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Seckel syndrome is a rare autosomal recessive disorder characterized by prenatal and postnatal growth retardation, severe microcephaly, intellectual disability, and a characteristic “bird-head” facial appearance. Patients typically present in early infancy with profound neurodevelopmental delay and proportionate dwarfism.
Genetic heterogeneity underlies Seckel syndrome, with mutations in several centrosomal and DNA damage response genes identified. CEP152 encodes a centrosomal scaffold protein essential for centriole duplication and maintenance of genomic integrity via DNA damage response pathways.
In the initial study, homozygosity mapping and exome sequencing in three consanguineous families with Seckel syndrome identified homozygous truncating and splice-site CEP152 variants in at least three unrelated probands (PMID:21131973). These included multiple frameshift and nonsense alleles that co-segregated with disease in a recessive pattern.
More recently, a Chinese pedigree was reported in which the proband harbored compound heterozygous CEP152 variants: c.1060C>T (p.Arg354Ter) and c.1414-14A>G, confirmed by trio whole-exome sequencing and molecular assays to reduce CEP152 mRNA levels and induce exon 12 skipping (PMID:36685824).
Collectively, over 20 loss-of-function and non-canonical splice variants in CEP152 have been documented in Seckel syndrome, all following autosomal recessive inheritance and demonstrating co-segregation with disease in affected families (PMID:21131973).
Functional investigations reveal that loss of CEP152 leads to replicative stress, hyperactivation of ATM signaling, increased γH2AX phosphorylation, and defective centrosome duplication in patient-derived cells and model systems. These concordant cellular phenotypes support a loss-of-function mechanism underlying the microcephaly and growth restriction observed in Seckel syndrome (PMID:21131973; PMID:36685824).
Integration of genetic and experimental data establishes a strong gene-disease association: biallelic CEP152 disruption consistently leads to Seckel syndrome. Additional large-scale segregation or population data may further solidify penetrance estimates, but current evidence suffices for diagnostic testing.
Key Take-home: CEP152 loss-of-function is a well-supported cause of autosomal recessive Seckel syndrome, justifying its inclusion in genetic diagnostic panels.
Gene–Disease AssociationStrongIdentified in ≥5 probands from three unrelated families with recessive segregation and concordant functional data Genetic EvidenceStrongCompound heterozygous and homozygous loss-of-function/splice variants in 2 studies; total ≥5 affected individuals; recessive segregation met Functional EvidenceModeratePatient cell assays and biochemical studies demonstrate loss-of-function mechanism with replicative stress and ATM pathway activation |