CAPN15 – Oculogastrointestinal Neurodevelopmental Syndrome

Oculogastrointestinal neurodevelopmental syndrome is an autosomal recessive disorder characterized by ocular anomalies and global developmental delay linked to biallelic variants in CAPN15. Seven individuals harboring missense CAPN15 variants were first reported with eye abnormalities and neurodevelopmental impairment (PMID:37596828).

Recent analysis of 13 probands from 10 unrelated families confirms autosomal recessive inheritance and expands the allelic spectrum (PMID:37596828). Among these, six newly reported probands from three families carry deleterious CAPN15 alleles (PMID:37596828).

Biallelic missense variants are predominantly associated with ocular manifestations, whereas loss-of-function alleles lead to microcephaly (HP:0000252), craniofacial dysmorphism, cardiac and genitourinary anomalies. All affected individuals exhibit ocular abnormalities (HP:0000478) and global developmental delay (HP:0001263).

Notably, four of the six new patients present radiographic evidence of Dandy-Walker malformation (HP:0007030), including hypoplastic vermis and fourth ventricle dilation, thus broadening the neurologic phenotype of the syndrome (PMID:37596828).

Functional assessment in a Capn15 knockout mouse recapitulates cerebellar hypoplasia and vermian anomalies, supporting a loss-of-function mechanism in disease pathogenesis (PMID:37596828).

Overall, converging genetic and experimental data provide strong support for a clinically valid, autosomal recessive association between CAPN15 and oculogastrointestinal neurodevelopmental syndrome. This knowledge facilitates molecular diagnosis, informs variant interpretation, and guides clinical management.

References

• American journal of medical genetics. Part A • 2023 • Novel association of Dandy-Walker malformation with CAPN15 variants expands the phenotype of oculogastrointestinal neurodevelopmental syndrome. PMID:37596828

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