An X‐linked syndrome with severe neurodevelopmental delay, hydrocephalus, and early lethality caused by a missense variation in the <scp><i>OTUD5</i></scp> gene

Tripolszki, Kornélia; Sasaki, Erina; Hotakainen, Ronja; Kassim, Abdul Halim; Pereira, Catarina; Rolfs, Arndt; Bauer, Péter; Bertoli‐Avella, Aida M.

doi:10.1111/cge.13873

Cited by 16 publications

(20 citation statements)

References 10 publications

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“…Phenotypically, early lethality was described in both previous reports associated with OTUD5 pathogenic variants (Beck et al, 2021;Tripolszki et al, 2021). Causes of death included congenital cardiac complications or sepsis.…”

Section: Discussionmentioning

confidence: 95%

“…Individuals 1 and 2 were male siblings and had a novel OTUD5 variant (c.878A>T, Asn293Ile) and sporadic Individual 3 had a known OTUD5 variant (c.1210C>T, Arg404Trp). Including our patients, almost all of the identified OTUD5 variants in affected individuals have been missense variants (Beck et al, 2021;Tripolszki et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…The OTUD5 variant identified in Individuals 1 and 2 was assumed to be inherited from their mother, but unfortunately a maternal sample was unavailable for this study. Tripolszki et al reported that females carriers were asymptomatic and X-inactivation study showed 100% inactivation of the maternally inherited X chromosome in four female carriers (Tripolszki et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…Abnormalities in genes encoding OTU DUBs cause various developmental or autoinflammatory diseases (Basar et al, 2020). Recently, a male-specific multiple congenital anomaly disorder caused by pathogenic variants in OTUD5 was reported by two groups (Beck et al, 2021;Tripolszki et al, 2021). Tripolszki et al described a large family with 13 affected individuals (Tripolszki et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, a male-specific multiple congenital anomaly disorder caused by pathogenic variants in OTUD5 was reported by two groups (Beck et al, 2021;Tripolszki et al, 2021). Tripolszki et al described a large family with 13 affected individuals (Tripolszki et al, 2021). 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).…”

Section: Introductionmentioning

confidence: 99%

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

Saida

Fukuda

Scott

et al. 2021

Front. Cell Dev. Biol.

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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.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Saida

Fukuda

Scott

et al. 2021

Front. Cell Dev. Biol.

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X‐Linked intellectual disability update 2022

Schwartz

Louie

Toutain

et al. 2022

American J of Med Genetics Pt A

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Genes that are involved in the transcription process, mitochondrial function, glycoprotein metabolism, and ubiquitination dominate the list of 21 new genes associated with X‐linked intellectual disability since the last update in 2017. The new genes were identified by sequencing of candidate genes (2), the entire X‐chromosome (2), the whole exome (15), or the whole genome (2). With these additions, 42 (21%) of the 199 named XLID syndromes and 27 (25%) of the 108 numbered nonsyndromic XLID families remain to be resolved at the molecular level. Although the pace of discovery of new XLID genes has slowed during the past 5 years, the density of genes on the X chromosome that cause intellectual disability still appears to be twice the density of intellectual disability genes on the autosomes.

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

Tian,

Li,

et al. 2023

Molec Gen & Gen Med

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BackgroundThe OTUD5 gene encodes a deubiquitinating enzyme (DUB) of the OTU family. Variants of OTUD5 are associated with X‐linked multiple congenital anomalies‐neurodevelopmental syndrome (MCAND). The case described in this study expands the clinical and molecular spectrum of OTUD5.MethodsTrio‐based clinical exome sequencing (trio‐CES) was performed on a Chinese boy with a clinical phenotype and both of his parents. Sanger sequencing was employed for validation of the variant detected.ResultsThe patient presented with characteristic facial features, intellectual disability, motor/language/cognitive, and global developmental delays, limb contractures, and kidney abnormalities, and trio‐CES identified a de novo missense variant, c.1305T>A, of the OTUD5 gene.DiscussionWe describe OTUD5 gene variation in the Chinese population, with the first report of this variant. Additionally, we provide a comprehensive summary of all published cases of MCAND to date, in order to elucidate the primary clinical features of the syndrome and the variability in phenotype severity. This case expands the genetic and clinical phenotypic spectrum of OTUD5‐associated MCAND.

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An X‐linked syndrome with severe neurodevelopmental delay, hydrocephalus, and early lethality caused by a missense variation in the OTUD5 gene

Cited by 16 publications

References 10 publications

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

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

X‐Linked intellectual disability update 2022

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

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