RNA-Seq detects a SAMD12-EXT1 fusion transcript and leads to the discovery of an EXT1 deletion in a child with multiple osteochondromas.
exostoses
gene fusion
multiple hereditary
osteochondroma
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
23
10
2018
revised:
29
11
2018
accepted:
13
12
2018
pubmed:
12
1
2019
medline:
9
5
2019
entrez:
12
1
2019
Statut:
ppublish
Résumé
We describe a patient presenting with pachygyria, epilepsy, developmental delay, short stature, failure to thrive, facial dysmorphisms, and multiple osteochondromas. The patient underwent extensive genetic testing and analysis in an attempt to diagnose the cause of his condition. Clinical testing included metaphase karyotyping, array comparative genomic hybridization, direct sequencing and multiplex ligation-dependent probe amplification and trio-based exome sequencing. Subsequently, research-based whole transcriptome sequencing was conducted to determine whether it might shed light on the undiagnosed phenotype. Clinical exome sequencing of patient and parent samples revealed a maternally inherited splice-site variant in the doublecortin (DCX) gene that was classified as likely pathogenic and diagnostic of the patient's neurological phenotype. Clinical array comparative genome hybridization analysis revealed a 16p13.3 deletion that could not be linked to the patient phenotype based on affected genes. Further clinical testing to determine the cause of the patient's multiple osteochondromas was unrevealing despite extensive profiling of the most likely causative genes, EXT1 and EXT2, including mutation screening by direct sequence analysis and multiplex ligation-dependent probe amplification. Whole transcriptome sequencing identified a SAMD12-EXT1 fusion transcript that could have resulted from a chromosomal deletion, leading to the loss of EXT1 function. Re-review of the clinical array comparative genomic hybridization results indicated a possible unreported mosaic deletion affecting the SAMD12 and EXT1 genes that corresponded precisely to the introns predicted to be affected by a fusion-causing deletion. The existence of the mosaic deletion was subsequently confirmed clinically by an increased density copy number array and orthogonal methodologies CONCLUSIONS: While mosaic mutations and deletions of EXT1 and EXT2 have been reported in the context of multiple osteochondromas, to our knowledge, this is the first time that transcriptomics technologies have been used to diagnose a patient via fusion transcript analysis in the congenital disease setting.
Sections du résumé
BACKGROUND
We describe a patient presenting with pachygyria, epilepsy, developmental delay, short stature, failure to thrive, facial dysmorphisms, and multiple osteochondromas.
METHODS
The patient underwent extensive genetic testing and analysis in an attempt to diagnose the cause of his condition. Clinical testing included metaphase karyotyping, array comparative genomic hybridization, direct sequencing and multiplex ligation-dependent probe amplification and trio-based exome sequencing. Subsequently, research-based whole transcriptome sequencing was conducted to determine whether it might shed light on the undiagnosed phenotype.
RESULTS
Clinical exome sequencing of patient and parent samples revealed a maternally inherited splice-site variant in the doublecortin (DCX) gene that was classified as likely pathogenic and diagnostic of the patient's neurological phenotype. Clinical array comparative genome hybridization analysis revealed a 16p13.3 deletion that could not be linked to the patient phenotype based on affected genes. Further clinical testing to determine the cause of the patient's multiple osteochondromas was unrevealing despite extensive profiling of the most likely causative genes, EXT1 and EXT2, including mutation screening by direct sequence analysis and multiplex ligation-dependent probe amplification. Whole transcriptome sequencing identified a SAMD12-EXT1 fusion transcript that could have resulted from a chromosomal deletion, leading to the loss of EXT1 function. Re-review of the clinical array comparative genomic hybridization results indicated a possible unreported mosaic deletion affecting the SAMD12 and EXT1 genes that corresponded precisely to the introns predicted to be affected by a fusion-causing deletion. The existence of the mosaic deletion was subsequently confirmed clinically by an increased density copy number array and orthogonal methodologies CONCLUSIONS: While mosaic mutations and deletions of EXT1 and EXT2 have been reported in the context of multiple osteochondromas, to our knowledge, this is the first time that transcriptomics technologies have been used to diagnose a patient via fusion transcript analysis in the congenital disease setting.
