Molecular diagnosis of somatic overgrowth conditions: A single-center experience.
PIK3CA-related overgrowth spectrum
mosaicism
somatic overgrowth
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:
25
07
2018
revised:
02
11
2018
accepted:
02
12
2018
pubmed:
15
2
2019
medline:
9
5
2019
entrez:
15
2
2019
Statut:
ppublish
Résumé
Somatic overgrowth conditions, including Proteus syndrome, Sturge-Weber syndrome, and PIK3CA-related overgrowth spectrum, are caused by post-zygotic pathogenic variants, result in segmental mosaicism, and give rise to neural, cutaneous and/or lipomatous overgrowth. These variants occur in growth-promoting pathways leading to cellular proliferation and expansion of tissues that arise from the affected cellular lineage. We report on 80 serial patients evaluated for somatic overgrowth conditions in a diagnostic laboratory setting, including three prenatal patients. In total, 166 tissues from these 80 patients were subjected to targeted sequencing of an 8-gene panel capturing 10.2 kb of sequence containing known pathogenic variants associated with somatic overgrowth conditions. Deep next-generation sequencing was performed with the IonTorrent PGM platform at an average depth typically >5,000×. Likely pathogenic or pathogenic variants were identified in 36 individuals and variants of unknown significance in four. The overall molecular diagnostic yield was 45% but was highly influenced by both submitted tissue type and phenotype. In the prenatal setting, two patients had pathogenic variants identified in cultured amniocytes but in a third patient, the pathogenic variant was only present in post-natal tissues. Finally, expanding the test to include full gene sequencing of PIK3CA in contrast to targeted sequencing identified likely pathogenic variants in 3 of 7 patients that tested negative on the original panel. Next-generation sequencing has enabled sensitive detection of somatic pathogenic variants associated with overgrowth conditions. However, as the pathogenic variant allele frequency varies by tissue type within an individual, submission of affected tissue(s) greatly increases the chances of a molecular diagnosis.
Sections du résumé
BACKGROUND
Somatic overgrowth conditions, including Proteus syndrome, Sturge-Weber syndrome, and PIK3CA-related overgrowth spectrum, are caused by post-zygotic pathogenic variants, result in segmental mosaicism, and give rise to neural, cutaneous and/or lipomatous overgrowth. These variants occur in growth-promoting pathways leading to cellular proliferation and expansion of tissues that arise from the affected cellular lineage.
METHODS
We report on 80 serial patients evaluated for somatic overgrowth conditions in a diagnostic laboratory setting, including three prenatal patients. In total, 166 tissues from these 80 patients were subjected to targeted sequencing of an 8-gene panel capturing 10.2 kb of sequence containing known pathogenic variants associated with somatic overgrowth conditions. Deep next-generation sequencing was performed with the IonTorrent PGM platform at an average depth typically >5,000×.
RESULTS
Likely pathogenic or pathogenic variants were identified in 36 individuals and variants of unknown significance in four. The overall molecular diagnostic yield was 45% but was highly influenced by both submitted tissue type and phenotype. In the prenatal setting, two patients had pathogenic variants identified in cultured amniocytes but in a third patient, the pathogenic variant was only present in post-natal tissues. Finally, expanding the test to include full gene sequencing of PIK3CA in contrast to targeted sequencing identified likely pathogenic variants in 3 of 7 patients that tested negative on the original panel.
CONCLUSION
Next-generation sequencing has enabled sensitive detection of somatic pathogenic variants associated with overgrowth conditions. However, as the pathogenic variant allele frequency varies by tissue type within an individual, submission of affected tissue(s) greatly increases the chances of a molecular diagnosis.
Identifiants
pubmed: 30761771
doi: 10.1002/mgg3.536
pmc: PMC6418364
doi:
Substances chimiques
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
PIK3CA protein, human
EC 2.7.1.137
Banques de données
GENBANK
['NM_006218.2', 'NM_004958.3', 'NM_005027.2', 'NM_005163.2', 'NM_001626.3', 'NM_005465.4', 'NM_002072.4', 'NM_000076.2']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e536Informations de copyright
© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
Références
JCI Insight. 2016 Jun 16;1(9):
pubmed: 27631024
Am J Med Genet C Semin Med Genet. 2016 Dec;172(4):402-421
pubmed: 27860216
J Am Acad Dermatol. 1987 Apr;16(4):899-906
pubmed: 3033033
Clin Genet. 2017 Jan;91(1):79-85
pubmed: 27307077
Nat Rev Genet. 2013 May;14(5):307-20
pubmed: 23594909
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
N Engl J Med. 2011 Aug 18;365(7):611-9
pubmed: 21793738
Am J Med Genet A. 2015 Feb;167A(2):287-95
pubmed: 25557259
Mol Genet Genomic Med. 2019 Mar;7(3):e536
pubmed: 30761771
Am J Med Genet A. 2014 Oct;164A(10):2633-7
pubmed: 25044986
Nat Genet. 2012 Jun 24;44(8):934-40
pubmed: 22729224
Sci Signal. 2013 Apr 02;6(269):pl1
pubmed: 23550210
Mol Cancer. 2016 Oct 18;15(1):63
pubmed: 27756406
J Mol Diagn. 2017 Jul;19(4):487-497
pubmed: 28502730
N Engl J Med. 1991 Dec 12;325(24):1688-95
pubmed: 1944469
Cancer Discov. 2012 May;2(5):401-4
pubmed: 22588877
J Mol Diagn. 2017 Jul;19(4):613-624
pubmed: 28502725
Genet Med. 2017 Sep;19(9):989-997
pubmed: 28151489
J Pediatr. 2015 Apr;166(4):1048-54.e1-5
pubmed: 25681199