Whole Exome Screening Identifies Novel and Recurrent WISP3 Mutations Causing Progressive Pseudorheumatoid Dysplasia in Jammu and Kashmir-India.
We report identification and genetic characterization of a rare skeletal disorder that remained unidentified for decades in a village of Jammu and Kashmir, India. The population residing in this region is highly consanguineous and a lack of understanding of the disorder has hindered clinical management and genetic counseling for the many affected individuals in the region. We collected familial information and identified two large extended multiplex pedigrees displaying apparent autosomal recessive inheritance of an uncharacterized skeletal dysplasia. Whole exome sequencing (WES) in members of one pedigree revealed a rare mutation in WISP3:c.156C > A (NP_003871.1:p.Cys52Ter), that perfectly segregated with the disease in the family. To our surprise, Sanger sequencing the WISP3 gene in the second family identified a distinct, novel splice site mutation c.643 + 1G > A, that perfectly segregated with the disease. Combining our next generation sequencing data with careful clinical documentation (familial histories, genetic data, clinical and radiological findings), we have diagnosed the families with Progressive Pseudorheumatoid Dysplasia (PPD). Our results underscore the utility of WES in arriving at definitive diagnoses for rare skeletal dysplasias. This genetic characterization will aid in genetic counseling and management, critically required to curb this rare disorder in the families.
Human Genetics Research Group, Department of Biotechnology, Shri Mata Vaishno Devi University, Katra, J&K, India.
Ekta
E
Rai
School of Biotechnology, University of Jammu, Jammu, J&K, India.
Ankit
A
Mahajan
Human Genetic Research and Counselling Centre, University of Jammu, Jammu, J&K, India.
Parvinder
P
Kumar
Human Genetics Research Group, Department of Biotechnology, Shri Mata Vaishno Devi University, Katra, J&K, India.
Arshia
A
Angural
School of Biotechnology, University of Jammu, Jammu, J&K, India.|Human Genetic Research and Counselling Centre, University of Jammu, Jammu, J&K, India.
Manoj K
MK
Dhar
7, Bhagwati Nagar, Jammu, J&K, India.
Sushil
S
Razdan
CSIR-Centre for Cellular and Molecular Biology, Hyderabad, Telangana, India.
Kumarasamy
K
Thangaraj
Sarah M. and Charles E. Seay Center for Musculoskeletal Research, TSRHC; Departments of Orthopaedic Surgery and Pediatrics, and McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Carol A
CA
Wise
Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan.
Shiro
S
Ikegawa
H.no:62, Lane 11, Swarn Vihar, Muthi, Jammu, J&K, India.
Kamal Kishore
KK
Pandita
Human Genetics Research Group, Department of Biotechnology, Shri Mata Vaishno Devi University, Katra, J&K, India.
Swarkar
S
Sharma
D000328:Adult; D055511:CCN Intercellular Signaling Proteins / Q000235:genetics*; D002648:Child; D003241:Consanguinity; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007194:India; D007592:Joint Diseases / Q000151:congenital* / Q000208:ethnology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
D055511:CCN Intercellular Signaling Proteins; C400081:CCN6 protein, human