHg diastolic. Neurological examination was normal. CT head was normal. Cranial MRI showed slight flattening of the optic nerve heads, mild engorgement of optic nerve sheath fluid, and no space-occupying mass. Sedated lumbar puncture revealed elevated opening pressure of 31 cm H2O. CSF analysis, including pathology, was benign. He was managed with acetazolamide. Based on these findings, he was diagnosed with pseudotumor cerebri secondary to the GnRH agonist. Follow-up by the Ophthalmologist one month after starting acetazolamide showed significant improvement of the papilledema. Conclusion: This case highlights that patients on GnRH agonist therapy are at risk for pseudotumor cerebri, and we recommend periodic ophthalmologic surveillance.

We report a previously well paediatric patient with two distinct presentations of invasive group A streptococcus (GAS) infection resulting in significant morbidity. The first episode, following GAS pharyngitis, involved multiorgan dysfunction syndrome. This included cardiorespiratory and acute hepatorenal failure and purpura fulminans that eventually necessitated four-limb amputation. The second episode occurred 12 months later, from undetermined aetiology, and resulted in septic shock. Molecular analysis of the emm gene and PCR for Serum Opacity Factor revealed that the initial isolate was M Type 4 and sof gene positive while the second isolate was M Type 1 and sof gene negative. Immunological investigations, including CH50, quantitative IgA, IgM and IgG, and flow cytometry measuring lymphocyte subsets, and vaccine response to measles, mumps, rubella and pneumococcus were normal. This is the first report of recurrent bacteraemia from different strains of Streptococcus pyogenes infection in an apparently immunocompetent child.