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This summary reviews the strong association between GPSM2 and Chudley-McCullough Syndrome, an autosomal recessive disorder characterized by profound sensorineural hearing loss and distinctive brain malformations. Multiple independent case reports have identified loss‑of‑function variants in GPSM2, including nonsense and frameshift mutations, in patients from diverse ethnic backgrounds (PMID:27180139, PMID:27064331). The disorder’s clinical presentation, with features such as agenesis of the corpus callosum and hydrocephalus, reinforces the role of GPSM2 in normal neurodevelopment.
Genetic evidence is robust. At least four distinct truncating variants, including the representative c.1055C>G (p.Ser352Ter), have been identified in unrelated probands and segregate with the disorder in familial studies. Additional affected relatives in several reports further support cosegregation (PMID:23494849). The collection of multiple pathogenic variants across different cohorts confirms the genetic etiology.
Functional and experimental assessments complement the genetic data. In vitro studies and in silico evaluations predict that these nonsense mutations abolish critical GoLoco domains in the GPSM2 protein, impairing its role in establishing planar cell polarity and spindle orientation (PMID:27180139). The loss‑of‑function mechanism has been replicated in animal models that recapitulate the key phenotypic abnormalities seen in patients with Chudley-McCullough Syndrome.
Segregation analysis across the studies has demonstrated that affected siblings and additional family members carry the same truncating mutations, strengthening the causal relationship. This degree of segregation, along with the recurrence of distinct loss‑of‑function alleles, underscores the high clinical validity of the association.
Reports from multi‑patient studies and founder mutation analyses have expanded the phenotypic spectrum. Children and adults with CMS typically exhibit sensorineural hearing impairment together with neurological anomalies such as agenesis of the corpus callosum, hydrocephalus, and frontal polymicrogyria (PMID:33016209). These observations are critical for refining diagnostic criteria and guiding genetic testing in suspected cases.
Integrating the genetic and functional evidence, the causal link between GPSM2 and Chudley-McCullough Syndrome is firmly established. The convergence of independent lines of evidence, including the identification of a representative pathogenic variant and supportive functional studies, exceeds the ClinGen scoring maximum but remains within a strong evidence band.
Key take‑home sentence: The compelling clinical, genetic, and functional evidence makes GPSM2 an essential diagnostic marker for Chudley-McCullough Syndrome, directly informing patient management and genetic counseling.
Gene–Disease AssociationStrongMultiple independent reports totaling ≥30 probands with clear loss‑of‑function variants exhibiting familial segregation support a strong association (PMID:27180139, PMID:27064331, PMID:33016209). Genetic EvidenceStrongAt least four distinct loss‑of‑function variants, including the representative c.1055C>G (p.Ser352Ter), have been identified in unrelated families with segregation data and founder effect evidence (PMID:23494849, PMID:27180139). Functional EvidenceModerateFunctional studies, including in silico predictions and domain disruption analyses, confirm that truncating mutations in GPSM2 impair its biological function critical for neurodevelopment (PMID:27180139). |