Format

Send to

Choose Destination
Eur J Med Genet. 2018 Dec;61(12):783-789. doi: 10.1016/j.ejmg.2018.10.018. Epub 2018 Oct 31.

Mutated zinc finger protein of the cerebellum 1 leads to microcephaly, cortical malformation, callosal agenesis, cerebellar dysplasia, tethered cord and scoliosis.

Author information

1
Neurogenetics Research Group, Research Cluster Reproduction, Genetics and Regenerative Medicine, Vrije Universiteit Brussel, Brussels, Belgium; Center for Medical Genetics, UZ Brussel, Brussels, Belgium; Department Clinical Genetics, Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, the Netherlands.
2
Department Clinical Genetics, Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, the Netherlands.
3
Department Pediatrics, Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, the Netherlands.
4
Department Child Neurology, Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, the Netherlands; NeMo Expertise Center, Rotterdam, the Netherlands.
5
Department of Radiology, Wilhelmina Children's Hospital, UMC, Utrecht, the Netherlands.
6
Department Radiology, Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, the Netherlands.
7
Neurogenetics Research Group, Research Cluster Reproduction, Genetics and Regenerative Medicine, Vrije Universiteit Brussel, Brussels, Belgium; Pediatric Neurology Unit, Department of Pediatrics, UZ Brussel, Brussels, Belgium.
8
Department Clinical Genetics, Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, the Netherlands. Electronic address: g.mancini@erasmusmc.nl.

Abstract

Heterozygous gain of function mutations in the ZIC1 gene have been described with syndromic craniosynostosis, variable cerebral or cerebellar abnormalities and mild to moderate developmental delay. Deletion of chromosome 3q25.1 including both adjacent ZIC1 and ZIC4 genes have been described as a cause of variable cerebellar abnormalities including Dandy-Walker malformation. We report two siblings presenting with neonatal microcephaly, agenesis of the corpus callosum, brachycephaly with reduced volume of the posterior fossa, cerebellar and pons hypoplasia, scoliosis and tethered cord (closed neural tube defect). One of the siblings had apparent partial rhombencephalosynapsis. Trio analysis of exome sequencing data revealed a novel heterozygous frameshift mutation in ZIC1 at the end of exon 3 in one sibling and was confirmed by Sanger sequencing in both children. The mutation was not detected in DNA of both parents, which suggests parental gonadal mosaicism. We show that expression of the mutant allele leads to synthesis of a stable abnormal transcript in patient cells, without evidence for nonsense-mediated decay. Craniosynostosis was not present at birth, which explains why ZIC1 mutations were not initially considered. This severe brain malformation indicates that premature closure of sutures can be independent of the abnormal brain development in subjects with pathogenic variants in ZIC1.

KEYWORDS:

Cerebellum; Corpus callosum; Microcephaly; Rhombencephalosynapsis; Tethered cord; ZIC1

PMID:
30391508
DOI:
10.1016/j.ejmg.2018.10.018
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center