Periventricular Nodular Heterotopia 6

A number sign (#) is used with this entry because of evidence that periventricular nodular heterotopia-6 (PVNH6) is caused by heterozygous mutation in the ERMARD gene (615532) on chromosome 6q27. One such family has been reported.

Clinical Features

Conti et al. (2013) reported a 7-year-old girl with delayed psychomotor development, delayed speech, strabismus, and onset of seizures with hypsarrhythmia at age 3 months. Brain MRI showed bilateral periventricular nodular heterotopia in the frontal horns.

Cytogenetics

By array CGH of 155 patients with brain malformations, Conti et al. (2013) identified 12 patients with heterozygous deletions of chromosome 6q27 involving the ERMARD gene. Eight of the deletions occurred de novo, and 2 were inherited from an affected parent. The size of the deletions varied, but all shared a common 1.2-Mb deleted region containing 4 known genes (DLL1, 606582; PHF10, 613069; TCTE3, 186977; and THBS2, 188061) and 2 predicted genes (ERMARD and WDR27). Developmental brain abnormalities were variable and included periventricular nodular heterotopia, hypoplastic corpus callosum, colpocephaly, polymicrogyria, under-rotated or hypoplastic hippocampi, and cerebellar hypoplasia. Associated clinical manifestations included epilepsy (9/12), developmental delay (12/12), ataxic or clumsy gait (6/12), joint laxity, and facial dysmorphism (10/12). Silencing of the Ermard gene in the developing rat neocortex produced periventricular nodular heterotopia, whereas silencing of the contiguous Phf10 or Dll1 genes only produced slightly delayed migration, but not periventricular nodular heterotopia. Conti et al. (2013) suggested that the complex brain phenotype and additional clinical features observed in these patients likely resulted from the combined haploinsufficiency of contiguous genes.

Molecular Genetics

In a girl with periventricular nodular heterotopia-6, Conti et al. (2013) identified a de novo heterozygous missense mutation in the ERMARD gene (I250N; 615532.0001). The mutation was found by whole-exome sequencing of 14 unrelated patients with isolated bilateral PVNH who did not carry copy number variations. Expression of the mutant protein in HEK293 cells resulted in a predominantly dispersed pattern of staining, suggesting that the mutation alters the subcellular localization. Western blot analysis showed markedly reduced mutant protein levels compared to wildtype (58% reduction for the longer isoform and 12% reduction for the shorter isoform).

Animal Model

Using in utero electroporation, Conti et al. (2013) demonstrated that knockdown of C6orf70 in developing rat brain caused a massive neuronal migration defect, significant arrest of cells within the ventricular zone, and development of heterotopic nodules along the walls of the lateral ventricles. Coexpression of human C6ORF70, which was resistant to the C6orf70 knockdown construct, prevented migration arrest in the ventricular zone.