Comprehensive rescreening of the known congenital hyperinsulinism genes provides a new genetic diagnosis for 18% of the Finnish cohort

E ännistö Jonna M; L Houghton Jayne A; Päivi Keskinen; Jasmin Hopkins; Joose Raivo; Timo Otonkoski; Hanna Huopio; Flanagan Sarah E

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ESPE Abstracts (2024) 98 FC1.6

ESPE2024 Free Communications Diabetes and Insulin (6 abstracts)

Comprehensive rescreening of the known congenital hyperinsulinism genes provides a new genetic diagnosis for 18% of the Finnish cohort

Jonna M E Männistö ^1,2 , Jayne A L Houghton ¹ , Päivi Keskinen ³ , Jasmin Hopkins ¹ , Joose Raivo ⁴ , Timo Otonkoski ⁵ , Hanna Huopio ⁶ & Sarah E Flanagan ¹

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¹Department of Clinical and Biomedical Science, University of Exeter Medical School, Exeter, United Kingdom. ²Department of Pediatrics, Unit of Clinical Genetics, Kuopio University Hospital, Kuopio, Finland. ³Department of Paediatrics, Tampere University Hospital, Tampere, Finland. ⁴Institute of Clinical Medicine, University of Eastern Finland Institute of Clinical Medicine, Kuopio, Finland. ⁵Department of Pediatrics, Helsinki University Hospital, Helsinki, Finland. ⁶Department of Paediatrics, Kuopio University Hospital, Kuopio, Finland.

Background: Congenital hyperinsulinism (HI) is a group of insulin secretion disorders with highly heterogeneous genetic aetiologies, which may significantly impact on treatment and follow-up. Genetic diagnosis is unsolved in up to 50% of the individuals, but the benefits of retesting including all the recent genetic discoveries has not been previously assessed.

Aim: We examined the effectiveness of rescreening the known HI genes in the genetically unsolved individuals in the nationwide Finnish HI cohort from 1972–2024.

Methods: ltogether 23 probands with persistent HI and either negative (n = 17) or inconclusive (n = 6) genetic results in previous genetic testing were included. We performed tNGS of 20 known HI genes (exons and flanking regions, CNV analysis, and previously reported non-coding variants) and screening for low-level mosaicism of five known HI genes. DNA analyses were performed from leukocyte DNA, including samples from parents of 22 probands and affected family members of three probands.

Results: Of the 23 probands, 57% were male and 61% had neonatal onset HI. The current median age was 21 years (range, 7–38 y). Six individuals needed near-total pancreatectomy or pancreatic resection. Of the remaining 17 medically treated individuals, five were still on medication at median age of 16.5 years. Genetic cause of HI was identified in three (18%) individuals with previous negative results and identified or changed in two (33%) with previous inconclusive results. New genetic diagnoses included an activating GCK in-frame duplication as low-level mosaicism (8% within leukocyte DNA) in an individual with partial response to diazoxide, a non-coding pathogenic dominant HK1 variant in a proband remaining on diazoxide in adulthood, and a non-coding dominant promoter variant in the SLC16A1 gene in a proband with three affected relatives. Changed genetic results included a confirmed recessive HI as we now detected a deep intronic pathogenic de novo ABCC8 variant on paternal allele in an individual previously known to carry a maternally inherited recessive ABCC8 variant, and a change from VUS to likely benign in one individual, allowing for further testing.

Conclusions: When covering the analysis of recent genetic discoveries, rescreening of known HI genes can serve as an effective tool for detecting new genetic diagnoses in individuals with high suspicion of monogenic HI, and the results may significantly impact on determining the recurrence risk or follow-up.