FBXO11 – Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities

Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (IDDFBA) is an autosomal dominant neurodevelopmental syndrome characterized by borderline-to-severe intellectual disability, behavioral anomalies, hypotonia, facial dysmorphism and variable ocular defects. Heterozygous FBXO11 variants, including frameshift and missense changes, underlie IDDFBA and lead to haploinsufficiency of the F-box protein 11.

To date, 16 probands have been reported: 12 individuals from five Chinese families (12 probands [PMID:38740982]), a multiplex pedigree with three affected members showing segregation (mother plus two daughters) (3 probands [PMID:32902151]), and a sporadic ocular case (1 proband [PMID:35940561]). Variants include frameshift duplications (e.g., c.2401_2405dup (p.Gly803LeufsTer6)), missense substitutions, in-frame deletions and partial gene deletions. Segregation in a three-member family and multiple de novo occurrences support pathogenicity.

Spectrum analysis shows recurrent loss-of-function alleles and diverse missense changes across functional domains. Notably, c.2401_2405dup (p.Gly803LeufsTer6) was identified in a familial cohort, and c.1166dup (p.Cys390MetfsTer3) arose de novo in a patient with complex ophthalmological features including persistent pupillary membrane (HP:0009917) and optic nerve hypoplasia.

Functional studies demonstrate that most FBXO11 missense variants impair nuclear localization or reduce protein levels in cell models ([PMID:34505148]). These data, together with cellular knock-out assays showing loss of ubiquitin ligase function, implicate haploinsufficiency as the primary mechanism.

No conflicting reports have been published disputing FBXO11’s role in IDDFBA. The collective genetic and experimental evidence thus fulfills ClinGen criteria for a strong gene–disease association.

Key Take-home: FBXO11 variant testing is recommended for individuals with unexplained intellectual disability, dysmorphic facies and behavioral anomalies to guide diagnosis and counseling.

References

• American journal of medical genetics. Part A • 2020 • The first familial case of inherited intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (IDDFBA) with a novel FBXO11 variant. PMID:32902151
• Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus • 2022 • New ocular findings in a patient with a novel pathogenic variant in the FBXO11 gene. PMID:35940561
• Journal of human genetics • 2024 • FBXO11 variants are associated with intellectual disability and variable clinical manifestation in Chinese affected individuals. PMID:38740982
• Human molecular genetics • 2022 • De novo missense variants in FBXO11 alter its protein expression and subcellular localization. PMID:34505148

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