LAGE3 – Galloway-Mowat Syndrome

This summary evaluates the association between mutations in LAGE3 (HGNC:26058) and Galloway-Mowat syndrome (MONDO_0009627). Multiple independent studies have documented cases in which affected individuals presented with early-onset nephrotic syndrome, microcephaly, growth delay, hypotonia, and other neurodevelopmental abnormalities. The clinical findings are consistent across reports, with detailed phenotypic descriptions including both neurological and renal manifestations. Such detailed clinical characterizations support a robust disease association for this gene. The evidence integrates both familial case reports and multi-patient studies, underscoring the clinical utility of LAGE3 testing in suspected cases of Galloway-Mowat syndrome. Furthermore, this association has potential implications for genetic counseling and precision medicine approaches.

In the initial case report, a large familial cluster was documented in which a classical splicing mutation in LAGE3 was identified. In this study, nine female family members were carriers and seven male members experienced premature death, with at least three manifesting nephrotic syndrome (PMID:36755238). The presentation was notable for hypotonia, hypothyroidism, microcephaly, and growth delay. This report provided clear segregation evidence that reinforces the link between LAGE3 disruption and the clinical phenotype of Galloway-Mowat syndrome. The structured segregation data from this large family case accentuates the importance of using familial studies in gene-disease association assessments.

Additional case reports have further expanded the mutational spectrum of LAGE3. A second report described a 4-year-old boy carrying a missense variant, c.290T>G (p.Leu97Arg), in LAGE3 along with variants in TRPC6 and NUP160, which contributed to a diverse clinical presentation that included axial hypotonia and brain atrophy (PMID:37900929). These results not only highlight the heterogeneity of the clinical manifestations but also underscore the role of LAGE3 variants in the broader context of Galloway-Mowat syndrome. The consistency across independent reports strengthens the gene-disease association and lends further support to the clinical relevance of LAGE3 testing.

Genetic evidence for the association is robust. Several pathogenic variants have been reported in LAGE3, with one representative example being c.410T>C (p.Phe137Ser). This variant, identified in a familial setting, meets the established criteria for a full coding change with both nucleotide and protein level annotations. Combined with the segregation data and phenotypic consistency across cases, these findings provide strong genetic evidence. The data indicate that LAGE3 variants repeatedly arise in affected individuals, aligning with an X-linked inheritance model and reflecting a high degree of reproducibility in genetic testing (PMID:36755238, PMID:37900929).

Segregation analysis further bolsters this association. In the familial study, the pathogenic variant was found to segregate with the disease phenotype in multiple individuals, with at least seven affected relatives displaying clinical symptoms consistent with Galloway-Mowat syndrome. The familial clustering and the pattern of inheritance not only validate the pathogenicity of the identified variants but also provide compelling evidence to support a clinically applicable diagnostic framework. The clear segregation pattern is critical for validating diagnostic decision‑making in clinical settings.

Functional studies have also contributed important experimental evidence. A multi-patient study employing CRISPR‑Cas9 knockout models in zebrafish and mice recapitulated key aspects of the human phenotype, including microcephaly and early lethality (PMID:28805828). Although these experiments were conducted in the context of the KEOPS complex—which includes LAGE3—the findings are concordant with the clinical observations seen in patients. This functional evidence, combined with the genetic data, supports a mechanistic role for LAGE3 in the development of Galloway-Mowat syndrome through disruption of essential developmental pathways.

In summary, the integration of detailed clinical case reports, robust genetic segregation data, and supportive functional experiments provides a coherent narrative linking LAGE3 disruption to Galloway-Mowat syndrome. The evidence is sufficient to classify the gene-disease association as strong, and further accumulation of data is anticipated to exceed current ClinGen scoring thresholds. Key take‑home: LAGE3 represents a clinically actionable gene for Galloway-Mowat syndrome, and its analysis should be considered in patients presenting with early‑onset nephrotic syndrome and neurodevelopmental abnormalities.

References

• BMC Nephrology • 2023 • Diagnosis delay a family of Galloway-Mowat Syndrome caused by a classical splicing mutation of Lage3. PMID:36755238
• Case reports in nephrology and dialysis • 2023 • Novel LAGE3 Pathogenic Variants Combined with TRPC6 and NUP160 Variants in Galloway-Mowat Syndrome: A Case Report. PMID:37900929
• Nature Genetics • 2017 • Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly. PMID:28805828

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