OTUD5 Variants Associated With X-Linked Intellectual Disability and Congenital Malformation

Abstract

BackgroundX-linked intellectual disability (XLID), which occurs predominantly in males, is a relatively common and genetically heterogeneous disorder in which over 100 mutated genes have been reported. The OTUD5 gene at Xp11.23 encodes ovarian tumor deubiquitinase 5 protein, which is a deubiquitinating enzyme member of the ovarian tumor family. LINKage-specific-deubiquitylation-deficiency-induced embryonic defects (LINKED) syndrome, arising from pathogenic OTUD5 variants, was recently reported as a new XLID with additional congenital anomalies.MethodsWe investigated three affected males (49- and 47-year-old brothers [Individuals 1 and 2] and a 2-year-old boy [Individual 3]) from two families who showed developmental delay. Their common clinical features included developmental delay, hypotonia, short stature, and distinctive facial features, such as telecanthus and a depressed nasal bridge. Individuals 1 and 2 showed epilepsy and brain magnetic resonance imaging showed a thin corpus callosum and mild ventriculomegaly. Individual 3 showed congenital malformations, including tetralogy of Fallot, hypospadias, and bilateral cryptorchidism. To identify the genetic cause of these features, we performed whole-exome sequencing.ResultsA hemizygous OTUD5 missense variant, c.878A>T, p.Asn293Ile [NM_017602.4], was identified in one family with Individuals 1 and 2, and another missense variant, c.1210 C>T, p.Arg404Trp, in the other family with Individual 3, respectively. The former variant has not been registered in public databases and was predicted to be pathogenic by multiple in silico prediction tools. The latter variant p.Arg404Trp was previously reported as a pathogenic OTUD5 variant, and Individual 3 showed a typical LINKED syndrome phenotype. However, Individuals 1 and 2, with the novel variant (p.Asn293Ile), showed no cardiac or genitourinary malformations.ConclusionsUnlike previous reports of LINKED syndrome, which described early lethality with congenital cardiac anomalies, our three cases are still alive. Notably, the adult brothers with the novel missense OTUD5 variant have lived into their forties. This may be indicative of a milder phenotype as a possible genotype-phenotype correlation. These findings imply a possible long-term prognosis for individuals with this new XLID syndrome, and a wider phenotypic variation than initially thought.

The Regulation and Double-Edged Roles of the Deubiquitinase OTUD5

“…In fact, life expectancy in LINKED syndrome may be longer than previously thought. Saida et al described three patients with in vivo OTUD5 missense variants associated with LINKED syndrome [ 93 ]. They identified three males with X-linked intellectual disability (XLID) in two families with developmental delay.…”

“…These included a pair of adult siblings with a novel missense OTUD5 variant. They had a relatively mild phenotype, showed no cardiac or urogenital malformations and lived into their 40s [ 93 ]. The p.Arg404Trp variant was previously reported by Beck et al to be a lethal variant of OTUD5 with a typical LINKED syndrome phenotype [ 86 ].…”

“…The p.Arg404Trp variant was previously reported by Beck et al to be a lethal variant of OTUD5 with a typical LINKED syndrome phenotype [ 86 ]. However, the case identified by Saida et al is currently alive [ 93 ] ( Table 2 ).…”

A novel missense variant in OTUD5 causes X‐linked multiple congenital anomalies‐neurodevelopmental syndrome

“…Beck et al (2021) independently reported 10 pediatric cases from seven different families with an OTUD5 pathogenic variant and named this disease LINKED syndrome. Saida et al (2021) also described three affected males in two families. These two cohort studies included patients with lifespans from neonatal death to the greatest age of 40 years, suggesting that the phenotype caused by OTUD5 genetic variation is more extensive than previously thought (Saida et al, 2021).…”

“…The OTUD5 (OTU domain‐containing protein 5) gene (MIM# 300713) at Xp11.23 encodes the protein ovarian tumor (OTU) deubiquitinase 5 (Yin et al., 2019), a K48/K63 linkage‐specific deubiquitinating enzyme (DUB) of the OTU family (Mevissen et al., 2013). The OTUD5 gene was previously suggested as a candidate gene for ID according to screening of three large cohorts of patients (Beck et al., 2021; Saida et al., 2021; Tripolszki et al., 2021). Twenty‐six patients with clinical symptoms of XLID have been described in three large cohort studies, with nine variants identified in the OTUD5 gene.…”