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The current evidence supporting the association between MAPK8IP1 and Potocki‑Shaffer syndrome (PSS) is limited. In studies of contiguous gene deletion and duplication syndromes, MAPK8IP1 is one of several genes encompassed by chromosomal aberrations that result in PSS. Fewer than 40 individuals with PSS have been reported (PMID:23239541), and genetic data are derived from case studies where a 137‑kb deletion including MAPK8IP1 was identified, and a duplication event was observed in a family with additional affected members (PMID:33836758).
The genetic evidence indicates that the implicated chromosomal events result in haploinsufficiency and/or altered gene dosage; however, the contribution of MAPK8IP1 cannot be isolated from adjacent candidate genes in the critical interval. Limited segregation data exist, with at least one additional affected relative in one of the duplication cases. Furthermore, no specific coding variant meeting the HGVS criteria (i.e. starting with “c.” and including a protein change in the correct three‑letter amino acid code format) has been reported for MAPK8IP1 in the context of PSS.
In terms of inheritance, PSS typically occurs as a de novo event with a presumed autosomal dominant mechanism, consistent with findings from contiguous gene deletion syndromes. The reported case studies and family analyses provide only modest segregation support for MAPK8IP1’s contribution to the disease phenotype.
The available functional evidence for MAPK8IP1 stems mostly from studies in neurological and cellular models unrelated to Potocki‑Shaffer syndrome; while these studies delineate the role of MAPK8IP1 in modulating kinase signaling pathways, no direct experimental data link altered MAPK8IP1 dosage to the PSS clinical features of developmental delay and hypotonia. Therefore, functional data do not conclusively reinforce a pathogenic role in PSS beyond the genomic correlation observed.
Overall, while both deletion and duplication studies implicate MAPK8IP1 as being located in the critical interval for PSS and associate it with key neurodevelopmental signs, the evidence remains limited by its non‐isolated nature and modest segregation data. Additional targeted studies are needed to delineate the gene’s specific contribution.
Key take‑home: Despite the association of MAPK8IP1 with PSS via chromosomal rearrangements, its diagnostic utility is currently limited and should be interpreted in the context of the entire genomic region.
Gene–Disease AssociationLimitedFewer than 40 individuals reported; association inferred from contiguous gene deletion/duplication studies that include MAPK8IP1 along with several candidate genes (PMID:23239541, PMID:33836758). Genetic EvidenceLimitedEvidence is based on two case studies showing deletion and duplication events incorporating MAPK8IP1 with minimal segregation data. Functional EvidenceLimitedAlthough MAPK8IP1 has been functionally characterized in neuronal models for other disorders, direct experimental evidence linking its haploinsufficiency or dosage alteration to Potocki‑Shaffer syndrome is lacking. |