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In a sib-pair study, compound heterozygous variants in CENPE were identified in two siblings presenting with microcephalic primordial dwarfism consistent with Seckel syndrome. Genetic analysis revealed c.4063A>G (p.Lys1355Glu) and c.2797G>A (p.Asp933Asn) segregating in an autosomal recessive pattern, with both parents as unaffected carriers and two affected offspring ([PMID:24748105]). Affected individuals exhibited profound microcephaly (HP:0000252) and global developmental delay (HP:0001263).
Functional studies on patient-derived cells documented severe spindle microtubule disorganization, mitotic progression delays, and chromosome segregation defects that phenocopied PCNT-mutant microcephalic osteodysplastic primordial dwarfism-type II cells, implicating a loss-of-function mechanism at the kinetochore ([PMID:24748105]). These findings solidify CENPE as a candidate for diagnostic screening in autosomal recessive Seckel syndrome.
Gene–Disease AssociationLimitedCompound heterozygous CENPE variants in two siblings with segregation and concordant functional data Genetic EvidenceLimited2 probands in one family with autosomal recessive segregation ([PMID:24748105]) Functional EvidenceModeratePatient cells and independent models show kinetochore-centric mitotic defects matching the human phenotype |