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Despite its first description nearly four decades ago, the precise molecular basis of this condition remained elusive until the recent discovery of de novo variants in the KIF5B-related kyphomelic dysplasia. We ascertained two unrelated consanguineous families with kyphomelic dysplasia. They had six affected offsprings and we performed a detailed clinical evaluation, skeletal survey, and exome sequencing in three probands. All the probands had short stature, cleft palate, and micro-retrognathia. Radiographs revealed kyphomelic femora, bowing of long bones, radial head dislocations and mild platyspondyly. We noted two novel homozygous variants in <jats:italic>CCN2<\/jats:italic> as possible candidates that segregated with the phenotype in the families: a missense variant c.443G&gt;A; p.(Cys148Tyr) in exon 3 and a frameshift variant, c.779_786del; p.(Pro260LeufsTer7) in exon 5. <jats:italic>CCN2<\/jats:italic> is crucial for proliferation and differentiation of chondrocytes. Earlier studies have shown that <jats:italic>Ccn2<\/jats:italic>-deficient mice exhibit twisted limbs, short and kinked sterna, broad vertebrae, domed cranial vault, shorter mandibles, and cleft palate. We studied the impact of <jats:italic>CCN2<\/jats:italic> knockout in zebrafish models via CRISPR-Cas9 gene editing. F0 knockouts of <jats:italic>ccn2a<\/jats:italic> in zebrafish showed altered body curvature, impaired cartilage formation in craniofacial region and either bent or missing tails. Our observations in humans and zebrafish combined with previously described skeletal phenotype of <jats:italic>Ccn2<\/jats:italic> knock out mice, confirm that biallelic loss of function variants in <jats:italic>CCN2<\/jats:italic> result in an autosomal recessive kyphomelic dysplasia.<\/jats:p>","DOI":"10.1038\/s41431-024-01725-5","type":"journal-article","created":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T17:03:39Z","timestamp":1730912619000},"page":"30-37","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Biallelic variants in CCN2 underlie an autosomal recessive kyphomelic dysplasia"],"prefix":"10.1038","volume":"33","author":[{"given":"Swati","family":"Singh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8973-370X","authenticated-orcid":false,"given":"Sumita","family":"Danda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neetu","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hitesh","family":"Shah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vrisha","family":"Madhuri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3533-7926","authenticated-orcid":false,"given":"Tariq Altaf","family":"Mir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadia Zipporah","family":"Padala","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raghavender","family":"Medishetti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alka","family":"Ekbote","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gandham SriLakshmi","family":"Bhavani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aarti","family":"Sevilimedu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0139-8239","authenticated-orcid":false,"given":"Katta M.","family":"Girisha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,11,6]]},"reference":[{"key":"1725_CR1","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1002\/ajmg.1320140218","volume":"14","author":"RN Maclean","year":"1983","unstructured":"Maclean RN, Prater WK, Lozzio CB. 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KMG holds shares and is a director of Suma Genomics Private Limited that has interests in clinical diagnostics.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"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) and Institutional Review Board Ethics and Research Committee members of the Christian Medical College, Vellore (Ref: IRB Min. No. 0424162). All experiments with zebrafish were done in a CCSEA-approved zebrafish facility at Dr. Reddy\u2019s Institute of Life Sciences (1100\/po\/Re\/s\/07\/CPCSEA) in Hyderabad, India. The facility also has US-NIH OLAW assurance (F22-00539). All procedures and protocols were reviewed and approved by the Institutional Animal Ethics Committee (Protocol approval DRILS\/IAEC\/AS\/2021-1). The \u201cGuidelines for Experimentation on Fishes, 2021\u201d published by CPCSEA was used as a reference.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}]}}