Novel Compound Heterozygous CEP152 Variants Associated with Atypical Seckel Syndrome 5 in a Chinese Child: Functional Characterization of a Novel Splice-Site Variant and Expansion of the Genotype–Phenotype Spectrum

Background: Seckel syndrome (SCKL) is a rare autosomal-recessive inherited disorder characterized by intrauterine and postnatal growth restriction, microcephaly, “bird-like” facial dysmorphisms, and mild-to-moderate intellectual disability (ID). CEP152 is one of the known causative genes, and pathogenic variants in CEP152 are responsible for SCKL5. To date, 18 CEP152 variants associated with SCKL5 have been reported in the peer-reviewed literature. According to the Human Gene Mutation Database (HGMD, version 2026.4), 51 CEP152 variants have been cataloged, including 28 disease-causing mutations (DMs) and 23 putative disease-causing mutations (DMs?). Methods: We conducted a retrospective analysis of a Chinese boy with suspected SCKL5 who was seen at our hospital in 2024, based on a review of his detailed clinical, genetic, and family history. Whole-exome sequencing (WES) followed by Sanger sequencing identified two novel CEP152 variants. A minigene splicing assay was performed to confirm the functional effect of the splice-site variant. We further analyzed the clinical phenotype of patients with SCKL5 carrying CEP152 variations based on the published literature. Results: Two novel compound heterozygous CEP152 (NM_014985.4) variants were identified: the paternal c.3661delA (p.(I1221Lfs*20)) and the maternal c.1577+3A>G. An in vitro minigene assay showed that c.1577+3A>G leads to aberrant splicing, including intron 12 retention (77 bp) and exon 12 skipping. Both splicing alterations introduce premature termination codons and are predicted to produce truncated protein. Conclusions: We discovered two novel CEP152 variants, c.3661delA and c.1577+3A>G, in a Chinese patient with SCKL5. Moreover, retention of intron 12 or exon 12 skipping due to the c.1577+3A>G variant was revealed by the minigene assay. These findings expand the variant and phenotypic spectrum of CEP152 and provide valuable insights for genetic counseling.