CUL4B – Cabezas syndrome (X-linked intellectual disability, Cabezas type)

The association between CUL4B and Cabezas syndrome is supported by robust evidence from multiple independent case reports and multi‐patient studies. In a seminal study, a novel nonsense mutation (c.2107A>T (p.Lys703Ter)) was identified in three affected brothers, and similar pathogenic variants have been reported in at least nine unrelated families (PMID:20002452) which supports strong gene‐disease validity. Multiple case reports document typical manifestations of Cabezas syndrome including severe intellectual disability, hyperactivity, abnormal facial features, short foot, seizures, intention tremor, and inguinal hernia (PMID:20002452; PMID:28144446).

Genetic evidence is compelling with several distinct pathogenic variants detected across independent studies. The observed segregation in affected males – as shown by the mutation’s inheritance from an asymptomatic carrier mother to affected sons – further strengthens the association (PMID:20002452). In addition, a genome‐first approach confirmed the detection of a similar nonsense mutation in an undiagnosed 5‑year‑old male leading to an unequivocal diagnosis of Cabezas syndrome (PMID:28144446).

Functional studies provide supporting evidence for a loss‑of‑function mechanism. Specifically, in vitro investigations have demonstrated that nonsense mutations in CUL4B lead to premature truncation, resulting in nonsense‑mediated mRNA decay and loss of E3 ubiquitin ligase activity (PMID:17273978). Additional experimental models also show impaired cellular proliferation and disrupted degradation of critical cell cycle regulators, further linking pathogenic variants in CUL4B to clinical cognitive deficits (PMID:19801544).

While some studies have noted overlapping phenotypes with other X‑linked intellectual disability disorders, the constellation of features with Cabezas syndrome is sufficiently distinct, minimizing alternative interpretations. The reported variants consistently produce a truncated, non‑functional protein, and the recurrence of such variants across independent studies exceeds the maximum threshold for ClinGen scoring.

The coherent narrative from both genetic and experimental evidence establishes a strong association between CUL4B and Cabezas syndrome with significant implications for diagnostic decision‑making and clinical management. This synthesis of evidence affirms that screening for CUL4B mutations should be integrated into the workup of males presenting with severe intellectual disability, speech impairment, and characteristic dysmorphic features.

Key Take‑home: Integrating both genetic and functional data, the association between CUL4B and Cabezas syndrome is well‑substantiated and offers a reliable basis for clinical diagnostics.

References

• Clinical genetics • 2010 • A novel nonsense mutation in CUL4B gene in three brothers with X‑linked mental retardation syndrome PMID:20002452
• Human genome variation • 2017 • Genome‑first approach diagnosed Cabezas syndrome via novel CUL4B mutation detection PMID:28144446
• American journal of human genetics • 2007 • Mutation in CUL4B, which encodes a member of cullin‑RING ubiquitin ligase complex, causes X‑linked mental retardation PMID:17273978
• Seizure • 2023 • CUL4B‑associated epilepsy: Report of a novel truncating variant promoting drug‑resistant seizures and systematic review of the literature PMID:36476360

Evidence Based Scoring (AI generated)