Neurodevelopmental Disorder with or without Variable Brain Abnormalities via the MAPK8IP3 Gene

MAPK8IP3-related neurodevelopmental disorder with or without variable brain abnormalities is a rare neurological disorder with onset in childhood. The major symptoms include spastic diplegia, intellectual disability, developmental delay, impaired language comprehension and skill with variable severity, gait instability, cerebral atrophy and corpus callosum hypoplasia (Iwasawa et al. 2019. PubMed ID: 30945334). Other features include short stature, obesity, facial dysmorphism, autistic behavior, hypotonia, scoliosis, cortical visual impairment, epilepsy, and behavioral abnormalities. MRI image analysis shows corpus callosum hypoplasia, cerebral or cerebellar atrophy, perisylvian polymicrogyria, and delayed myelination. EEG also presents abnormalities. Phenotype of patients is variable (Iwasawa et al. 2019. PubMed ID: 30945334; Platzer et al. 2019. PubMed ID: 30612693).  

As neurodevelopmental disorders 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.

MAPK8IP3-related neurodevelopmental disorder with or without variable brain abnormalities is inherited in an autosomal dominant manner. Pathogenic variants in MAPK8IP3 include missense, nonsense, and splicing variants (Human Gene Mutation Database, Platzer et al. 2019. PubMed ID: 30612693). Large deletions/duplications have not been reported in the MAPK8IP3 locus (HGMD). De novo variants in this gene have been reported to be pathogenic (Iwasawa et al. 2019. PubMed ID: 30945334; Platzer et al. 2019. PubMed ID: 30612693).

MAPK8IP3 encodes mitogen-activated protein kinase 8-interacting protein 3, which is a member of the kinesin superfamily of proteins, a scaffold protein for mitogen-activated protein kinase (MAPK), and an adaptor protein for the kinesin-1 complex. This protein plays an essential role in intracellular transport such as axonal transport in neurons. This protein was also known as c-Junamino-terminal kinase (JNK)-interacting protein 3 (JIP3). It is highly expressed in the brain and at lower levels in the heart and other tissues. It presents in the cytoplasm and is accumulated in the growth cones of developing neurites of neurons (Kelkar et al. 2000. PubMed ID: 10629060). A zebrafish embryo model with pathogenic variants in MAPK8IP3 showed axon varicosities of the posterior lateral line nerve, suggesting an adverse effect on the developing axons (Iwasawa et al. 2019. PubMed ID: 30945334). Of six variants investigated using Caenorhabditis elegans models, two led to a significantly elevated density of axonal lysosomes, and five were associated with adverse locomotion (Platzer et al. 2019. PubMed ID: 30612693). In cell mod­els, MAPK8IP3 protein was identified as a regulator of axonal lysosome abundance (Gowrishankar et al. 2021. PubMed ID: 33788575) or a regulator of multiple components of the axonal cytoskeleton (Rafiq et al. 2022. PubMed ID: 35013510). MAPK8IP3 is intolerant to loss-of-function variants (Genome Aggregation Database). MAPK8IP3 has been cited as a non-essential gene for growth of human tissue culture cells (Online Gene Essentiality). 

Pathogenic variants in MAPK8IP3 are considered a very rare cause of neurodevelopment disorders. To date, MAPK8IP3-related neurodevelopmental disorder with or without variable brain abnormalities has been reported in 18 patients (Iwasawa et al. 2019. PubMed ID: 30945334; Platzer et al. 2019. PubMed ID: 30612693). 

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 MAPK8IP3 gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to 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).