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RIPPLY2 variants cause spondylocostal dysostosis 6, an autosomal recessive disorder of vertebral segmentation presenting with hemivertebrae, scoliosis, rib anomalies, and myelopathy due to disrupted somite patterning.
A singleton case detailed a healthy 7-year-old who suffered out-of-hospital cardiac arrest after minor whiplash secondary to cervical spine instability from multiple segmentation defects; imaging revealed vertebral abnormalities leading to hypoxia and collapse before diagnosis of SCDO6 attributable to a RIPPLY2 mutation (PMID:30420309).
In a cohort study, three individuals from two unrelated families harbored bi-allelic RIPPLY2 variants in NM_001009994.2: compound heterozygous c.238A>T (p.Arg80Ter) and c.240-4T>G in two sisters and a homozygous c.238A>T (p.Arg80Ter) in an unrelated boy. All exhibited scoliosis, hemivertebrae, abnormal spinal cord morphology, and variable rib involvement characteristic of SCDO6 (PMID:33410135).
Genetic evidence supports autosomal recessive inheritance with compound heterozygous and homozygous loss-of-function and splice variants, totaling four probands across three families with appropriate segregation and consistent clinical phenotypes.
Functional assays in transiently transfected C2C12 mouse myoblasts demonstrated that RIPPLY2 p.Arg80Ter lacks normal transcriptional repression activity despite stable expression, confirming a loss-of-function mechanism aligned with vertebral segmentation defects seen in model organisms (PMID:25343988).
Together, the genetic and experimental data establish moderate clinical validity for RIPPLY2 in SCDO6. AR RIPPLY2 testing should be considered in patients with unexplained vertebral segmentation anomalies to enable early recognition, cervical stabilization, and prevention of catastrophic outcomes.
Gene–Disease AssociationModerate4 probands across three families with bi-allelic likely loss-of-function and splice RIPPLY2 variants and concordant functional data Genetic EvidenceModerateFour AR probands harboring compound heterozygous and homozygous LoF and splice variants with segregation across three families Functional EvidenceModerateIn vitro C2C12 assays show loss of transcriptional repression for p.Arg80Ter consistent with pathogenic mechanism |