Submission Details

TUBB4B was first described in relation to Leber congenital amaurosis with early-onset deafness in 2019 (Mechaussier et al., PMID: 31884617). Some of the most common phenotypes among patients with this diagnosis include early onset loss of visual acuity, extinguished or severely reduced rod and cone electroretinogram responses, peripheral retinal atrophy, photophobia, nyctalopia, and high hypermetropia. Affected individuals also exhibited congenital or childhood onset sensorineural hearing impairment. TUBB4B variants were subsequently described in relation to primary ciliary dyskinesia in 2024 (PMID: 38662826). Patient phenotypes included recurrent infections, neonatal respiratory distress, bronchiectasis, decreased nasal nitric oxide, chronic productive cough, sensorineural or conductive hearing impairment, hydrocephalus, abnormal ciliary motility, recurrent ear infections, short stature, and loss of visual acuity. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance (autosomal dominant) and molecular mechanism (frequently caused by de novo missense variants) were found to be consistent between the cases diagnosed with Leber congenital amaurosis with early-onset deafness and those diagnosed with primary ciliary dyskinesia. In addition, the shared feature of hearing loss among both groups of patients was consistent with a single spectrum of disease. Therefore, cases caused by inherited TUBB4B variants have been lumped for the purposes of gene curation into a single disease entity referred to as "TUBB4B-related ciliopathy"

This curation includes 11 variants that have been reported in 21 probands in 6 publications (PMIDs: 38662826, 37448631, 35240325, 38719929, 39876836, 29198720). Most of the probands carried de novo variants, while some had affected family members carrying the same variant. Some degree of genotype-phenotype correlation was observed in which the missense variants at amino acid 390 or 391 were present in cases diagnosed as Leber congenital amaurosis, while missense variants located at amino acid 259 were associated with diagnosis of primary ciliary dyskinesia. Overall, the mechanism of pathogenicity among all cases appears to be dominant negative.

This gene-disease relationship was also supported by the finding that TUBB4B is primarily expressed in testis, fallopian tubes, lung, and other respiratory tissues known to harbor multiciliated cells (PMID: 23715323). TUBB4B encodes β4B-tubulin, which localizes within the cilium (PMID: 38031972). A knockout mouse model recapitulated the hydrocephalus seen in the human probands and showed microtubule defects in motile cilia, absence of the central pair apparatus, male infertility, and spermatogenesis defects. A second knockout model recapitulated the hearing loss, ear infections, hydrocephalus, and motile ciliary defects in epithelial cells (PMID: 39277687). Cultured cells expressing mutant TUBB4B were able to fold, form αβ-heterodimers, and co-assemble them into the endogenous microtubule lattice, however, the growth dynamics of the microtubules were consistently altered (PMID: 29198720).

In conclusion, TUBB4B has a Definitive association with TUBB4B-related ciliopathy. This classification has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the Motile Ciliopathy GCEP on April 10th, 2025 in collaboration with the Hearing Loss GCEP (SOP Version 11).