Deafness_IsolatedAndComplex

Gene: TUBB4B

Green List (high evidence)

ESHG 2023:
De novo heterozygous TUBB4B variants found in:
-8 patients with recurrent respiratory infections (PCD phenotype), irregular corpus callosum, and dilated ventricles (suggesting motile cilia anomaly)
-3 patients with retinal dystrophy, SNHL, and PCD respiratory issues

Functional studies:
-variants showed decreased cilia number and length, and mislocalisation of dyenin motors
-mouse models had decreased cilia number and length in trachea, and reduction in cilia in choroid plexus cells leading to hydrocephaly

Created: 25 Jul 2023, 2:22 a.m. | Last Modified: 25 Jul 2023, 2:22 a.m.

Panel Version: 1.157

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Primary ciliary dyskinesia

Green List (high evidence)

Phenotypes
Leber congenital amaurosis with early-onset deafness, MIM# 617879

Green List (high evidence)

The TUBB4B gene has been associated with autosomal dominant Leber congenital amaurosis with early-onset deafness using the ClinGen Clinical Validity Framework as of 6/12/2018. This association was made using case-level data only. At least 2 missense variants have been reported de novo in humans, p.Arg391His and p.Arg391Cys. TUBB4B was first associated with this disease in humans in 2017 (Luscan et al.). Association is seen in at least 4 probands in 1 publication (29198720). Variants in this gene segregated with disease in 3 additional family members. This gene-disease association is supported by an in vitro functional assay. According to Luscan et al. 2017, the Arg391, Arg390 and Lys392 residues form a binding pocket that interacts with alpha-tubulin in the longitudinally adjacent tubulin alpha-beta-heterodimer. It is possible that a substitution at Arg391 destabilizes the hydrophobic interactions between the residues.

Created: 28 Jan 2020, 11:36 p.m. | Last Modified: 28 Jan 2020, 11:36 p.m.

Panel Version: 0.265

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Leber congenital amaurosis with early-onset deafness

Publications

• 29198720