RESUMO
BACKGROUND: 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. 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. METHODS: We 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. RESULTS: A 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. CONCLUSIONS: Unlike 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.
RESUMO
Benzene is a common element of environmental pollution. Although this substance is not recognized as a teratogenic agent, it is not known whether prenatal exposure to benzene may induce neurobehavioral changes in the progeny. Benzene 0.1mg/kg was injected subcutaneously (s.c.) acutely at day 15 of gestation into pregnant female rats of the Sprague-Dawley strain and neurotoxicity of the substance was studied in pups and male adult animals of the same progeny. No change was found in total number of neonates, body weight and eye opening time between benzene-exposed animals and controls. No malformations were observed. At birth, neonatal reflexes (cliff aversion, forelimb placing, bar holding, forelimb grasping, startle) were scored in benzene-exposed pups and their percent appearance was found to be anticipated (more benzene-exposed pups exhibited reflexes each day) in comparison to that of control animals. Also, the completion (maximum appearance, i.e. 100% of the brood was found to exhibit each reflex) of neonatal reflexes in benzene-exposed animals preceded that of controls. Starting 2 months after birth, cognitive and motor performance was assessed only in male animals of the prenatally benzene-exposed progeny. The overall evaluation of motor activity in benzene-exposed animals in the open-field test revealed reduced ambulation in these rats as compared to control animals. Acquisition of active avoidance responses in the shuttle-box test, as assessed by the number of conditioned avoidance responses and the percent of learners, was impaired in benzene-exposed rats as compared to control animals. Prenatal exposure to benzene was also followed by reduced retention latency in a step-through passive avoidance task in two retention tests. These results suggest that acute exposure to benzene during gestational organogenesis may cause long-lasting changes in motor behavior and cognitive processes. This may be relevant for the assessment of benzene toxic profile for the progeny of pregnant subjects, although teratogenic effects are not observed.