First copy number variant in trans with single nucleotide variant in CCN6 causing progressive pseudorheumatoid dysplasia revealed by genome sequencing and deep phenotyping in monozygotic twins.

Autor: Xu K; Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China.; Key Laboratory of Big Data for spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China., Li G; Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China.; Key Laboratory of Big Data for spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China., Niu Y; Clinical Biobank, Medical Research Center, National Science and Technology Key Infrastructure on Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Wu Z; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China.; Key Laboratory of Big Data for spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China.; Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China., Zhang TJ; Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China.; Key Laboratory of Big Data for spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China.; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China., Zhang S; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.; Department of Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China., Wu N; Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China.; Key Laboratory of Big Data for spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China.; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2024 Nov; Vol. 194 (11), pp. e63801. Date of Electronic Publication: 2024 Jul 03.
DOI: 10.1002/ajmg.a.63801
Abstrakt: Biallelic pathogenic variants in CCN6 cause progressive pseudorheumatoid dysplasia (PPD), a rare skeletal dysplasia. The predominant features include noninflammatory progressive joint stiffness and enlargement, which are not unique to this condition. Nearly 100% of the reported variants are single nucleotide variants or small indels, and missing of a second variant has been reported. Genome sequencing (GS) covers various types of variants and deep phenotyping (DP) provides detailed and precise information facilitating genetic data interpretation. The combination of GS and DP improves diagnostic yield, especially in rare and undiagnosed diseases. We identified a novel compound heterozygote involving a disease-causing copy number variant (g.112057664_112064205del) in trans with a single nucleotide variant (c.624dup(p.Cys209MetfsTer21)) in CCN6 in a pair of monozygotic twins, through the methods of GS and DP. The twins had received three nondiagnostic results before. The g.112057664_112064205del variant was missed by all the tests, and the recorded phenotypes were inaccurate or even misleading. The twins were diagnosed with PPD, ending a 13-year diagnostic odyssey. There may be other patients with PPD experiencing underdiagnosis and misdiagnosis due to inadequate genetic testing or phenotyping methods. This case highlights the critical role of GS and DP in facilitating an accurate and timely diagnosis.
(© 2024 Wiley Periodicals LLC.)
Databáze: MEDLINE
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