Type of Mutations
The majority of the OTUD6B variants reported in previous patients have been nonsense or missense variants. Frameshift and splice variants have also been reported. Several patients are homozygous for the nonsense variant c.433C>T (p.Arg145*) or are compound heterozygous for this variant with another variant.
Suspected Pathophysicologic Mechanism
OTUD6B encodes a member of the ovarian tumor domain-containing subfamily of deubiquinating enzymes, which reverse the process of ubiquitination and are important regulators of the ubiquitin system. Ubiquitination is a posttranslational modification process that regulates many cellular processes including protein degradation, intracellular trafficking, cell signalling, and protein-protein interactions. Functional studies have suggested that mutations in OTUD6B impact proteasome function, which is an important component of the ubiquitination processes.
Genotype-Phenotype Correlations
There are not currently any clearly established genotype-phenotype correlations. There is an ongoing research study for collection of clinical information from additional affected individuals to better define genotype-phenotype correlations. Please contact the website moderators for additional details about the study.
Some evidence has suggested that homozygosity or compound heterozygosity for a missense variant in OTUD6B may result in a milder phenotype than biallelic nonsense variants, but further investigation is needed.
Genetic Testing
The majority of previous patients have been diagnosed with OTUD6B-associated syndrome by exome sequencing. A multi-gene panel including OTUD6B or OTUD6B single gene testing would also be appropriate if clinical suspicion for this condition is high. Parents of a proband with OTUD6B-associated syndrome should be offered targeted testing for the variants identified in the proband, and testing of the proband’s siblings should be considered.
OTUD6B