Undiagnosed arthrogryposis: further expanding the molecular and phenotypic spectrum

Turgut G. T., Altunoğlu U., Saraç Sivrikoz T., Kalaycı T., Toksoy G., Avcı Ş., ...Daha Fazla

European Human Genetics Conference, Glasgow, İngiltere, 10 - 13 Haziran 2023, cilt.31, ss.101

  • Yayın Türü: Bildiri / Özet Bildiri
  • Cilt numarası: 31
  • Basıldığı Şehir: Glasgow
  • Basıldığı Ülke: İngiltere
  • Sayfa Sayıları: ss.101
  • İstanbul Üniversitesi Adresli: Evet

Özet

Background/Objectives: Arthrogryposis multiplex congenita (AMC) is a phenotypic descriptor implying congenital contractures in two or more body areas. Exome sequencing provides an effective approach in elucidating the molecular basis, considering the presence of genetic and phenotypic heterogeneity. We aimed to identify the molecular etiology in undiagnosed fetuses within the AMC spectrum, using exome sequencing. Methods: 14 patients from ten families displaying AMC were enrolled. Array-CGH analysis was performed in all fetuses, followed by exome analysis. Sanger sequencing was performed to validate variants. Results: We identified known or novel candidate variants in COG6, NEB, RAPSN, KIAA1109, DOK7, HSPG2, PSAT1, and PIEZO2. Three patients were shown to harbor additional biallelic variants in VPS13B, DNAH9, and USH2A, complicating the phenotype. Moreover, we identified a frameshift variant in USP14 in three similarly affected fetuses. The resemblance of the fetal findings to the previously reported Usp14 mouse models supported that our variant likely led to a novel intrauterine-onset human AMC phenotype (1). Conclusion: Our results provide new insights into the clinical and molecular characterization of a small AMC cohort; to contribute to phenotype-genotype correlation, expand the clinical spectrum, report novel variants, and present the first human phenotype that appears to be attributable to a truncating variant in USP14. References: (1) Turgut, Gozde Tutku et al. “Functional loss of ubiquitinspecific protease 14 may lead to a novel distal arthrogryposis phenotype.” Clinical genetics, https://doi.org/10.1111/cge.14117. 23 Jan. 2022, https://doi.org/10.1111/cge.14117. Grants: This project is granted by the Scientific Research Projects Coordination Unit of Istanbul University (Project ID 37765). Conflict of Interest: G. Tutku Turgut This project is granted by the Scientific Research Projects Coordination Unit of Istanbul University (Project ID 37765), Umut Altunoglu: None declared, Tugba Sarac-Sivrikoz: None declared, Tugba Kalayci: None declared, Guven Toksoy: None declared, Sahin Avci: None declared, Birsen Karaman: None declared, Cagri Gulec: None declared, Gozde Yesil Sayin This project is granted by the Scientific Research Projects Coordination Unit of Istanbul University (Project ID 37765)., Seher Basaran: None declared, Hülya Kayserili: None declared, Zehra Oya Uyguner: None declared.