TEDC1 – Autosomal Recessive Primary Microcephaly

This summary outlines the association of TEDC1 (HGNC:20127) with autosomal recessive primary microcephaly (MONDO_0016660). The reported evidence comes from a study that detailed the genetic etiology in an Iranian consanguineous family, where two affected brothers presented with cognitive impairment (HP:0100543) and microcephaly. The study is notable for being the second documented report implicating TEDC1 in the MCPH phenotype (PMID:38252227).

Genetic evidence is supported by the identification of a novel homozygous missense mutation, c.806A>G (p.Gln269Arg), detected through whole-exome sequencing. The mutation was shown to co-segregate with the disease within the family, with segregation analysis confirming inheritance from heterozygous parents (PMID:38252227). This establishes a critical link between the gene and the observed phenotype in a genetically heterogeneous condition.

Further supporting the association, functional assessment studies have provided concordant data. In silico protein modeling and experimental assays suggest that the c.806A>G (p.Gln269Arg) variant disrupts normal protein function, contributing to abnormal neurodevelopment. These findings affirm the functional impact of the identified variant and reinforce the pathogenic mechanism consistent with autosomal recessive microcephaly (PMID:38252227).

There is no significant conflicting evidence reported in the literature to dispute the gene-disease association. All available data from genetic analyses and functional studies point towards a coherent pathogenic mechanism involving loss of normal TEDC1 function. This convergence of evidence streamlines diagnostic decision‑making, particularly in consanguineous families presenting with microcephaly and cognitive impairment.

In summary, the integration of genetic and functional studies supports a Moderate level of evidence for the association between TEDC1 and autosomal recessive primary microcephaly. The existence of a well-defined homozygous variant that co-segregates in an affected family, alongside functional data, underpins the utility of genetic testing in diagnosing this condition. Key take‑home: Genetic confirmation of TEDC1 mutations can serve as a reliable diagnostic marker in families with primary microcephaly.

References

• Molecular Biology Reports • 2024 • Second report of TEDC1-related microcephaly caused by a novel biallelic mutation in an Iranian consanguineous family PMID:38252227

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