Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Genetics in medicine, 2018-04, Vol.20 (4), p.464-469

Ort / Verlag

United States: Elsevier Limited

Erscheinungsjahr

2018

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.