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The association between PRUNE1 (HGNC:13420) and neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (MONDO_0060490) is supported by multiple independent studies demonstrating robust genetic evidence. Several case reports and series have identified biallelic pathogenic variants in PRUNE1 across unrelated families, with a cumulative total of 47 affected individuals reported (PMID:35194938). Segregation analyses in consanguineous and multi‐ethnic cohorts have confirmed co‑segregation of the variants with the disorder, underscoring the strong inheritance pattern of autosomal recessive transmission. In these studies, affected relatives in several families consistently demonstrated the presence of mutant alleles, further strengthening the genetic association (PMID:35379233). The evidence also highlights that a variety of mutation types—including missense, splice‐site, start loss, and even a synonymous variant impacting splicing—are causative. This heterogeneity in the variant spectrum provides additional support for the gene‑disease relationship.
Genetic evidence has been further bolstered by the identification of a representative variant, c.933G>A (p.Thr311=), which was shown to induce exon 7 skipping that leads to partial deletion of the critical DHHA2 domain. This synonymous variant, although not altering the encoded amino acid, results in aberrant splicing that disrupts the protein’s functional integrity (PMID:35194938). Other studies have reported mutations affecting the canonical splice sites and coding regions, culminating in loss‐of‑function effects via different mechanisms. The overall genetic evidence is drawn from distinct populations, with multiple independent findings across geographically diverse families. The cumulative data satisfy ClinGen criteria for a strong gene‑disease association by combining multiple probands, robust segregation data, and concordant variant effects across studies. The broad mutation spectrum reaffirms the importance of careful variant interpretation in clinical diagnostics.
Functional studies have played a key role in establishing the pathogenicity of PRUNE1 variants. Experiments using patient-derived fibroblasts and model systems have demonstrated that the c.933G>A variant causes in-frame exon skipping, leading to a truncated form of the protein that lacks vital components of the DHHA2 domain. Additionally, in vitro assays confirm that altered splicing is accompanied by reduced exopolyphosphatase activity essential for normal brain development. Animal and cell model experiments further corroborate that loss-of-function alleles in PRUNE1 disrupt key cellular processes such as cell migration and proliferation (PMID:28211990). Collectively, these functional data, although sometimes limited by model-specific variables, are consistent and reinforce the deleterious effect of the variants. They provide a mechanistic link between the observed molecular defects and the neurodevelopmental phenotype.
While the majority of evidence supports a strong association, some studies have noted variability in the phenotypic spectrum, including atypical presentations that complicate the diagnostic picture. In one report, patients exhibited features such as spastic diplegia in the absence of classical brain malformations, highlighting the phenotypic heterogeneity inherent to PRUNE1‑related disorders (PMID:35194938). Nonetheless, the core features of microcephaly, hypotonia, and variable brain anomalies recur across independent studies. There have been no robust studies to date that refute the gene‑disease association, although the variable expressivity calls for comprehensive clinical evaluation in suspected cases. These observations underscore the need for careful clinical correlation and genetic testing when evaluating children with neurodevelopmental delays. The presence of additional rare variants or modifier effects may further influence the clinical phenotype.
Integrating the genetic and functional data, the evidence conclusively supports a strong association between PRUNE1 and neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies. The diverse mutation types, ranging from synonymous splice-altering variants to canonical splice-site and truncating mutations, converge on a common pathogenic mechanism—loss-of-function of the PRUNE1 protein. The experimental studies provide critical mechanistic insights that align with the genetic findings, lending further weight to the association. Importantly, the consistency of the data across multiple cohorts from different ethnicities and the demonstration of segregation in affected families exceed the maximum ClinGen scoring threshold. This integrated evidence supports the use of PRUNE1 testing in clinical diagnostics and its relevance for patient management.
Key take‐home sentence: The comprehensive genetic and functional evidence establishes a strong, clinically actionable association between PRUNE1 loss-of‑function and neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies, making it a critical target for diagnostic screening and therapeutic development.
Gene–Disease AssociationStrong47 affected individuals across multiple independent studies with confirmed segregation and diverse variant types (PMID:35194938, PMID:35379233). Genetic EvidenceStrongMultiple variant classes, including the representative c.933G>A (p.Thr311=) synonymous splice-altering mutation, have been identified in unrelated probands with corroborative segregation data across several families. Functional EvidenceModerateFunctional assays demonstrate that pathogenic variants lead to exon skipping and loss of critical protein domains, with experimental data consistent with the neurodevelopmental phenotype. |