Periventricular heterotopia in 6q terminal deletion syndrome: role of the C6orf70 gene

Abstract

Periventricular nodular heterotopia is caused by defective neuronal migration that results in heterotopic neuronal nodules lining the lateral ventricles. Mutations in filamin A (FLNA) or ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2) cause periventricular nodular heterotopia, but most patients with this malformation do not have a known aetiology. Using comparative genomic hybridization, we identified 12 patients with developmental brain abnormalities, variably combining periventricular nodular heterotopia, corpus callosum dysgenesis, colpocephaly, cerebellar hypoplasia and polymicrogyria, harbouring a common 1.2 Mb minimal critical deletion in 6q27. These anatomic features were mainly associated with epilepsy, ataxia and cognitive impairment. Using whole exome sequencing in 14 patients with isolated periventricular nodular heterotopia but no copy number variants, we identified one patient with periventricular nodular heterotopia, developmental delay and epilepsy and a de novo missense mutation in the chromosome 6 open reading frame 70 (C6orf70) gene, mapping in the minimal critical deleted region. Using immunohistochemistry and western blots, we demonstrated that in human cell lines, C6orf70 shows primarily a cytoplasmic vesicular puncta-like distribution and that the mutation affects its stability and subcellular distribution. We also performed in utero silencing of C6orf70 and of Phf10 and Dll1, the two additional genes mapping in the 6q27 minimal critical deleted region that are expressed in human and rodent brain. Silencing of C6orf70 in the developing rat neocortex produced periventricular nodular heterotopia that was rescued by concomitant expression of wild-type human C6orf70 protein. Silencing of the contiguous Phf10 or Dll1 genes only produced slightly delayed migration but not periventricular nodular heterotopia. The complex brain phenotype observed in the 6q terminal deletion syndrome likely results from the combined haploinsufficiency of contiguous genes mapping to a small 1.2 Mb region. Our data suggest that, of the genes within this minimal critical region, C6orf70 plays a major role in the control of neuronal migration and its haploinsufficiency or mutation causes periventricular nodular heterotopia.

Search for Rare Copy-Number Variants in Congenital Heart Defects Identifies Novel Candidate Genes and a Potential Role for FOXC1 in Patients With Coarctation of the Aorta

“…Haploinsufficiency of ERMARD causes periventricular nodular heterotopia. 47 Because periventricular nodular heterotopia has been related to cardiovascular defects, it is conceivable that duplication of ERMARD plays a role in CHD. 48 By combining genes present in de novo CNVs, in overlapping CNVs (between our patients or public databases), and from TFBS analyses (http://hgdownload.soe.ucsc.edu/ goldenPath/hg19/database/tfbsConsSites.txt.gz), we identified a set of 113 candidate genes for CHD (Table VI in the Data Supplement) and a short list of 10 top-candidate genes (Table 3).…”

Genetics and mechanisms leading to human cortical malformations

“…Moreover, a role of the heterotrimeric G-protein (Gαi2) was recently suggested in cortical development, and the encoding gene (GNAI2) was found mutated in a single PVH patient [196]. Another candidate gene playing a role in this cortical malformation is C6orf70 (ERMARD, for ER-membrane associated RNA degradation), found mutated in a patient with PVH [197].…”

“…Defects in progenitor cells, neuronal positioning and terminal translocation were identified by in utero electroporation. Furthermore, down-regulation of the α subunit, Gαi2, or C6orf70, affects neuron morphology and induces migration defects during corticogenesis in rodents [196,197].…”

Delineation of candidate genes responsible for structural brain abnormalities in patients with terminal deletions of chromosome 6q27

“…The subunits of the npBAF complex are essential for neural-progenitor proliferation, and mice with reduced dosage for the genes encoding these subunits have defects in neuraltube closure similar to those in human spina bifida. 29 A more recent study by Conti et al 30 showed that a 1.2 Mb SRO common to 12 patients in the 6q27 region contains plausible genes THBS2, PHF10, TCTE3, DLL1, WDR27, and C6orf70. Of the 12 patients reported in the study, 9 patients had PNH, in addition to other brain malformations.…”