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The gene MPP3 (HGNC:7221) is recurrently interrogated in studies of X-linked intellectual disability (MONDO:0100284). Although MPP3 is included in large XLID screening panels, the evidence directly linking it to the disorder remains sparse. This summary synthesizes the available genetic and functional data, which overall support a limited gene-disease association.
Assessment of clinical validity places the MPP3–XLID association in the Limited category. While several multi‐patient studies have examined panels of XLID genes (PMID:25649377), the number of unrelated probands with definitive pathogenic variants in MPP3 is low, and clear segregation data are lacking (PMID:32021600).
From a genetic evidence standpoint, targeted next-generation sequencing across XLID cohorts has identified pathogenic variants in several genes, yet no conclusive loss-of-function or missense variant meeting stringent pathogenicity criteria has been reported for MPP3. The gene is therefore considered a candidate based on its inclusion in these panels, but without strong mutational evidence.
The disorder under review follows an X-linked inheritance pattern, with affected hemizygous males presenting with intellectual disability and, in some cases, additional features such as pectus excavatum. The limited segregation data further underscore the need for caution in interpreting any rare variants in MPP3 during diagnostic evaluations.
Regarding functional evidence, no direct experimental studies (e.g., in vitro assays, animal models, or rescue experiments) have been conducted to assess the impact of MPP3 perturbation on neurodevelopment. In contrast, other genes in similar neural pathways have functional support, which, while indirectly informative, does not substitute for direct evidence.
In summary, while MPP3 is routinely included in XLID gene panels, the current genetic and experimental data provide only limited support for its role in X-linked intellectual disability. Clinicians and researchers should therefore interpret variants in MPP3 with caution, integrating them with additional clinical and laboratory findings for diagnostic decision-making.
Gene–Disease AssociationLimitedWhile MPP3 is frequently included in XLID screening panels (PMID:25649377), very few, if any, independent pathogenic variants or robust segregation data have been directly attributed to MPP3 (PMID:32021600). Genetic EvidenceLimitedDespite its inclusion in multi‐gene XLID panels, no definitive, pathogenic variant meeting strict genetic criteria has been reported for MPP3, limiting the genetic evidence for this association. Functional EvidenceLimitedNo direct functional assays, animal models, or rescue experiments have been performed specifically evaluating the impact of MPP3 alterations on neural development or cognitive function in the context of XLID. |