Universität zu Köln

Weitensteiner, Valerie, Zhang, Rong, Bungenberg, Julia, Marks, Matthias, Gehlen, Jan, Ralser, Damian J., Hilger, Alina C., Sharma, Amit ORCID: 0000-0002-2216-5389, Schumacher, Johannes, Gembruch, Ulrich ORCID: 0000-0001-8284-4669, Merz, Waltraut M., Becker, Albert, Altmueller, Janine, Thiele, Holger, Herrmann, Bernhard G., Odermatt, Benjamin, Ludwig, Michael and Reutter, Heiko (2018). Exome sequencing in syndromic brain malformations identifies novel mutations in ACTB, and SLC9A6, and suggests BAZ1A as a new candidate gene. Birth Defects Res., 110 (7). S. 587 - 598. HOBOKEN: WILEY. ISSN 2472-1727

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Abstract

BackgroundSyndromic 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. MethodsWES analysis was applied in eight case-parent trios, six aborted fetuses, and two children. ResultsWES 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. ConclusionIn 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Weitensteiner, Valerie UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Rong UNSPECIFIED UNSPECIFIED UNSPECIFIED Bungenberg, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Marks, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Gehlen, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Ralser, Damian J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hilger, Alina C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sharma, Amit UNSPECIFIED orcid.org/0000-0002-2216-5389 UNSPECIFIED Schumacher, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Gembruch, Ulrich UNSPECIFIED orcid.org/0000-0001-8284-4669 UNSPECIFIED Merz, Waltraut M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Albert UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Herrmann, Bernhard G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Odermatt, Benjamin UNSPECIFIED UNSPECIFIED UNSPECIFIED Ludwig, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Reutter, Heiko UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-189236
DOI:	10.1002/bdr2.1200
Journal or Publication Title:	Birth Defects Res.
Volume:	110
Number:	7
Page Range:	S. 587 - 598
Date:	2018
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	2472-1727
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CENTRAL-NERVOUS-SYSTEM; CHROMOSOMAL MICROARRAY; MENTAL-RETARDATION; COMPLEX; BINDING; ACF1; DNA; BROMODOMAIN; ENRICHR; PACKAGE Multiple languages Developmental Biology; Toxicology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/18923