OTUD6B – Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies

Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies (IDDFSDA) is an autosomal recessive neurodevelopmental syndrome characterized by global cognitive impairment, seizure activity, distinctive facial gestalt, and malformations of the distal limbs. Biallelic pathogenic variants in the deubiquitinating enzyme gene OTUD6B underlie this disorder.

Genetic evidence includes original reports of six unrelated families and a first replication in an Italian pedigree, together encompassing at least eight probands with confirmed biallelic inheritance (PMID:30364145). Parental segregation analyses demonstrated carrier status without clinical features, consistent with autosomal recessive inheritance.

The variant spectrum comprises canonical splice-site mutations (e.g., c.324+1G>C and c.405+1G>A) disrupting exon inclusion (PMID:30364145), ultrarare frameshift alleles, and missense substitutions clustering in the OTU domain. A representative splice variant, c.324+1G>C, abolishes the exon 2 donor site and leads to <1% wild-type transcript.

Functional assays include RT-PCR demonstrating aberrant splicing and near-complete loss of transcript for donor-site variants, coupled with molecular dynamics simulations predicting that missense substitutions (e.g., Ile274Arg) distort OTUD6B folding and stability (PMID:35430327). Nonsense and frameshift alleles are anticipated to undergo nonsense-mediated decay.

No conflicting evidence has been reported for OTUD6B in IDDFSDA. Clinical variability correlates with predicted impact on protein structure, supporting a loss-of-function mechanism.

The combined case-level and experimental data fulfill ClinGen criteria for a Strong gene–disease association and Strong genetic evidence, with Moderate functional support. OTUD6B variant analysis should be included in diagnostic gene panels for individuals presenting with intellectual disability, seizures, facial dysmorphism, and distal limb anomalies.

References

• Frontiers in genetics • 2018 • First Replication of the Involvement of OTUD6B in Intellectual Disability Syndrome With Seizures and Dysmorphic Features PMID:30364145
• European journal of medical genetics • 2022 • Novel biallelic variants affecting the OTU domain of the gene OTUD6B associate with severe intellectual disability syndrome and molecular dynamics simulations PMID:35430327

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