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CEP85L – Lissencephaly Spectrum Disorders

CEP85L has emerged as a significant contributor to lissencephaly spectrum disorders, a group of conditions characterized by abnormal cortical development and a smooth brain appearance. This association is supported by multi‐patient studies that provide robust clinical and experimental evidence.

In the landmark study published in Neuron (2020) (PMID:32097630), 13 unrelated individuals with heterozygous CEP85L variants were identified, including two families exhibiting autosomal dominant inheritance. This study provided strong segregation data with multiple affected relatives carrying the variant.

A subsequent study in Journal of Human Genetics (2024) (PMID:39123069) further implicated CEP85L in lissencephaly by reporting additional patients with pathogenic variants. Together, these independent cohorts reinforce the association between CEP85L and the lissencephaly spectrum.

The genetic evidence is bolstered by the identification of a reported variant, c.173G>A (p.Ser58Asn), which exemplifies the mutation spectrum observed in affected individuals. The heterozygous state of such variants is consistent with autosomal dominant inheritance, as indicated by familial segregation analysis (PMID:32097630).

Functional studies have demonstrated that CEP85L localizes to the centrosome and plays a critical role in neuronal migration. Knockdown experiments in mouse models resulted in migration defects that mirror the human lissencephaly phenotype, supporting a pathogenic mechanism likely due to haploinsufficiency or dominant-negative effects (PMID:32097630).

In summary, the integration of genetic data from multiple probands and supportive functional assays provides strong evidence that CEP85L is causally linked to posterior predominant lissencephaly. This synthesis not only reinforces the clinical utility of CEP85L testing in diagnostic workflows but also encourages its use in guiding further research and commercial genetic panels.

References

  • Neuron • 2020 • Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly PMID:32097630
  • Journal of Human Genetics • 2024 • Exploring unsolved cases of lissencephaly spectrum: integrating exome and genome sequencing for higher diagnostic yield PMID:39123069

Evidence Based Scoring (AI generated)

Gene–Disease Association

Strong

13 probands identified in the Neuron study (PMID:32097630) and additional supportive cases from a 2024 study (PMID:39123069), with demonstrated autosomal dominant segregation and concordant experimental data.

Genetic Evidence

Strong

Multiple heterozygous variants, including c.173G>A (p.Ser58Asn), have been reported across independent cohorts, reinforcing the autosomal dominant inheritance pattern and establishing a robust genotype–phenotype correlation.

Functional Evidence

Moderate

Functional assays confirmed CEP85L localization to the centrosome and demonstrated that knockdown in animal models leads to neuronal migration defects, which align with the lissencephaly phenotype.