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

Item Type:	Article
Title:	Exome sequencing in syndromic brain malformations identifies novel mutations in ACTB, and SLC9A6, and suggests BAZ1A as a new candidate gene
Creators Name:	Weitensteiner, V. and Zhang, R. and Bungenberg, J. and Marks, M. and Gehlen, J. and Ralser, D.J. and Hilger, A.C. and Sharma, A. and Schumacher, J. and Gembruch, U. and Merz, W.M. and Becker, A. and Altmüller, J. and Thiele, H. and Herrmann, B.G. and Odermatt, B. and Ludwig, M. and Reutter, H.
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.
Keywords:	BAZ1A, Brain Malformations, In Situ Hybridization, VATER/VACTERL Association, Whole-Exome Sequencing, Animals
Source:	Birth Defects Research
ISSN:	2472-1727
Publisher:	Wiley
Volume:	110
Number:	7
Page Range:	587-597
Date:	17 April 2018
Official Publication:	https://doi.org/10.1002/bdr2.1200
PubMed:	View item in PubMed

Repository Staff Only: item control page