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RIPPLY2 is an essential part of the formation of somite patterning during embryogenesis and in establishment of rostro-caudal polarity. Here, we describe three individuals from two families with compound-heterozygous variants in RIPPLY2 (NM_001009994.2): c.238A > T, p.(Arg80*) and c.240-4 T > G, p.(?), in two 15 and 20-year-old sisters, and a homozygous nonsense variant, c.238A > T, p.(Arg80*), in an 8 year old boy. All patients had multiple vertebral body malformations in the cervical and thoracic region, small or absent rib involvement, myelopathies, and common clinical features of SCDO6 including scoliosis, mild facial asymmetry, spinal spasticity and hemivertebrae. The nonsense variant can be classified as likely pathogenic based on the ACMG criteria while the splice variants must be classified as a variant of unknown significance. With this report on two further families, we confirm RIPPLY2 as the gene for SCDO6 and broaden the phenotype by adding myelopathy with or without spinal canal stenosis and spinal spasticity to the symptom spectrum., (© 2021 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Competing Interests: Competing interests: None declared.

Spondylocostal dysostosis is a congenital disorder of the axial skeleton documented in human families from diverse racial backgrounds. The condition is characterised by truncal shortening, extensive hemivertebrae and rib anomalies including malalignment, fusion and reduction in number. Mutations in the Notch signalling pathway genes DLL3, MESP2, LFNG, HES7 and TBX6 have been associated with this defect. In this study, spondylocostal dysostosis in an outbred family of miniature schnauzer dogs is described. Computed tomography demonstrated that the condition mirrors the skeletal defects observed in human cases, but unlike most human cases, the affected dogs were stillborn or died shortly after birth. Through gene mapping and whole genome sequencing, we identified a single-base deletion in the coding region of HES7. The frameshift mutation causes loss of functional domains essential for the oscillatory transcriptional autorepression of HES7 during somitogenesis. A restriction fragment length polymorphism test was applied within the immediate family and supported a highly penetrant autosomal recessive mode of inheritance. The mutation was not observed in wider testing of 117 randomly sampled adult miniature schnauzer and six adult standard schnauzer dogs; providing a significance of association of Praw = 4.759e-36 (genome-wide significant). Despite this apparently low frequency in the Australian population, the allele may be globally distributed based on its presence in two unrelated sires from geographically distant locations. While isolated hemivertebrae have been observed in a small number of other dog breeds, this is the first clinical and genetic diagnosis of spontaneously occurring spondylocostal dysostosis in a non-human mammal and offers an excellent model in which to study this devastating human disorder. The genetic test can be utilized by dog breeders to select away from the disease and avoid unnecessary neonatal losses.

Objective: The aim of this study was to perform a detailed tomographic analysis of the skull base, craniocervical junction, and the entire spine in seven patients with spondylocostal dysostosis syndrome., Method: Detailed scanning images have been organized in accordance with the most prominent clinical pathology. The reasons behind plagiocephaly, torticollis, short immobile neck, scoliosis and rigid back have been detected. Radiographic documentation was insufficient modality., Results: Detailed computed tomography scans provided excellent delineation of the osseous abnormality pattern in our patients., Conclusion: This article throws light on the most serious osseous manifestations of spondylocostal dysostosissyndrome.

Short trunk dwarfism with multiple vertebral segmentation defects (MVSD) represents a heterogeneous group of disorders characterized by the presence of multiple vertebral and rib abnormalities. A two and one-half year-old female with the spondylothoracic dysostosisform of MVSD is presented. In addition to skeletal anomalies, a lumbar hemangioma, bilateral foot deformities, distal leg atrophy and weakness, and areflexia at the ankles were present. An underlying neuropathic process was suspected. Results of urodynamic studies were suggestive of a neurogenic bladder. Magnetic resonance imaging of the spine demonstrated a tethered spinal cord. Although various brain and spinal cord anomalies have been described in MVSD, this is the first reported case, to our knowledge, of a tethered spinal cord in a patient with MVSD. We recommend that the management of patients with MVSD include comprehensive neurological evaluation and monitoring with appropriate electrodiagnostic, urodynamic, and neuroimaging studies.