Identifiants
pubmed: 30632316
doi: 10.1002/mgg3.560
pmc: PMC6418362
doi:
Substances chimiques
Nerve Tissue Proteins
0
RNA, Messenger
0
SAMD12 protein, human
0
N-Acetylglucosaminyltransferases
EC 2.4.1.-
exostosin-1
EC 2.4.1.224
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e00560Informations de copyright
© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
Références
Genet Med. 2017 Feb;19(2):209-214
pubmed: 27441994
J Mol Diagn. 2008 Jan;10(1):85-92
pubmed: 18165274
Nucleic Acids Res. 2002 Jun 15;30(12):e57
pubmed: 12060695
Eur J Hum Genet. 2012 Nov;20(11):1141-7
pubmed: 22549408
Genet Test Mol Biomarkers. 2010 Jun;14(3):371-6
pubmed: 20578942
BMC Med Genet. 2011 Jun 26;12:85
pubmed: 21703028
Mol Biol Rep. 2009 Apr;36(4):661-7
pubmed: 18330718
Nucleic Acids Res. 2018 Jan 4;46(D1):D754-D761
pubmed: 29155950
Sci Rep. 2013;3:1346
pubmed: 23439489
Mol Genet Genomic Med. 2019 Mar;7(3):e00560
pubmed: 30632316
J Bone Joint Surg Am. 1994 Jul;76(7):986-92
pubmed: 8027127
Int J Genomics. 2017;2017:4798474
pubmed: 28630856
BMC Med Genet. 2017 Nov 10;18(1):126
pubmed: 29126381
J Clin Immunol. 2018 Apr;38(3):307-319
pubmed: 29671115
Autism Res. 2014 Apr;7(2):254-63
pubmed: 24634087
Am J Med Genet A. 2011 Mar;155A(3):612-7
pubmed: 21344629
Genome Res. 2010 Sep;20(9):1297-303
pubmed: 20644199
Springerplus. 2016 Jan 22;5:71
pubmed: 26839764
Oncol Rep. 2014 Feb;31(2):713-8
pubmed: 24297320
Genome Res. 1997 Apr;7(4):359-67
pubmed: 9110175
Nat Genet. 1996 Sep;14(1):25-32
pubmed: 8782816
J Med Genet. 1991 Apr;28(4):262-6
pubmed: 1856833
Hum Mutat. 2011 Feb;32(2):E2036-49
pubmed: 21280143
N Engl J Med. 2017 Jan 5;376(1):21-31
pubmed: 27959697
Am J Hum Genet. 1998 Feb;62(2):346-54
pubmed: 9463333
Gene. 2013 Feb 25;515(2):339-48
pubmed: 23262345
Clin Genet. 2018 Jul;94(1):174-178
pubmed: 29652076
Nat Genet. 2018 Apr;50(4):581-590
pubmed: 29507423
Sci Transl Med. 2017 Apr 19;9(386):
pubmed: 28424332
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
Eur J Hum Genet. 2013 Jan;21(1):112-4
pubmed: 22669415
Am J Hum Genet. 1997 Sep;61(3):520-8
pubmed: 9326317
Hum Mutat. 2009 Dec;30(12):1620-7
pubmed: 19810120
Genet Test Mol Biomarkers. 2009 Dec;13(6):825-30
pubmed: 19839753
Nat Genet. 1998 Jun;19(2):158-61
pubmed: 9620772
Nat Genet. 1995 Oct;11(2):137-43
pubmed: 7550340
Genet Test Mol Biomarkers. 2009 Feb;13(1):43-9
pubmed: 19309273
Biopreserv Biobank. 2015 Oct;13(5):311-9
pubmed: 26484571
Am J Med Genet B Neuropsychiatr Genet. 2015 Dec;168(8):669-77
pubmed: 26290131
Genet Test Mol Biomarkers. 2010 Dec;14(6):865-72
pubmed: 21039224
Tohoku J Exp Med. 2017;242(3):173-181
pubmed: 28690282
Genome Biol. 2011 Aug 11;12(8):R72
pubmed: 21835007
Clin Genet. 2004 Aug;66(2):144-51
pubmed: 15253765
Cytogenet Genome Res. 2011;132(3):135-43
pubmed: 21042007
Hum Mutat. 2004 Jul;24(1):86-92
pubmed: 15221792
Genes Chromosomes Cancer. 2013 Apr;52(4):431-6
pubmed: 23341036
Genet Med. 2008 Jun;10(6):415-29
pubmed: 18496225
Hum Mutat. 2000;15(3):220-7
pubmed: 10679937
J Bone Joint Surg Am. 2011 Dec 21;93(24):2294-302
pubmed: 22258776
Bioinformatics. 2014 Sep 15;30(18):2678-80
pubmed: 24876377
J Mol Biol. 1990 Oct 5;215(3):403-10
pubmed: 2231712
Mol Genet Genomic Med. 2018 May;6(3):382-392
pubmed: 29529714
Eur J Hum Genet. 2003 Jul;11(7):527-34
pubmed: 12825074
J Pathol. 2007 Mar;211(4):399-409
pubmed: 17226760
J Inherit Metab Dis. 2018 May;41(3):525-532
pubmed: 29372369