Oegema et al. (2017) reported 3 adult sibs with a similar neurodevelopmental disorder. All had global developmental delay with severely impaired intellectual dev...
Oegema et al. (2017) reported 3 adult sibs with a similar neurodevelopmental disorder. All had global developmental delay with severely impaired intellectual development, no language, and inability to walk due to spastic paraplegia. Additional neurologic abnormalities included seizures and optic atrophy. The patients also had short stature, irregularly implanted and overlapping toes, borderline microcephaly (-2 to -3 SD), and dysmorphic facial features, including hypertelorism and a prominent glabella. Brain imaging showed cerebellar hypoplasia, reduced volume of the pons and brainstem, and periventricular nodular heterotopia.
The transmission pattern of NEDCHS in the family reported by Oegema et al. (2017) was consistent with autosomal recessive inheritance.
▼ Molecular Genetics
In 3 adult sibs with NEDCHS, Oegema et al. (2017) identified compound heterozygous mutations in the INTS8 gene (611351.0001 and 611351.0002). The mutations, which were found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was found in the ExAC or gnomAD databases. Analysis of patient cells, reported transcript structures, and expression studies in HEK293 or HeLa cells were consistent with a loss-of-function effect and suggested that the mutations impaired the ability of INTS8 to associate with other proteins in the Integrator complex. Global transcriptome analysis of patient cells showed changes in gene regulation and altered splicing patterns. Sequencing of the INTS8 gene in 25 additional patients with periventricular nodular heterotopia and 266 other patients with brain malformations did not identify any patients with biallelic mutations, suggesting that it is a rare cause of the phenotype.