Journal
GENETICS IN MEDICINE
Volume 20, Issue 4, Pages 464-469Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gim.2017.128
Keywords
infantile neuroaxonal dystrophy; infantile systemic hyalinosis; leukoencephalopathy with vanishing white matter; Undiagnosed Diseases Network; whole-exome sequencing
Categories
Funding
- National Institutes of Health (NIH) Common Fund, through the Office of Strategic Coordination/Office of the NIH [1U01HG007672-01]
Ask authors/readers for more resources
Purpose: To describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.& para;& para;Methods: Guided by phenotypic information, three children with negative WES underwent targeted single-gene testing. & para;& para;Results: Individual I had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.& para;& para;Conclusion: These cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available