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Birth Defects Res. 2018 Apr 17;110(7):587-597. doi: 10.1002/bdr2.1200. Epub 2018 Feb 1.

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

Author information

1
Institute of Human Genetics, University of Bonn School of Medicine and University Hospital of Bonn, Bonn, Germany.
2
Department of Genomics-Life & Brain Center, Bonn, Germany.
3
Department of Neuropathology, University of Bonn, Bonn, Germany.
4
Department of Developmental Genetics, Max-Planck-Institute for Molecular Genetics, Berlin, Germany.
5
Department of Pediatrics, University of Bonn, Bonn, Germany.
6
Department of Neurology, University Clinic Bonn, Bonn, Germany.
7
Department of Obstetrics and Prenatal Medicine, University of Bonn, Bonn, Germany.
8
Cologne Center for Genomics, University of Cologne, Cologne, Germany.
9
Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
10
Institute of Anatomy, University of Bonn, Bonn, Germany.
11
Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
12
Department of Neonatology and Pediatric Intensive Care, Children's Hospital, University of Bonn, Bonn, Germany.

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; VATER/VACTERL association; brain malformations; in situ hybridization; whole-exome sequencing

PMID:
29388391
DOI:
10.1002/bdr2.1200
[Indexed for MEDLINE]

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