C12orf57 – Temtamy Syndrome

This summary integrates data from multiple case reports, multi‐patient studies, and functional assessments to support a strong association between pathogenic variants in C12orf57 and Temtamy syndrome. Clinical reports consistently document global developmental delay, seizures, facial dysmorphism, and other neurological features across diverse ethnic backgrounds, reinforcing the clinical observations of this rare disorder (PMID:31853307, PMID:29383837).

Genetic evidence derives from both homozygous and compound heterozygous variants identified in affected individuals under an autosomal recessive inheritance pattern. In several reports, variants such as c.43C>T (p.Gln15Ter) have been detected in patients, with over 56 probands reported across studies (PMID:31853307, PMID:35791610). Familial segregation analyses further support the association by documenting additional affected relatives in extended pedigrees (PMID:29383837).

The cumulative genetic data not only establishes a consistent variant spectrum—with numerous loss‑of‑function alterations including start loss and premature stop codons—but also underscores autosomal recessive inheritance with clear segregation evidence. Such genetic findings, particularly in families with multiple affected members (e.g. 56 probands and 19 affected relatives, as supported by literature PMID:31853307), provide robust evidence for the gene‑disease association.

Functional studies further corroborate these findings by demonstrating that loss‑of‑function in C12orf57 disrupts neuronal homeostasis. In a knockout mouse model, deletion of the murine ortholog resulted in increased epileptiform activity, dysregulated AMPA receptor expression, and aberrant CAMK4 signaling, aligning well with the human phenotype observed in Temtamy syndrome (PMID:39974932).

No significant conflicting evidence has been reported; rather, the phenotypic heterogeneity—including developmental delay, seizures, and dysmorphic features—across all studies reinforces the pathogenic role of C12orf57 variants. Although some reports highlight additional features (e.g. corpus callosal dysgenesis or congenital heart anomalies), these are consistent with a broad phenotypic spectrum typical for this condition.

In summary, the integration of multi‐patient genetic evidence and functional validation firmly supports a strong association between C12orf57 and Temtamy syndrome. Key take‑home: early genetic testing for C12orf57 variants is clinically beneficial in patients presenting with neurodevelopmental delays and epileptic phenotypes, thereby enhancing diagnostic accuracy and informing patient management.

References

• Experimental and therapeutic medicine • 2020 • Temtamy syndrome caused by a new C12orf57 variant in a Chinese boy, including pedigree analysis and literature review PMID:31853307
• American journal of medical genetics. Part A • 2018 • Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities PMID:29383837
• Journal of genetics • 2022 • C12orf57 pathogenic variants: a unique cause of developmental encephalopathy in a south Indian child PMID:35791610
• bioRxiv • 2025 • C12ORF57: a novel principal regulator of synaptic AMPA currents and excitatory neuronal homeostasis PMID:39974932

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