Claudin-11-Mediated Hypomyelinating Leukodystrophy 22: New Insights Into Pathogenic Mechanisms

CLDN11 has recently been associated with hypomyelinating leukodystrophy caused by de novo stop-loss variants. Here, we present a new case involving a homozygous variant in order to expand the genetic and clinical spectrum of the disease. We performed a comprehensive clinical, neuroradiological, and genetic evaluation in a child presenting with global developmental delay. Brain MRI and MR spectroscopy were obtained, and next-generation sequencing with parental segregation analysis was conducted. The patient presented with developmental delay, hypotonia, limb hypertonia, esotropia, and an absence of early developmental milestones in infancy, followed by partial motor improvement and persistent language and cognitive impairment. Brain MRI revealed diffuse supratentorial hypomyelination with stability over time. Genetic analysis identified a novel homozygous CLDN11 start-loss variant (c.1A>G; p.Met1Val), which is predicted to result in biallelic loss of function. Both parents were found to be heterozygous carriers. This case supports an autosomal recessive mechanism of CLDN11-related disease, which differs from the dominant stop-loss variants reported previously. The phenotype partially overlaps with that of earlier cases, but is characterized by milder motor involvement and more pronounced cognitive impairment. These findings broaden the mutational spectrum and suggest distinct pathogenic mechanisms, with important implications for diagnosis and genetic counselling.