Rare dosage abnormalities flanking the SHOX gene

Egyptian Journal of Medical Human Genetics

卷:22

Aruna Goturu¹  Muriel Holder-Espinasse²  Roxane Van-Heurk³  Maria Teresa Carminho-Rodrigues³  Zainaba Mohamed⁴  Michal Ajzensztejn⁵  Claire R. Hughes⁶  Laure Lemmens⁷  Philippe Klee⁸  James I. Hobbs⁹  Rachel J. Howarth⁹  N. Simon Thomas⁹  Philippa J. Duncan-Flavell⁹  David J. Bunyan⁹  Evelien Gevers¹⁰ 

[1]Children’s and Adolescent Services, Frimley Park Hospital

[2]|Department of Clinical Genetics, Guy’s Hospital

[3]|Department of Medical Genetics, University Hospitals of Geneva

[4]|Department of Paediatric Endocrinology and Diabetes, Birmingham Childrens’ Hospital

[5]|Department of Paediatric Endocrinology, Evelina London Children’s Hospital, St Thomas’s Hospital

[6]|Department of Paediatric Endocrinology, Royal London Children’s Hospital

[7]|Laboratoire de Diagnostic Moléculaire et Génomique, University Hospitals of Geneva

[8]|Paediatric Endocrine and Diabetes Unit, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals of Geneva

[9]|Wessex Regional Genetics Laboratory, Salisbury District Hospital

[10]|William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London

关键词: SHOX;    Regulatory element;    Deletion;    Duplication;   

DOI  :  10.1186/s43042-021-00209-1

来源: DOAJ

【 摘 要 】

Abstract Background Transcriptional regulation of the SHOX gene is highly complex. Much of our understanding has come from the study of copy number changes of conserved non-coding sequences both upstream and downstream of the gene. Downstream deletions have been frequently reported in patients with Leri–Weill dyschondrosteosis or idiopathic short stature. In contrast, there are only four cases in the literature of upstream deletions that remove regulatory elements. Although duplications flanking the SHOX gene have also been reported, their pathogenicity is more difficult to establish. To further evaluate the role of flanking copy number variants in SHOX-related disorders, we describe nine additional patients from a large SHOX diagnostic cohort. Results The nine cases presented here include five with duplications (two upstream of SHOX and three downstream), one with a downstream triplication and three with upstream deletions. Two of the deletions remove a single conserved non-coding element (CNE-3) while the third does not remove any known regulatory element but is just 4 kb upstream of SHOX, and the deleted region may be important in limb bud development. We also describe six families with novel sequence gains flanking SHOX. Three families had increased dosage of a proposed regulatory element approximately 380 kb downstream of SHOX (X:970,000), including one family with the first ever reported triplication of this region. One family had two in cis downstream duplications co-segregating with LWD, and the two others had a duplication of just the upstream SHOX regulatory element CNE-5. Conclusions This study further extends our knowledge of the range of variants that may potentially cause SHOX-related phenotypes and may aid in determining the clinical significance of similar variants.

【 授权许可】

Unknown