Multilocus Genetic Variants in a Child With Neuro‐Ichthyosis: A Case of Pharmacoresistant Epilepsy and Developmental Delay Associated With CC2D2A, ABCA12, DOCK6 Variants, and a 14q31.3–q32.11 Deletion

TL;DR

A rare case of neuro-ichthyosis in a child is linked to multiple genetic variants and a deletion, highlighting the need for early genetic testing in diagnosing complex disorders.

Contribution

The paper reports an unprecedented multilocus genetic mechanism involving CC2D2A, ABCA12, DOCK6, and a chromosomal deletion in a case of neuro-ichthyosis.

Findings

A homozygous CC2D2A variant consistent with Joubert syndrome type 9 was identified.

Heterozygous variants in ABCA12 and DOCK6, along with a 14q31.3–q32.11 deletion, were found to contribute to the neurocutaneous phenotype.

The findings expand the genotypic and phenotypic spectrum of neuro-ichthyosis.

Abstract

Neuro‐ichthyosis is a rare group of disorders characterized by the coexistence of neurological dysfunction and ichthyotic skin changes. We report a 5‐year‐old girl born to consanguineous parents who presented with pharmacoresistant epilepsy, severe developmental delay, microcephaly, and ichthyosis. Family history revealed similarly affected siblings, suggesting a hereditary basis. Despite multiple antiepileptic drugs, seizures remained uncontrolled. Whole exome sequencing identified a homozygous CC2D2A variant consistent with Joubert syndrome type 9, along with heterozygous variants in ABCA12 and DOCK6, and a 14q31.3–q32.11 deletion. This unique combination represents an unprecedented multilocus pathogenic mechanism contributing to the complex neurocutaneous phenotype. The findings expand the known genotypic and phenotypic spectrum of neuro‐ichthyosis and highlight the importance of early whole exome sequencing for accurate diagnosis, genetic counseling, and management of patients with severe neurocutaneous disorders, especially in consanguineous populations where multilocus pathogenicity may underlie atypical or severe presentations.

Early Whole Exome Sequencing is crucial for diagnosing complex neurocutaneous phenotypes, especially in consanguineous populations. This case highlights an unprecedented multilocus pathogenic mechanism involving CC2D2A (primary), ABCA12, DOCK6 variants, and a 14q31.3–q32.11 deletion (modifiers), which collectively shape the severe neuro‐ichthyosis phenotype and guide prognosis and management.