Refinement of the critical genomic region for congenital hyperinsulinism in the Chromosome 9p deletion syndrome

Wellcome Open Research

article

Indraneel Banerjee¹  Senthil Senniappan²  Thomas W. Laver³  Richard Caswell³  Martin Zenker⁴  Klaus Mohnike⁵  Tim Cheetham⁶  Matthew N. Wakeling³  Dunia Ismail⁷  Belinda Lennerz⁸  Miranda Splitt⁹  Merih Berberoğlu^1,10  Susann Empting⁵  Martin Wabitsch⁸  Simone Pötzsch^1,11  Pratik Shah^1,12  Zeynep Siklar^1,10  Charles F. Verge^1,13  Michael N. Weedon³  Sian Ellard³  Khalid Hussain^1,14  Sarah E. Flanagan³ 

[1] Department of Paediatric Endocrinology, Royal Manchester Children's Hospital;Department of Paediatric Endocrinology, Alder Hey Children's NHS Foundation Trust;Institute of Biomedical and Clinical Science, University of Exeter Medical School;Institute of Human Genetics, University Hospital, Otto-von-Guericke University;Department of Paediatrics, University Hospital, Otto-von-Guericke University;Department of Paediatric Endocrinology, Royal Victoria Infirmary;Department of Paediatric Endocrinology & Diabetes, Royal Alexandra Children’s Hospital;Department of Paediatrics and Adolescent Medicine, Ulm University Hospital;Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust;Department of Pediatric Endocrinology, Ankara University School of Medicine;Department for Children and Adolescent Medicine;Endocrinology Department, Great Ormond Street Hospital for Children NHS Foundation Trust;Department of Endocrinology, Sydney Children's Hospital, Randwick and School of Women's and Children's Health;Department of Pediatric Medicine, Sidra Medicine

关键词: Chromosome 9p;    Deletions;    Hyperinsulinism;    Hypoglycaemia;   

DOI  :  10.12688/wellcomeopenres.15465.2

学科分类：内科医学

来源: Wellcome

【 摘 要 】

Background: Large contiguous gene deletions at the distal end of the short arm of chromosome 9 result in the complex multi-organ condition chromosome 9p deletion syndrome.  A range of clinical features can result from these deletions with the most common being facial dysmorphisms and neurological impairment. Congenital hyperinsulinism is a rarely reported feature of the syndrome with the genetic mechanism for the dysregulated insulin secretion being unknown. Methods: We studied the clinical and genetic characteristics of 12 individuals with chromosome 9p deletions who had a history of neonatal hypoglycaemia. Using off-target reads generated from targeted next-generation sequencing of the genes known to cause hyperinsulinaemic hypoglycaemia (n=9), or microarray analysis (n=3), we mapped the minimal shared deleted region on chromosome 9 in this cohort. Targeted sequencing was performed in three patients to search for a recessive mutation unmasked by the deletion.Results: In 10/12 patients with hypoglycaemia, hyperinsulinism was confirmed biochemically. A range of extra-pancreatic features were also reported in these patients consistent with the diagnosis of the Chromosome 9p deletion syndrome. The minimal deleted region was mapped to 7.2 Mb, encompassing 38 protein-coding genes.In silico analysis of these genes highlightedSMARCA2 andRFX3 as potential candidates for the hypoglycaemia. Targeted sequencing performed on three of the patients did not identify a second disease-causing variant within the minimal deleted region.Conclusions: This study identifies 9p deletions as an important cause of hyperinsulinaemic hypoglycaemia and increases the number of cases reported with 9p deletions and hypoglycaemia to 15 making this a more common feature of the syndrome than previously appreciated.  Whilst the precise genetic mechanism of the dysregulated insulin secretion could not be determined in these patients, mapping the deletion breakpoints highlighted potential candidate genes for hypoglycaemia within the deleted region.

【 授权许可】

CC BY