Flanagan Sarah E, Lazaridi Isabella-Anna, Männistö Jonna M E, Bennett Jasmin J, Kalyon Oguzhan, Johnson Matthew B, Wakeling Matthew N, Houghton Jayne A L, Laver Thomas W
Department of Clinical and Biomedical Science, University of Exeter, Exeter, United Kingdom.
Kuopio Pediatric Research Unit (KuPRu), University of Eastern Finland, Kuopio, Finland.
Front Endocrinol (Lausanne). 2025 Feb 18;16:1514916. doi: 10.3389/fendo.2025.1514916. eCollection 2025.
Congenital hyperinsulinism (HI) is characterized by inappropriate insulin secretion from the pancreatic beta-cells which causes severe hypoglycemia. Copy number variants (CNVs) encompassing multiple genes (contiguous gene CNVs) can cause syndromic forms of HI although they are not typically screened for during routine genetic testing for this condition. We aimed to assess the prevalence of disease-causing contiguous gene CNVs in a cohort of individuals referred for HI genetic testing.
Our cohort consisted of 3,763 individuals, of which 1,916 had received a genetic diagnosis for their HI and 1,847 were genetically unsolved following routine testing. We screened for 6 different contiguous gene CNVs using next-generation sequencing data from all individuals in the genetically unsolved cohort and searched for patients in our solved cohort who had already been found to have one of these CNVs.
We identified a contiguous gene CNV affecting 5 of the 6 genomic loci in 53 probands; 28 from the solved cohort and 25 from the genetically unsolved cohort. Variants on the X chromosome were most common, being detected in 24/53 children. Overall, these variants represented 2.7% (53/1,941) of genetic diagnoses, which is similar to the prevalence of variants in other commonly screened HI genes.
These results confirm that contiguous gene CNVs are an important cause of HI which should be included in standard gene panel testing processes as this will improve pick-up rates for genetic diagnoses in HI.
先天性高胰岛素血症（HI）的特征是胰腺β细胞分泌胰岛素不当，导致严重低血糖。包含多个基因的拷贝数变异（CNV，相邻基因CNV）可导致综合征形式的HI，尽管在针对这种疾病的常规基因检测中通常不会对其进行筛查。我们旨在评估一组接受HI基因检测的个体中致病相邻基因CNV的患病率。
我们的队列由3763名个体组成，其中1916人已获得HI的基因诊断，1847人在常规检测后基因问题未得到解决。我们使用基因问题未解决队列中所有个体的二代测序数据筛查了6种不同的相邻基因CNV，并在我们已解决队列中寻找已被发现患有这些CNV之一的患者。
我们在53名先证者中鉴定出一种影响6个基因组位点中5个的相邻基因CNV；28名来自已解决队列，25名来自基因问题未解决队列。X染色体上的变异最为常见，在24/53名儿童中被检测到。总体而言，这些变异占基因诊断的2.7%（53/1941），这与其他常用筛查的HI基因中变异的患病率相似。
这些结果证实相邻基因CNV是HI的一个重要病因，应纳入标准基因检测流程，因为这将提高HI基因诊断的检出率。
