ESPE2023 Poster Category 1 Fetal, Neonatal Endocrinology and Metabolism (34 abstracts)
Whole-exome sequencing results in patients with congenital hyperinsulinism.
Maria Melikyan 1,2,3 , Diliara Gubaeva 4,3 , Anna Bolmasova 3 , Anna Kolodkina 3 , Anatoly Tiulpakov 5 , Viktor Bogdanov 3 & Valentina Peterkova 3
1Yerevan State Medical University, Yerevan, Armenia. 2Muratsan University Hospital, Yerevan, Armenia. 3Institute of Pediatric Endocrinology, Moscow, Russian Federation. 4Alder Hey Children’s Hospital, Liverpool, United Kingdom. 5Research Centre for Medical Genetics, Moscow, Russian Federation
Background: Congenital hyperinsulinism (CHI) is a heterogeneous group of disorders, characterized by hypoglycemia due to inappropriate insulin secretion. Despite huge progress in understanding the pathophysiology of CHI, its etiology remains unknown in about 30% of cases.
Aim: To perform whole-exome sequencing in patients with CHI.
Results: A total of 314 patients with congenital hyperinsulinism underwent genetic testing using NGS panel (GLUD1, HNF1A, GCK, ABCC8, HNF4A, INSR, KCNJ11, SLC16A1, HADH, KDM6A, KMT2D). Additional tests for syndromic CHI forms included chromosome 11 methylation analysis (n=28), karyotype (n=9), transferrin isoelectric focusing (n=13) and Chromosome microarray (n=5). Pathogenic variants were found in 187 (59.5%) cases: KCNJ11/ABCC8 (n=138); GLUD1 (n=18), GCK (n=6), HNF4A (n=6), HADH (n=2), INSR (n=2), HNF1A (n=1), SLC16A1 (n=1), Beckwith-Wiedemann syndrome (n=8), Kabuki (n=3), Turner (n=2). 94.6% of the cases with negative genetics were diazoxide (Dzx) responsive. Whole exome sequencing was performed in 17 patients with either Dzx unresponsive CHI (n=4) or those having unusual clinical phenotype (n=13). Mutations in various genes were found in 3/4 and 6/13 patients with Dzx-unresponsive and Dzx-responsive CHI resp (Table 1). Some of these genes are well-known to cause CHI whereas others are not clearly established. Two patients with medically resistant CHI required subtotal pancreatectomy and conservative treatment after the surgery (somatostatin analogues, Dzx, insulin receptor antibody).
| Case | Gene | Variant | Inheritance | Age at onset | Phenotype |
| 1* | CACNA1D | p.Phe767del | Denovo | 1 d | Profound developmental delay, muscle hypotonia, subclinical hyperaldosteronism, congenital glaucoma |
| 2* | NOTCH2** | p.S2427T, heteroz | Denovo | 8 m | UR |
| 3* | ABCC5** | c.129G>A: p.P43P, heteroz | Denovo | 3 y | UR |
| 4 | EIF2S3 | с.671Т>G, heteroz | Maternal | 21 m | Obesity, dysmorphism, mental delay |
| 5 | EP300 | c.3163C>T, p.R1055X. heteroz | Denovo | 1 d | IUGR, short stature, facial dysmorphism, |
| 6 | CREBBP | c.4270C>T, p.Pro1424Ser, heteroz | ND | 3 w | Developmental delay, facial dysmorphism, epilepsy, cerebral palsy, corpus collosum hypoplasia |
| 7 | KCNH6 | c.1136G>A, p.Arg379Gln, heteroz | ND | 3 d | Facial hemi hyperplasia, flat nasal bridge. |
| 8 | MAFA** | p.Hiz208del, heteroz | Denovo | 3 m | Muscle hypotonia, cerebral palsy |
| 9 | DNAJC3 | p.Arg393Ter/p.Arg346Ter | ND | 6 m | hypothyroidism, short stature, dysmorphic features |
| *Dzx unresponsive **genes not previously described in CHI d- days, m – months, w – weeks, y – years, UR - unremarkable | |||||
Conclusions:Whole exome sequencing is helpful to diagnose rare syndromic forms of CHI. Studies on bigger cohorts will allow to estimate significance of the candidate genes and to modify CHI gene panel.
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