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Tytuł:
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Imprinted genes in clinical exome sequencing: Review of 538 cases and exploration of mouse-human conservation in the identification of novel human disease loci.
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Autorzy:
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Bhoj EJ; Division of Human Genetics, Children's Hospital of Philadelphia, The University of Pennsylvania School of Medicine, 3401 Civic Center Boulevard, Philadelphia, PA, 19104, USA. Electronic address: .
Rajabi F; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 4, Boston, MA, 02115, USA. Electronic address: .
Baker SW; Division of Genomics Diagnosis, Children's Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA, 19104, USA. Electronic address: .
Santani A; Division of Genomics Diagnosis, Children's Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA, 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, The University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Electronic address: .
Tan WH; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 4, Boston, MA, 02115, USA. Electronic address: .
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Źródło:
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European journal of medical genetics [Eur J Med Genet] 2020 Jun; Vol. 63 (6), pp. 103903. Date of Electronic Publication: 2020 Mar 10.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Original Publication: Amsterdam : Elsevier, c2005-
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MeSH Terms:
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Conserved Sequence*
Exome*
Genetic Loci*
Genomic Imprinting*
Genetic Diseases, Inborn/*genetics
Animals ; Databases, Genetic ; Humans ; Mice ; Mutation ; Whole Genome Sequencing/methods
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Contributed Indexing:
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Keywords: Animal models; Exome sequencing; Genetic epigenesis; Genomic imprinting; Medical genetics; Molecular diagnostics; Uniparental disomy
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Entry Date(s):
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Date Created: 20200315 Date Completed: 20201229 Latest Revision: 20201229
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Update Code:
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20240105
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DOI:
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10.1016/j.ejmg.2020.103903
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PMID:
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32169557
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Human imprinting disorders cause a range of dysmorphic and neurocognitive phenotypes, and they may elude traditional molecular diagnosis such exome sequencing. The discovery of novel disorders related to imprinted genes has lagged behind traditional Mendelian disorders because current diagnostic technology, especially unbiased testing, has limited utility in their discovery. To identify novel imprinting disorders, we reviewed data for every human gene hypothesized to be imprinted, identified each mouse ortholog, determined its imprinting status in the mouse, and analyzed its function in humans and mice. We identified 17 human genes that are imprinted in both humans and mice, and have functional data in mice or humans to suggest that dysregulated expression would lead to an abnormal phenotype in humans. These 17 genes, along with known imprinted genes, were preferentially flagged 538 clinical exome sequencing tests. The identified genes were: DIRAS3 [1p31.3], TP73 [1p36.32], SLC22A3 [6q25.3], GRB10 [7p12.1], DDC [7p12.2], MAGI2 [7q21.11], PEG10 [7q21.3], PPP1R9A [7q21.3], CALCR [7q21.3], DLGAP2 [8p23.3], GLIS3 [9p24.2], INPP5F [10q26.11], ANO1 [11q13.3], SLC38A4 [12q13.11], GATM [15q21.1], PEG3 [19q13.43], and NLRP2 [19q13.42]. In the 538 clinical cases, eight cases (1.7%) reported variants in a causative known imprinted gene. There were 367/758 variants (48.4%) in imprinted genes that were not known to cause disease, but none of those variants met the criteria for clinical reporting. Imprinted disorders play a significant role in human disease, and additional human imprinted disorders remain to be discovered. Therefore, evolutionary conservation is a potential tool to identify novel genes involved in human imprinting disorders and to identify them in clinical testing.
Competing Interests: Declaration of competing interest Drs. Bhoj, Rajabi, Baker, Santani and Tan have no conflicts of interest to report.
(Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
