CLDN11

Inheritance Pattern: AD

Disease ID:MONDO:0025701

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0025701

Submitter: ClinGen

CLDN11: Hypomyelinating Leukodystrophy 22, autosomal dominant CLDN11 was first associated with autosomal dominant hypomyelinating leukodystrophy 22 (HLD22) in 2021 (OMIM 619328, PMID 33313762). HLD22 is characterized by early-onset spastic movement disorders, expressive speech disorders, and eye abnormalities, as well as hypomyelination in the brain. Affected individuals have borderline intellectual disability, dysarthria, drooling, lower limb hyperreflexia, lower and upper limb hypertonia. Additional features often include delayed milestones including speech and language development and ability to sit and/or walk, as well as eye findings including astigmatism, hypermetropia, nystagmus, and strabismus. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a consistent phenotype and no difference in molecular mechanism or inheritance pattern; therefore, the single disease entity of HLD22 has been maintained. The CLDN11 gene encodes claudin 11, also known as oligodendrocyte transmembrane protein (OTM) or oligodendrocyte specific protein (OSP). Claudin 11 is a member of the claudin tight junction family, which plays a structural role in the radial component of the myelin sheath, acting as a diffusion barrier. Two stop-loss variants have been reported in 3 probands across 1 publication (PMID 33313762). All variants occurred de novo in the affected individuals. The mechanism of pathogenicity is not well understood; at the protein level, the de novo stop-loss variants occur in the last exon (exon 3) and are predicted to lead to an extension of 39 amino acids to the cytoplasmic C-terminus of claudin-11 (PMID 33313762). The gene-disease relationship is also supported by experimental evidence. CLDN11 is highly expressed specifically in oligodendrocytes and early oligodendrocyte progenitor cells (PMID 10797530). Claudin-11 knockout mice exhibit hindlimb weakness and absent tight junction strands in optic nerves, which mirror the neurologic and visual phenotype in affected patients (PMID: 10612400). Cultured cells with mutated CLDN11 demonstrated decreased morphological differentiation and decreased expression of oligodendroglial differentiation marker proteins PLP1 and MBP (PMID 41752091). In summary, there is moderate evidence supporting the relationship between CLDN11 and autosomal dominant hypomyelinating leukodystrophy 22, also known as CLDN11-related hypomyelinating leukodystrophy. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date of March 5, 2025 (SOP Version 12).