Kyphomelic dysplasia, characterized by bowing of the limbs severely affecting femora, has eluded a clear molecular etiology for nearly four decades. We ascertained two unrelated consanguineous families with kyphomelic dysplasia. We performed clinical and radiographic evaluation followed by exome sequencing in three probands. Impact of CCN2 knockout was studied in zebrafish models via CRISPR-Cas9 gene editing. All the probands had short stature, cleft palate, micro-retrognathia. Kyphomelic femora, bowing of long bones, radial head dislocations and spondyloepimetaphyseal dysplasia. We noted two novel biallelic (homozygous) variants in CCN2 as possible candidates: a missense variant c.443G>A; p.(Cys148Tyr) in exon 31 and a frameshift variant, c.779_786del; p.(Pro260LeufsTer7) in exon 5. CCN2 is crucial for proliferation and differentiation of chondrocytes. Earlier studies have shown that CCN2-deficient mice exhibit twisted limbs, short and kinked sterna, broad vertebrae, domed cranial vault, shorter mandibles, cleft palate and impaired osteoclastogenesis. We generated F0 knockouts of ccn2a in zebrafish, which showed altered body curvature, impaired cartilage formation in craniofacial region and either bent or missing tails recapitulating the human phenotype. Our observations confirm biallelic loss of function variants in CCN2 result in an autosomal recessive kyphomelic dysplasia, for the first time.

The authors have declared no competing interest.

We gratefully acknowledge the support provided by DBT/Wellcome Trust India Alliance for the project titled Center for Rare Disease Diagnosis, Research and Training (Grant Reference number: IA/CRC/20/1/600002) awarded to Katta M Girisha; Joint CSIR-UGC NET Junior Research Fellowship awarded by Human Resource Development Group under Council of Scientific and Industrial Research (CSIR), Government of India, to Swati Singh (08/028(0002)/2019-EMR-I).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Informed consents were obtained from the participants for the study and publication of clinical photographs. The research protocol is approved by the Institutional Ethics Committee, Kasturba Medical College and Hospital, Manipal (IEC: 363/2020).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Most of the The data that support the findings of this study are part of this manuscript. However further data is available from the corresponding author upon reasonable request.