First Replication of the Involvement of OTUD6B in Intellectual Disability Syndrome With Seizures and Dysmorphic Features

Abstract

Biallelic mutations in the ovarian tumor domain-containing 6B (OTUD6B) gene, coding for a deubiquitinating enzyme, were recently described to cause an intellectual disability syndrome characterized by seizures and dysmorphic features in six families worldwide. We here report on a 6-year-old Italian girl, presenting mild intellectual disability, speech and motor delay, and recurrent seizures, who came to our attention after being screened for genes responsible for Rubinstein–Taybi syndrome, Kabuki syndrome, and epilepsy. We hence submitted the proband’s DNA to whole-exome sequencing, disclosing two candidate heterozygous splicing mutations in the OTUD6B gene: c.324+1G>C and c.405+1G>A. Both variants are reported in the GnomAD database with a frequency lower than the 10−5 and affect the donor splicing site, of exons 2 and 3, respectively. Sanger sequencing confirmed the segregation of the variants in the family, showing that both parents are carriers of one mutation. RT-PCR experiments demonstrated that both variants affect OTUD6B splicing and lead to the production of aberrant transcripts, the major ones being, in both cases, the skipping of the upstream exon. Quantitative analysis performed by competitive-fluorescent RT-PCR on the patient RNA showed that the proband presents less than 1% of wild-type transcripts, further strengthening the causative role of these variants. This represents the first replication of the involvement of the OTUD6B gene in this syndrome and points to the appropriateness of screening OTUD6B in suspected Rubinstein–Taybi syndrome patients with negative results after the screening of the major genes.

Deubiquitylase OTUD6B Governs pVHL Stability in an Enzyme‐Independent Manner and Suppresses Hepatocellular Carcinoma Metastasis

“…Recent studies found that biallelic pathogenic variants in OTUD6B in 12 individuals from 6 independent families with an intellectual disability syndrome associated with seizures and dysmorphic features. [ 50,51 ] Homozygous OTUD6B knockout mice were dead at the birth day, smaller in size, and had congenital heart defects. [ 50 ] Here, we found that OTUD6B knockdown dramatically enhances migration features of human HCC cells in vitro and in vivo.…”

Comparison of Genetic Variants and Manifestations of OTUD6B-Related Disorder: The First Mexican Case

“…Our patient’s clinical features were initially compatible with the diagnosis of Kabuki syndrome (OMIM 147920) and consistent with other reports. 2 , 3 Other diagnoses, such as Rubinstein-Taybi syndrome (OMIM 180849) and DiGeorge syndrome (OMIM 188400), among others, had been suggested as differential diagnoses. Consequently, diagnosing cases with partially overlapping complex phenotypes warrants the use of broad genetic tests, such as exome sequencing.…”

“…Later, 3 other cases were detected after a genetic research odyssey was undertaken, also by ES. 2 - 4 …”

“…Later, 3 other cases were detected after a genetic research odyssey was undertaken, also by ES. [2][3][4] This syndrome is a serious multisystemic disorder characterized by poor general growth, developmental delay, earlyonset seizures, intellectual disability, as well as dysmorphic craniofacial and distal extremity features. The phenotypic manifestations are variable, whereby the most severe include a neurodevelopmental disorder with microcephaly, the lack of speech, and an inability to walk, as well as the need for feeding probes.…”

“…nonsense, missense, and intronic site variants) in 15 cases (9 families) affected by this syndrome, of which the truncating c.433C>T variant (rs368313959) has been identified as the most common (12 of 30 alleles). [1][2][3] After random mating calculation, the prevalence of this variant in the homozygous state in a Latino population is estimated to be 1/145 000. 1 In this article, we herein report the first Mexican case of OTUD6B-related disorder.…”