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European journal of human genetics : EJHG
Nov 06, 2024;

Biallelic variants in CCN2 underlie an autosomal recessive kyphomelic dysplasia.

Swati Singh, Sumita Danda, Neetu Sharma, Hitesh Shah, Vrisha Madhuri, Tariq Altaf Mir, Nadia Zipporah Padala, Raghavender Medishetti, Alka Ekbote, Gandham SriLakshmi Bhavani, Aarti Sevilimedu, Katta M Girisha
Author Information
  1. Swati Singh: Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.
  2. Sumita Danda: Department of Medical Genetics, Christian Medical College and Hospital, Vellore, Tamil Nadu, India. ORCID
  3. Neetu Sharma: Centre for Innovation in Molecular and Pharmaceutical Sciences, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, Telangana, India.
  4. Hitesh Shah: Department of Pediatric Orthopedics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.
  5. Vrisha Madhuri: Department of Pediatric Orthopedics, Christian Medical College and Hospital, Vellore, Tamil Nadu, India.
  6. Tariq Altaf Mir: Department of Pediatric Orthopedics, Christian Medical College and Hospital, Vellore, Tamil Nadu, India. ORCID
  7. Nadia Zipporah Padala: Centre for Innovation in Molecular and Pharmaceutical Sciences, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, Telangana, India.
  8. Raghavender Medishetti: Centre for Innovation in Molecular and Pharmaceutical Sciences, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, Telangana, India.
  9. Alka Ekbote: Department of Medical Genetics, Christian Medical College and Hospital, Vellore, Tamil Nadu, India.
  10. Gandham SriLakshmi Bhavani: Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.
  11. Aarti Sevilimedu: Centre for Innovation in Molecular and Pharmaceutical Sciences, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, Telangana, India.
  12. Katta M Girisha: Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India. girish.katta@manipal.edu. ORCID
PMID: 39506047 DOI: 10.1038/s41431-024-01725-5

Abstract

Kyphomelic dysplasia is a rare heterogenous group of skeletal dysplasia, characterized by bowing of the limbs, severely affecting femora with distinct facial features. 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 CCN2 as possible candidates that segregated with the phenotype in the families: a missense variant c.443G>A; p.(Cys148Tyr) in exon 3 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, and cleft palate. We studied the impact of CCN2 knockout in zebrafish models via CRISPR-Cas9 gene editing. F0 knockouts of ccn2a 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 Ccn2 knock out mice, confirm that biallelic loss of function variants in CCN2 result in an autosomal recessive kyphomelic dysplasia.

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Grants

  1. Grant Reference number: IA/CRC/20/1/600002)/DBT India Alliance (Wellcome Trust/DBT India Alliance)
  2. 08/028(0002)/2019-EMR-I/Council of Scientific and Industrial Research (CSIR)
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