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Seckel syndrome type 4 (SCKL4) is a rare autosomal recessive primordial dwarfism and microcephaly disorder characterized by pre‐ and postnatal growth restriction, “bird‐like” facies, and variable neurodevelopmental anomalies (Seckel syndrome).
Pathogenic biallelic variants in CENPJ were first reported in a consanguineous Pakistani family with classical SCKL4. Linkage and homozygosity mapping identified a novel splice‐site variant c.2693-2A>G segregating with the phenotype under autosomal recessive inheritance ([PMID:20522431]).
Subsequent reports expanded the allelic spectrum to include a homozygous intronic splice variant with leaky expression in four affected male siblings ([PMID:35451063]) and a truncating variant c.130A>T (p.Lys44Ter) in a Caucasian individual presenting with hydranencephaly and focal epilepsy ([PMID:36334884]).
Across these three independent families (total ≥5 affected), all CENPJ alleles are predicted loss‐of‐function or splicing defects that fully segregate under autosomal recessive inheritance (segregation in four additional affected relatives) and are absent from population databases.
Functional studies in patient‐derived cells demonstrate reduced wild‐type CENPJ transcript and protein levels, defective centrosome duplication, delayed mitotic progression, and impaired microtubule destabilization consistent with the human phenotype ([PMID:35451063]; [PMID:36334884]; [PMID:18586240]).
These data establish a strong clinical validity for CENPJ in SCKL4. Genetic testing for CENPJ loss‐of‐function and splice variants is recommended for patients with primordial dwarfism and microcephaly, and functional assays of centrosome integrity may inform therapeutic strategies.
Gene–Disease AssociationStrongBiallelic CENPJ variants in three unrelated families (≥5 affected) with full segregation under autosomal recessive inheritance and concordant microcephaly and growth restriction phenotypes Genetic EvidenceStrongLoss-of-function and splice variants in CENPJ identified in ≥5 probands across three families with autosomal recessive Seckel syndrome, meeting ClinGen genetic evidence cap Functional EvidenceModeratePatient cell studies demonstrate defective centrosome duplication, mitotic delay, and impaired microtubule destabilization consistent with human SCKL4 phenotypes |