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The association between MYORG and basal ganglia calcification (idiopathic, MONDO_0024538) is supported by multiple independent case reports and large cohort studies that collectively highlight an autosomal recessive pattern of inheritance. Several studies have demonstrated that patients with biallelic MYORG variants exhibit characteristic calcifications in the basal ganglia, thalamus, cerebellum, and additional brain regions, accompanied by neurological features such as dysarthria, parkinsonism, and movement disorders (PMID:32873236). These investigations not only provide a robust clinical profile of the disorder but also establish vital genotype–phenotype correlations across diverse populations.
Genetic evidence for this association is compelling. Multiple reports describe both homozygous and compound heterozygous variants in MYORG, including missense, frameshift, and nonframeshift insertions. For example, one study identified the variant c.850T>C (p.Cys284Arg) among affected individuals, supporting pathogenicity via autosomal recessive transmission (PMID:32873236). Segregation analysis in several families confirms that additional affected relatives carry the causative variants, and recurrent mutations have been documented in unrelated probands (PMID:33372568).
Functional and experimental studies further substantiate the role of MYORG in disease pathogenesis. Advanced imaging modalities, such as MR susceptibility weighted imaging and SPECT, have revealed disrupted cerebral perfusion and dopaminergic dysfunction in patients harboring MYORG mutations. In vitro and animal model assessments have demonstrated that these variants impair MYORG function, which may disrupt normal cerebral calcium homeostasis and lead to extensive calcification (PMID:32211515).
While the majority of the evidence supports a strong association, some studies note reduced penetrance in heterozygous carriers, reinforcing the autosomal recessive pattern of inheritance and underscoring the need for comprehensive genetic screening. The wide phenotypic spectrum—from movement disorders to cognitive decline—calls for careful clinical evaluation to optimize diagnostic accuracy and individualized patient management.
In summary, the genetic and functional data converge to support a strong gene-disease association between MYORG and basal ganglia calcification, providing essential insights for diagnostic decision‑making, therapeutic development, and future research. Additional evidence exists that, while exceeding the ClinGen scoring maximum, underscores the critical role of MYORG in the pathophysiology of primary familial brain calcification.
Key Take-home: MYORG mutation analysis is crucial in patients with widespread brain calcification and movement disorders, as it delivers significant clinical utility in diagnosing autosomal recessive primary familial brain calcification.
Gene–Disease AssociationStrongMultiple independent case reports and large multigenerational studies encompassing over 23 probands with clear autosomal recessive segregation support a strong gene-disease association (PMID:32873236, PMID:33372568). Genetic EvidenceStrongA spectrum of pathogenic variants including missense, frameshift, and nonframeshift insertions across several unrelated probands, along with segregation data in multiple families, has been well documented (PMID:32873236, PMID:33372568). Functional EvidenceModerateFunctional imaging studies and in vitro assays demonstrating altered cerebral perfusion and disrupted MYORG function provide supportive evidence for a mechanistic link between MYORG dysfunction and brain calcification (PMID:32211515). |