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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.

© 2021 American Society of Human Genetics, EDEM3 encodes a protein that converts Man8GlcNAc2 isomer B to Man7-5GlcNAc2. It is involved in the endoplasmic reticulum-associated degradation pathway, responsible for the recognition of misfolded proteins that will be targeted and translocated to the cytosol and degraded by the proteasome. In this study, through a combination of exome sequencing and gene matching, we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3. The affected individuals present with an inherited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable facial dysmorphisms. Experiments in human fibroblast cell lines, human plasma, and mouse plasma and brain tissue demonstrated decreased trimming of Man8GlcNAc2 isomer B to Man7GlcNAc2, consistent with loss of EDEM3 enzymatic activity. In human cells, Man5GlcNAc2 to Man4GlcNAc2 conversion is also diminished with an increase of Glc1Man5GlcNAc2. Furthermore, analysis of the unfolded protein response showed a reduced increase in EIF2AK3 (PERK) expression upon stimulation with tunicamycin as compared to controls, suggesting an impaired unfolded protein response. The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing. We propose to call this deficiency EDEM3-CDG., This work was supported by the EU FP7 large-scale integrating project Genetic and Epigenetic Networks in Cognitive Dysfunction (241995) (to H.v.B.); National Institutes of Health (NIH) grants 5R01GM115730-03 (to M.H.), U54 NS115198 (to A.C.E. and M.H.), and T32GM008638 (to A.C.E.); and the Transatlantic Network of Excellence grant (10CVD03) from the Fondation Leducq and NIH NHGRI U01HG006398 (to D.J.R.). Family 4 was enrolled in the CAUSES Study; investigators include Shelin Adam, Christele Du Souich, Alison Elliott, Anna Lehman, Jill Mwenifumbo, Tanya Nelson, Clara Van Karnebeek, and Jan Friedman; it is funded by Mining for Miracles, British Columbia Children’s Hospital Foundation (grant number F15-01355) and Genome British Columbia (grant number F16-02276). D.L.P. is recipient of a CAPES Fellowship (99999.013311/2013-01). X.B. is supported by an AHA career development award (19CDA34630032).

Neurofibromatosis type 1 is diagnosed clinically based on the presence of two of seven criteria developed by a panel of experts in 1987. The sixth criterion focuses on skeletal findings and is as follows: "A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis." The wording for this criterion is misleading. In particular, "thinning of long bone cortex" is not the characteristic radiographic presentation, and no mention of long bone bowing is included. The distinctive clinical feature of long bone dysplasia in neurofibromatosis type 1 is anterolateral bowing of the lower leg (portion of the body delimited by the knee and ankle). The usual radiographic findings of long bone dysplasia in neurofibromatosis type 1 at first presentation, prior to fracture, are anterolateral bowing with medullary canal narrowing and cortical thickening at the apex of the bowing. We suggest that anterolateral bowing of the lower leg, with or without fracture or pseudarthrosis, is a more appropriate description of the primary finding that a clinician will use to fulfill the sixth diagnostic criterion for neurofibromatosis type 1. Clarification of this diagnostic criterion is important for the clinician and for research protocols. Appropriate interpretation will improve understanding of the natural history and pathophysiology of neurofibromatosis type 1.