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.
Highlights
MATERIALS AND METHODSX-linked intellectual disability (XLID) is a relatively common disorder that is predominantly observed in males
At 22 years of age, his height was 142 cm (–5.0 standard deviation (SD)) and his weight was 41.0 kg (–2.1 SD). He was able to walk independently, his gait was short-stepped with arm flexion and knee extension
During his most recent evaluation, at 48 years of age, he was still able to walk independently and his epileptic seizures were controlled with carbamazepine and zonisamide; he had intellectual disability
Summary
MATERIALS AND METHODSX-linked intellectual disability (XLID) is a relatively common disorder that is predominantly observed in males. XLID is genetically heterogeneous, and is caused by more than 100 protein-coding genes in the X chromosome (Muthusamy et al, 2017; Neri et al, 2018) Aberrations in these X-linked genes are estimated to account for 5–10% of male patient with intellectual disability (Lubs et al, 2012; Tzschach et al, 2015; Muthusamy et al, 2017). Beck et al independently reported ten pediatric cases from seven different families with an OTUD5 pathogenic variant and named this disease LINKage-specific-deubiquitylationdeficiency-induced embryonic defects (LINKED) syndrome (Beck et al, 2021). X-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. 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
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