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MINPP1 mutations have been robustly associated with pontocerebellar hypoplasia. Case report and multi‐patient studies provide converging evidence supporting an autosomal recessive disease mechanism with clear segregation of loss‑of‑function mutations. The detailed clinical reports identify multiple probands carrying biallelic MINPP1 variants, including the recurrent variant c.903G>A (p.Trp301Ter) (PMID:33257696) and additional variants detected in independent families (PMID:33168985).
Genetic evidence is reinforced by the identification of eight affected individuals from four unrelated families with pontocerebellar hypoplasia, supporting strong segregation with the phenotype. The pattern of inheritance is clearly autosomal recessive, as all reported cases require bi‐allelic disruption of MINPP1 to manifest the disease. Functional studies further corroborate these findings by demonstrating that loss‑of‑function mutations in MINPP1 lead to impaired neuronal differentiation and increased cell death, aligning with the clinical neurodegenerative phenotype observed in patients (PMID:33257696).
The variant c.903G>A (p.Trp301Ter) is notable for its early truncation effect and is observed in multiple studies. This variant, along with others described in the literature, underscores the critical role that MINPP1 plays in regulating inositol phosphate metabolism in neuronal development. The genetic data, therefore, meet the ClinGen criteria for a strong gene-disease association through the compilation of both case-level and segregation evidence.
Experimental evidence from patient-derived induced pluripotent stem cells and genome-edited models indicates that MINPP1 deficiency results in abnormal accumulation of highly phosphorylated inositols, particularly IP6. These functional assays demonstrate biochemical and cellular phenotypes consistent with the disease mechanism of pontocerebellar hypoplasia, thereby substantiating the pathogenicity of the identified variants. The concordance between genetic and functional data supports the hypothesis that disrupted inositol metabolism is a key driver of the neurodegenerative process.
Integrating the clinical, genetic, and experimental findings, the overall strength of the association between MINPP1 (HGNC:7102) and pontocerebellar hypoplasia (MONDO_0020135) is classified as Strong. This integrated evidence not only solidifies the diagnostic utility of MINPP1 variant screening but also provides a foundation for future therapeutic exploration and clinical publication.
Key take‑home: The strong association and underlying mechanistic insights make MINPP1 a critical diagnostic marker for pontocerebellar hypoplasia with significant implications for patient care.
Gene–Disease AssociationStrongEight probands from four unrelated families with robust segregation and concordant functional data support a strong gene-disease association (PMID:33168985, PMID:33257696). Genetic EvidenceStrongMultiple loss-of-function variants, including c.903G>A (p.Trp301Ter), identified across independent cohorts with autosomal recessive inheritance satisfy ClinGen criteria. Functional EvidenceModerateFunctional assays in patient-derived and genome-edited models demonstrate impaired neuronal differentiation and disrupted inositol phosphate metabolism consistent with the disease phenotype (PMID:33257696). |