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This report describes a strong association between GRAMD1B (HGNC:29214) and multiple sclerosis (MONDO_0005301). The genetic evidence originates from a whole-genome sequencing study in a consanguineous Italian family where four affected individuals were identified carrying a novel missense variant. Further sequencing in 91 familial MS cases uncovered additional rare missense and splice-site variants, bolstering the gene‐disease link (PMID:36553660).
The identified variant, reported as c.1801T>C (p.Ser601Pro), was observed in the index family and supported by segregation analysis. Multiple affected relatives in the study consistently harbored the variant, which adds significant weight to the familial segregation data (PMID:36553660).
Genetic evidence is further underscored by the detection of two additional rare missense variants and two splice-site variants in a larger cohort. These findings indicate that GRAMD1B may contribute to MS susceptibility through a spectrum of coding changes, providing a robust genetic basis for the association (PMID:36553660).
Functional studies have demonstrated that GRAMD1B is expressed in central nervous system cell types including astrocytes, microglia, and neurons, and is also present in peripheral immune cells. Notably, downregulation of GRAMD1B in vessel-associated astrocytes of active MS lesions, as well as its modulation by inflammatory stimuli in monocytes, supports its role in the disease pathophysiology (PMID:36553660).
The integration of both genetic and experimental data has led to a classification of the GRAMD1B–multiple sclerosis association as Strong. The convergence of segregation, recurrence of coding variants across multiple families, and functional evidence from disease-relevant models provides a coherent narrative that supports its utility in diagnostic decision-making and potential commercial applications.
Key take‑home sentence: GRAMD1B variants, including the c.1801T>C (p.Ser601Pro) change, offer strong evidence for involvement in multiple sclerosis, highlighting their clinical relevance for future diagnostic and therapeutic strategies.
Gene–Disease AssociationStrongFour affected individuals in a consanguineous family (PMID:36553660) and additional rare variant findings in 91 familial MS cases provide robust evidence for the association. Genetic EvidenceStrongMultiple rare missense and splice-site variants identified in familial studies, including the c.1801T>C (p.Ser601Pro) variant, strongly support the genetic contribution to MS (PMID:36553660). Functional EvidenceModerateFunctional assays showing downregulation of GRAMD1B in active MS lesions and upon inflammatory stimuli indicate a contributory role in disease pathogenesis (PMID:36553660). |