Clinical and genetic analysis in a Chinese cohort of children and adolescents with diabetes/persistent hyperglycemia

Abstract

Aims/Introduction: To investigate the genetic etiology and evaluate the diagnostic application of next-generation sequencing for diabetes/persistent hyperglycemia in children and adolescents. Materials and Methods: Patients with diabetes/persistent hyperglycemia, presenting with at least one other clinical manifestation (other than diabetes) or with a family history of diabetes, were recruited. The clinical and laboratory characteristics of the patients were recorded. Next-generation sequencing was carried out, and candidate variants were verified by Sanger sequencing. Variant pathogenicity was further evaluated according to the American College of Medical Genetics and Genomics guidelines. Results: This study included 101 potential probands, 36 of whom were identified as positive by genetic testing. A further 51.2 and 20.9% of variants were determined to be pathogenic or likely pathogenic, respectively. Variants associated with the disease were primarily identified in 21 genes and three regions of copy number variants. Among the 39 variants in 21 genes, 61.5% (24/39) were novel. The genetic diagnosis of 23 patients was confirmed based on genetic evidence and associated clinical manifestations. We reported GCK variants (21.7%, 5/23) as the most common etiology in our cohort. Different clinical manifestations were observed in one family with WFS1 variants. Conclusions: Our findings support the use of next-generation sequencing as a standard method in patients with diabetes/persistent hyperglycemia and provide insights into the etiologies of these conditions.

Complex clinical manifestations and new insights in RNA sequencing of children with diabetes and WFS1 variants

“…The clinical data of other family members were collected. The genetic detection and analysis were performed on probands and thirteen other members in family 1 which was initially described in the previous clinical cohort ( 9 ), one proband and four relatives in family 2, and the third proband and parents in family 3. Four gender- and age-matched children with type 1 diabetes mellitus (T1DM) from different families were recruited as a control group and RNA sequencing was performed on their blood samples.…”

Genetic and Functional Analyses of the Novel KLF11 Pro193Thr Variant in a Three-Generation Family with MODY7

“…The 1 μg each of empty plasmid vector, wild-type, and mutant Pro193Thr, His418Gln-KLF11 plasmid were transiently transfected into INS1 cells into each well of a 24-well plate. After 48 hours of transfection, insulin secretion was tested using glucose-stimulated insulin secretion assay, as previously described 13 17 . In brief, cells were washed once with Krebs-Ringer bicarbonate HEPES (KRBH) buffer containing 0.5% bovine serum albumin (BSA) without glucose.…”

“…KLF11 have been reported, but only 5 variants were identified in families with earlyonset diabetes [7,[13][14][15][16][17][18][19]. Owing to their rarity, KLF11 variants associated with MODY7 are not well characterized.…”

“…KLF11 can bind to the GC-rich sequences (the Sp1-like sites) within promoters to regulate target genes 12 . To date, at least 27 different variants in KLF11 have been reported, but only 5 variants were identified in families with early-onset diabetes 7 13 14 15 16 17 18 19 . Owing to their rarity, KLF11 variants associated with MODY7 are not well characterized.…”