RBBP8 – Seckel syndrome

RBBP8 encodes CtIP, a key mediator of DNA end resection and homologous recombination downstream of BRCA1. Biallelic RBBP8 variants have been implicated in Seckel syndrome, a congenital microcephaly disorder (HP:0000252, HP:0011451) characterized by growth retardation, intellectual disability, and DNA damage sensitivity.

Clinical evidence for RBBP8 in Seckel syndrome stems from three independent autosomal recessive families. In a consanguineous Pakistani pedigree, affected siblings homozygous for c.919A>G (p.Arg307Gly) presented with severe microcephaly, white matter disease, epilepsy, diabetes mellitus, and intellectual disability, segregating recessively ([PMID:24440292]). The PLoS Genetics study described two unrelated families: one with a frameshift c.1808_1809del (p.Ile603fs) and another with a splice-site mutation yielding a dominant-negative CtIP, both causing typical Seckel and Jawad syndromes ([PMID:21998596]). A third report identified the recurrent c.1807_1808delAT (p.Ile603LysfsTer7) variant in non-syndromic primary microcephaly, confirming allelic overlap with Seckel syndrome ([PMID:36864288]).

All reported RBBP8 variants are loss-of-function or dominant-negative and fully segregate with disease in consanguineous and outbred families, totaling six affected individuals across three pedigrees. The inheritance mode is autosomal recessive with complete cosegregation of biallelic CtIP defects in each family, supporting a strong genetic association.

Functional characterization confirms that truncated CtIP impairs DNA damage responses. Patient-derived cell lines with CtIP mutations exhibit defective damage-induced single-stranded DNA formation, hypersensitivity to genotoxic stress, and reduced ATR activation ([PMID:21998596]). Biophysical and crystallographic studies show that disruption of CtIP tetramerization abrogates DNA-end resection and homologous recombination in vitro and in cells ([PMID:25558984]).

Together, genetic and experimental data establish haploinsufficiency and dominant-negative mechanisms by which RBBP8 loss disrupts genome stability during neurodevelopment, causing the Seckel phenotype. No conflicting evidence has been reported.

Key take-home: RBBP8 should be included in diagnostic gene panels for microcephaly and Seckel syndrome, and functional assays of CtIP resection activity can aid variant interpretation and patient management.

References

• Gene • 2014 • A complex microcephaly syndrome in a Pakistani family associated with a novel missense mutation in RBBP8 and a heterozygous deletion in NRXN1. PMID:24440292
• PLoS genetics • 2011 • CtIP Mutations Cause Seckel and Jawad Syndromes. PMID:21998596
• Journal of human genetics • 2023 • Recurrence mutation in RBBP8 gene causing non-syndromic autosomal recessive primary microcephaly; geometric simulation approach for insight into predicted computational models. PMID:36864288
• Nature structural & molecular biology • 2015 • CtIP tetramer assembly is required for DNA-end resection and repair. PMID:25558984

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