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

Abstract

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 highlighted SMARCA2 and RFX3 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.

Syndromic forms of congenital hyperinsulinism

“…However, the rare possibility of parental germ cell mosaicism cannot be excluded, and recurrence of CHI in siblings has, for example, been reported in Schaaf-Yang syndrome ( 150 ). Autosomal recessive or X-linked inheritance ( Table 1 ), as well as familial balanced chromosomal translocations as reported, for example, in one family with 9p monosomy ( 78 ) may be associated with a substantial risk of recurrence. Since several of those syndromes have serious consequences on health and life quality besides the ones conferred by CHI itself, prenatal counseling and genetic testing may be indicated.…”

“…CHI has been observed in a number of cases with monosomy 9p: Banerjee et al. reported 12 cases with neonatal hypoglycemia, ten of them with biochemically confirmed hyperinsulinism, and reviewed three previously reported cases ( 78 ). Kostopoulou et al.…”

“…A minimal deleted region was mapped to 7.2 Mb, encompassing 38 protein-coding genes. SMARCA2 and RFX3 were proposed as potential candidates for the hypoglycemia, but no experimental evidence has been provided ( 78 ).…”

From karyotypes to precision genomics in 9p deletion and duplication syndromes

“…Genomic data were collected from the literature where approximate breakpoints are known for 53 individuals with 9p deletion and duplication syndromes. 12 , 14 , 15 , 16 , 17 , 19 , 27 , 29 , 30 , 33 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 …”

Chromosome 20p11.2 deletions cause congenital hyperinsulinism via the likely disruption ofFOXA2

“…The phenotype resulting from these large deletions can be readily explained when the deletion disrupts known monogenic disease genes, for example a deletion on chromosome 11p15 causes HI, enteropathy and deafness with loss of the ABCC8 gene responsible for the HI and loss of the adjacent gene, USH1C, causing the enteropathy and deafness [7]. In other large deletion syndromes where HI is a rare feature, for example partial or full monosomy of the X chromosome causing Turner syndrome [8], and the 9p deletion syndrome [9], the precise genetic mechanism leading to the HI has not been fully determined [10].…”