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  Exome sequencing in syndromic brain malformations identifies novel mutations in ACTB, and SLC9A6, and suggests BAZ1A as a new candidate gene

Weitensteiner, V., Zhang, R., Bungenberg, J., Marks, M., Gehlen, J., Ralser, D. J., et al. (2018). Exome sequencing in syndromic brain malformations identifies novel mutations in ACTB, and SLC9A6, and suggests BAZ1A as a new candidate gene. Birth Defects Research, 110(7), 587-597. doi:10.1002/bdr2.1200.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-854C-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-854D-1
Genre: Journal Article

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 Creators:
Weitensteiner, Valerie , Author
Zhang, Rong , Author
Bungenberg, Julia , Author
Marks, Matthias1, Author              
Gehlen, Jan, Author
Ralser, Damian J. , Author
Hilger, Alina C. , Author
Sharma, Amit , Author
Schumacher , Johannes , Author
Gembruch, Ulrich , Author
Merz, Waltraut M., Author
Becker, Albert , Author
Altmüller, Janine , Author
Thiele, Holger , Author
Herrmann, Bernhard G.1, Author              
Odermatt , Benjamin , Author
Ludwig, Michael, Author
Reutter, Heiko , Author
Affiliations:
1Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433548              

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Free keywords: BAZ1A; VATER/VACTERL association; brain malformations; in situ hybridization; whole-exome sequencing
 Abstract: BACKGROUND: Syndromic brain malformations comprise a large group of anomalies with a birth prevalence of about 1 in 1,000 live births. Their etiological factors remain largely unknown. To identify causative mutations, we used whole-exome sequencing (WES) in aborted fetuses and children with syndromic brain malformations in which chromosomal microarray analysis was previously unremarkable. METHODS: WES analysis was applied in eight case-parent trios, six aborted fetuses, and two children. RESULTS: WES identified a novel de novo mutation (p.Gly268Arg) in ACTB (Baraitser-Winter syndrome-1), a homozygous stop mutation (p.R2442*) in ASPM (primary microcephaly type 5), and a novel hemizygous X-chromosomal mutation (p.I250V) in SLC9A6 (X-linked syndromic mentaly retardation, Christianson type). Furthermore, WES identified a de novo mutation (p.Arg1093Gln) in BAZ1A. This mutation was previously reported in only one allele in 121.362 alleles tested (dbSNP build 147). BAZ1A has been associated with neurodevelopmental impairment and dysregulation of several pathways including vitamin D metabolism. Here, serum vitamin-D (25-(OH)D) levels were insufficient and gene expression comparison between the child and her parents identified 27 differentially expressed genes. Of note, 10 out of these 27 genes are associated to cytoskeleton, integrin and synaptic related pathways, pinpointing to the relevance of BAZ1A in neural development. In situ hybridization in mouse embryos between E10.5 and E13.5 detected Baz1a expression in the central and peripheral nervous system. CONCLUSION: In syndromic brain malformations, WES is likely to identify causative mutations when chromosomal microarray analysis is unremarkable. Our findings suggest BAZ1A as a possible new candidate gene.

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Language(s): eng - English
 Dates: 2018-02-012018-04-17
 Publication Status: Published in print
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 Identifiers: DOI: 10.1002/bdr2.1200
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Title: Birth Defects Research
Source Genre: Journal
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Publ. Info: John Wiley & Sons, Inc.
Pages: 11 Volume / Issue: 110 (7) Sequence Number: - Start / End Page: 587 - 597 Identifier: -