Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases

Purpose To describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing. Methods Guided by phenotypic information, three children with negative WES underwent targeted single-gene testing. Results Individual 1 ha...

Full description

Saved in:

Bibliographic Details
Published in:	Genetics in medicine Vol. 20; no. 4; pp. 464 - 469
Main Authors:	Pena, Loren D M, Jiang, Yong-Hui, Schoch, Kelly, Spillmann, Rebecca C, Walley, Nicole, Stong, Nicholas, Rapisardo Horn, Sarah, Sullivan, Jennifer A, McConkie-Rosell, Allyn, Kansagra, Sujay, Smith, Edward C, El-Dairi, Mays, Bellet, Jane, Keels, Martha Ann, Jasien, Joan, Kranz, Peter G, Noel, Richard, Nagaraj, Shashi K, Lark, Robert K, Wechsler, Daniel S G, del Gaudio, Daniela, Leung, Marco L, Hendon, Laura G, Parker, Collette C, Jones, Kelly L, Goldstein, David B, Shashi, Vandana
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-04-2018 Elsevier Limited
Subjects:	631/208/514 692/700/139/1512 Alleles Biomedical and Life Sciences Biomedicine Biopsy brief-report Child Child, Preschool Exome Exome Sequencing Female Genetic Association Studies - methods Genetic Diseases, Inborn - diagnosis Genetic Diseases, Inborn - genetics Genetic Predisposition to Disease Genotype Human Genetics Humans Infant Laboratory Medicine Molecular Diagnostic Techniques - methods Molecular Diagnostic Techniques - standards Phenotype Polymorphism, Single Nucleotide Rare Diseases - diagnosis Rare Diseases - genetics Whole Genome Sequencing infantile neuroaxonal dystrophy infantile systemic hyalinosis leukoencephalopathy with vanishing white matter Undiagnosed Diseases Network whole-exome sequencing
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Purpose To describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing. Methods Guided by phenotypic information, three children with negative WES underwent targeted single-gene testing. Results Individual 1 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. Conclusion These cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.
Bibliography:	ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3
ISSN:	1098-3600 1530-0366
DOI:	10.1038/gim.2017.128