OTUD5 – Multiple congenital anomalies-neurodevelopmental syndrome, X-linked

The deubiquitylase OTUD5 regulates K48/K63 linkage-specific ubiquitin cleavage during embryonic development and is disrupted in an X-linked disorder characterized by multiple congenital anomalies and neurodevelopmental delay, termed LINKED syndrome or multiple congenital anomalies-neurodevelopmental syndrome, X-linked.

Genetic evidence stems from 10 unrelated hemizygous male patients carrying distinct OTUD5 missense variants identified by exome sequencing (PMID:33523931). Inheritance follows an X-linked recessive pattern with no reported additional segregating affected relatives.

The variant spectrum comprises eight missense changes across the catalytic and ubiquitin-binding domains. A representative alteration is c.863T>C (p.Met288Thr), which resides in the catalytic OTU domain and disrupts K48-specific deubiquitylase activity.

Functional studies in induced pluripotent stem cell models demonstrate that patient OTUD5 variants impair deubiquitylation of chromatin remodelers (ARID1A/B, HDAC2, HCF1), leading to reduced chromatin accessibility at neuroectodermal enhancers and aberrant gene expression during differentiation (PMID:33523931).

Mechanistically, loss of OTUD5 activity results in accelerated proteasomal degradation of critical chromatin regulators, indicating a loss-of-function paradigm underlies embryonic neurodevelopmental defects.

In summary, 10 hemizygous OTUD5 variants in males and concordant cellular phenotype provide Moderate clinical validity and functional evidence for this X-linked syndrome. Key take-home: OTUD5 genetic testing aids diagnosis of LINKED syndrome and informs on underlying deubiquitylation-based pathogenic mechanisms.

References

• Science Advances • 2021 • Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation. PMID:33523931

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