Hereditary neuropathy or pain disorder

Gene: MAPK8IP3

I don't know

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. This decision was made because the phenotype associated with MAPK8IP3 variants is broader than this panel (Hereditary neuropathy or pain disorder, R78) and is covered by the Paediatric disorders (R27) and Intellectual disability (R29) panels, where MAPK8IP3 already has a green rating.

Created: 24 Feb 2025, 4:26 p.m. | Last Modified: 25 Feb 2025, 10:10 a.m.

Panel Version: 6.148

I don't know

Comment on list classification: Promoting to amber and tagging for promotion to green, but GLH expert review is needed to decide whether there is clear enough mode of inheritance data and a strong enough association with neuropathy to report diagnostically particularly for people with isolated neuropathy presentations who are more likely to be tested via this route.

Created: 14 Nov 2024, 3:41 p.m. | Last Modified: 14 Nov 2024, 3:41 p.m.

Panel Version: 6.137

Awaiting clinical feedback before deciding on rating.

Created: 27 Oct 2024, 12:24 a.m. | Last Modified: 27 Oct 2024, 12:24 a.m.

Panel Version: 5.104

Associated with Neurodevelopmental disorder with or without variable brain abnormalities, OMIM:618443 (AD) and MAPK8IP3-related Intellectual Disability with Variable Brain Anomalies (strong) on the Developmental disorders panel in Gene2Phenotype.


1 individual with compound het variants:

PMID: 37462082 - Kárteszi et al 2023 - report on an individual with severe congenital muscle hypotonia and compound heterozygous variants in MAPK8IP3 identified by WES. The diagnosis was lower motor neuron disease. The variants were a splice donor variant c.1667 + 2 T > C (ACMG likely pathogenic) and a missense variant c.3709G > A p.(Asp1237Asn) (ACMG VUS) which were maternally and paternally inherited, respectively. These variants are absent in the gnomAD reference population. JIP3 protein (encoded by MAPK8IP3) expression measured by Western blot was decreased in the muscle by 65.5% compared to healthy age-matched controls

4 familes with heterozygous variants. Two individuals from 1 family displayed sensory impairment below the knees:

PMID: 30945334 - Iwasawa et al 2019 - 5 individuals from 4 unrelated families with recurrent de novo variants c.1732C>T (p.Arg578Cys) and c.3436C>T (p.Arg1146Cys) in MAPK8IP3. The core phenotype includes spastic diplegia, intellectual disability, cerebral atrophy, and corpus callosum hypoplasia. Sensory impairment below the knees was observed in individuals 1 and 2 (both from family 1). Loss of myelinated fibers was seen on sural nerve biopsy seen in 1 of the sibs.

Additional cases with intellectual disability and heterozygous variants:
PMID: 30612693 - Platzer et al 2019 - identified de novo variants in MAPK8IP3 in 13 unrelated individuals presenting with an overlapping phenotype of mild to severe intellectual disability. Two individuals presented with signs of ataxia, and one presented with an unstable gait. In addition, two individuals had cortical visual impairment, and three individuals had scoliosis. Neuropathy is not described.

Created: 27 Oct 2024, 12:14 a.m. | Last Modified: 27 Oct 2024, 12:14 a.m.

Panel Version: 5.104

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Neurodevelopmental disorder with or without variable brain abnormalities, OMIM:618443; neurodevelopmental disorder with or without variable brain abnormalities, NEDBA, MONDO:0032755

Publications

• 37462082
• 30945334
• 30612693

Green List (high evidence)

Sources: Expert list

Created: 19 Oct 2024, 10:50 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
developmental delay; motor axonal neuropathy

Publications

• 37462082: 30945334