Periventricular Nodular Heterotopia 7 Via the NEDD4L Gene

NEDD4L-related periventricular nodular heterotopia 7 is a rare neurological disorder with onset at birth or during the prenatal period. The major symptoms include bilateral periventricular nodular heterotopia, severe neurodevelopmental delay, refractory seizures, and perisylvian polymicrogyria, cleft palate, and bilateral toe syndactyly. Minor features include variable dysmorphic facial features, hearing impairment, optic atrophy, contractures, and hypospadias (Stouffs et al. 2020. PubMed ID: 32117442; Broix et al. 2016. PubMed ID: 27694961). In the prenatal period, hypokinesia and flexion contractures can be seen (Elbracht et al. 2018. PubMed ID: 30393983).

As periventricular nodular heterotopia can be caused by defects in many genes with variable and overlapping presentations, it is difficult to diagnose by clinical manifestation and image studies only. An accurate molecular diagnosis is critical for treatment, prognosis, and prediction of recurrence risk as well as future family planning.

NEDD4L-related periventricular nodular heterotopia 7 is inherited in an autosomal dominant manner. The vast majority of pathogenic variants in NEDD4L are missense variants. Some variants are located in the HECT domain, and cause deregulation of signaling pathways, such as the AKT/mTOR pathway, whereas others are in the WW domain, which is probably related to the recognition of substrates for ligation (Broix et al. 2016. PubMed ID: 27694961; Stouffs et al. 2020. PubMed ID: 32117442). One large deletion has also been reported in the NEDD4L locus (Human Gene Mutation Database). De novo pathogenic variants are common and parental mosaicism has been reported (Broix et al. 2016. PubMed ID: 27694961). NEDD4L is relatively intolerant to loss of function variants (Genome Aggregation Database).

NEDD4L encodes E3 ubiquitin ligase (Yanpallewar et al. 2016. PubMed ID: 27604420). A mouse model showed that NEDD4L is homogenously expressed in the cortical plate, ventricular zone, and ganglionic eminences (Broix et al. 2016. PubMed ID: 27694961), and deletion of this gene causes perinatal lethality (Yanpallewar et al. 2016. PubMed ID: 27604420).

Analytical sensitivity of NEDD4L testing is high. However, periventricular nodular heterotopia caused by defects in NEDD4L is rare (Broix et al. 2016. PubMed ID: 27694961).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the NEDD4L gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).