title: Diagnostic use of computational retrotransposon detection: Successful definition of pathogenetic mechanism in a ciliopathy phenotype.
abstract: Among more than 5,000 human monogenic disorders with known causative genes, transposable element insertion of a Long Interspersed Nuclear Element 1 (LINE1, L1) is known as the mechanistic basis in only 13 genetic conditions. Meckel-Gruber syndrome is a rare ciliopathy characterized by occipital encephalocele and cystic kidney disease. Here, we document a boy with occipital encephalocele, post-axial polydactyly, and multicystic renal disease. A medical exome analysis detected a heterozygous frameshift mutation, c.4582_4583delCG p.(Arg1528Serfs*17) in CC2D2A in the maternally derived allele. The further use of a dedicated bioinformatics algorithm for detecting retrotransposon insertions led to the detection of an L1 insertion affecting exon 7 in the paternally derived allele. The complete sequencing and sequence homology analysis of the inserted L1 element showed that the L1 element was classified as L1HS (L1 human specific) and that the element had intact open reading frames in the two L1-encoded proteins. This observation ranks Meckel-Gruber syndrome as only the 14th disorder to be caused by an L1 insertion among more than 5,000 known human genetic disorders. Although a transposable element detection algorithm is not included in the current best-practice next-generation sequencing analysis, the present observation illustrates the utility of such an algorithm, which would require modest computational time and resources. Whether the seemingly infrequent recognition of L1 insertion in the pathogenesis of human genetic diseases might simply reflect a lack of appropriate detection methods remains to be seen.
authors.affiliation: Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.|Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Toshiki
authors.identifier: http://orcid.org/0000-0002-7311-4135
authors.initials: T
authors.lastname: Takenouchi
authors.affiliation: Department of Medical Genetics, Tokyo Metropolitan Children's Medical Center, Fuchu, Tokyo, Japan.
authors.forename: Tomu
authors.initials: T
authors.lastname: Kuchikata
authors.affiliation: Department of Medical Genetics, Tokyo Metropolitan Children's Medical Center, Fuchu, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoshihashi
authors.affiliation: Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Mineko
authors.initials: M
authors.lastname: Fujiwara
authors.affiliation: Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Uehara
authors.affiliation: Department of Neurology, Tokyo Metropolitan Children's Medical Center, Fuchu, Tokyo, Japan.
authors.forename: Sahoko
authors.initials: S
authors.lastname: Miyama
authors.affiliation: Division of Human Genetics, National Institute of Genetics, Mishima, Japan.|Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kosaki
mesh_terms: D000483:Alleles; D002675:Child, Preschool; D002925:Ciliary Motility Disorders / Q000235:genetics* / Q000503:physiopathology; D000072661:Ciliopathies / Q000235:genetics* / Q000503:physiopathology; D019295:Computational Biology; D003598:Cytoskeletal Proteins; D004677:Encephalocele / Q000235:genetics* / Q000503:physiopathology; D059472:Exome / Q000235:genetics; D016368:Frameshift Mutation; D006579:Heterozygote; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics / Q000503:physiopathology; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008297:Male; D007690:Polycystic Kidney Diseases / Q000235:genetics* / Q000503:physiopathology; D011506:Proteins / Q000235:genetics*; D012174:Retinitis Pigmentosa
chemical_list: C528701:CC2D2A protein, human; D003598:Cytoskeletal Proteins; D011506:Proteins
keywords: CC2D2A; L1 element; Meckel-Gruber syndrome; ciliopathy; exome; transposable element