Research: Congenital posterior cervical spine malformation due to biallelic c.240-4T>G RIPPLY2 variant: A discrete entity

Am J Med Genet A

. 2020 Jun;182(6):1466-1472. doi: 10.1002/ajmg.a.61549. Epub 2020 Mar 25.

Congenital posterior cervical spine malformation due to biallelic c.240-4T>G RIPPLY2 variant: A discrete entity

Margaux Serey-Gaut 1Marcello Scala 2 3Bruno Reversade 4 5 6Lyse Ruaud 7 8Christelle Cabrol 1Francesco Musacchia 9Annalaura Torella 9 10Andrea Accogli 2 3Nathalie Escande-Beillard 4 6Jean Langlais 11Gianluca Piatelli 3Alessandro Consales 3Vincenzo Nigro 9 10Valeria Capra 3Lionel Van Maldergem 1Affiliations expand

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The clinical and radiological spectrum of spondylocostal dysostosis syndromes encompasses distinctive costo-vertebral anomalies. RIPPLY2 biallelic pathogenic variants were described in two distinct cervical spine malformation syndromes: Klippel-Feil syndrome and posterior cervical spine malformation. RIPPLY2 is involved in the determination of rostro-caudal polarity and somite patterning during development. To date, only four cases have been reported. The current report aims at further delineating the posterior malformation in three new patients. Three patients from two unrelated families underwent clinical and radiological examination through X-ray, 3D computed tomography and brain magnetic resonance imaging. After informed consent was obtained, family-based whole exome sequencing (WES) was performed. Complex vertebral segmentation defects in the cervico-thoracic spine were observed in all patients. WES led to the identification of the homozygous splicing variant c.240-4T>G in all subjects. This variant is predicted to result in aberrant splicing of Exon 4. The current report highlights a subtype of cervical spine malformation with major atlo-axoidal malformation compromising spinal cord integrity. This distinctive mutation-specific pattern of malformation differs from Klippel-Feil syndrome and broadens the current classification, defining a sub-type of RIPPLY2-related skeletal disorder. Of note, the phenotype of one patient overlaps with oculo-auriculo-vertebral spectrum disorder.

Keywords: RIPPLY2; cervical spine malformation; oculo-auriculo-vertebral spectrum; spondylocostal dysostosis type 6; supernumerary ribs.

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