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

  • Author(s): Pena, Loren DM
  • 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 SG
  • Del Gaudio, Daniela
  • Leung, Marco L
  • Hendon, Laura G
  • Parker, Collette C
  • Jones, Kelly L
  • Undiagnosed Diseases Network Members
  • Goldstein, David B
  • Shashi, Vandana
  • et al.
Abstract

PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 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.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.

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