TY - JOUR
T1 - Looking beyond the exome
T2 - A phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases
AU - Undiagnosed Diseases Network Members
AU - Pena, Loren D.M.
AU - Jiang, Yong Hui
AU - Schoch, Kelly
AU - Spillmann, Rebecca C.
AU - Walley, Nicole
AU - Stong, Nicholas
AU - Horn, Sarah Rapisardo
AU - Sullivan, Jennifer A.
AU - McConkie-Rosell, Allyn
AU - Kansagra, Sujay
AU - Smith, Edward C.
AU - El-Dairi, Mays
AU - Bellet, Jane
AU - Keels, Martha Ann
AU - Jasien, Joan
AU - Kranz, Peter G.
AU - Noel, Richard
AU - Nagaraj, Shashi K.
AU - Lark, Robert K.
AU - Wechsler, Daniel S.G.
AU - Del Gaudio, Daniela
AU - Leung, Marco L.
AU - Hendon, Laura G.
AU - Parker, Collette C.
AU - Jones, Kelly L.
AU - Goldstein, David B.
AU - Shashi, Vandana
AU - Alejandro, Mercedes E.
AU - Bacino, Carlos A.
AU - Balasubramanyam, Ashok
AU - Bostwick, Bret L.
AU - Burrage, Lindsay C.
AU - Chen, Shan
AU - Clark, Gary D.
AU - Craigen, William J.
AU - Dhar, Shweta U.
AU - Emrick, Lisa T.
AU - Graham, Brett H.
AU - Hanchard, Neil A.
AU - Jain, Mahim
AU - Lalani, Seema R.
AU - Lee, Brendan H.
AU - Lewis, Richard A.
AU - Azamian, Mashid S.
AU - Moretti, Paolo M.
AU - Nicholas, Sarah K.
AU - Orange, Jordan S.
AU - Posey, Jennifer E.
AU - Potocki, Lorraine
AU - Schroeder, Molly C.
N1 - Publisher Copyright:
© 2018 American College of Medical Genetics and Genomics.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - 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.
AB - 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.
KW - Undiagnosed Diseases Network
KW - infantile neuroaxonal dystrophy
KW - infantile systemic hyalinosis
KW - leukoencephalopathy with vanishing white matter
KW - whole-exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85045219803&partnerID=8YFLogxK
U2 - 10.1038/gim.2017.128
DO - 10.1038/gim.2017.128
M3 - Article
C2 - 28914269
AN - SCOPUS:85045219803
SN - 1098-3600
VL - 20
SP - 464
EP - 469
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 4
ER -