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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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