Diagnostic use of computational retrotransposon detection: Successful definition of pathogenetic mechanism in a ciliopathy phenotype
| Autor: | Tomu Kuchikata, Toshiki Takenouchi, Sahoko Miyama, Mineko Fujiwara, Kenjiro Kosaki, Shiro Yamada, Tomoko Uehara, Hiroshi Yoshihashi |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Heterozygote Biology CC2D2A Frameshift mutation 03 medical and health sciences Cystic kidney disease Genetics medicine Humans Exome Allele Frameshift Mutation Genetics (clinical) Alleles Encephalocele Polycystic Kidney Diseases Polydactyly Computational Biology Proteins Kidney Diseases Cystic medicine.disease Ciliopathies Long interspersed nuclear element Ciliopathy Cytoskeletal Proteins 030104 developmental biology Long Interspersed Nucleotide Elements Child Preschool Retinitis Pigmentosa Ciliary Motility Disorders |
| Zdroj: | American journal of medical genetics. Part A. 173(5) |
| ISSN: | 1552-4833 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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