ESPE Abstracts (2019) 92 RFC1.4

Estimation of Mody Frequency and Prevalent Subtypes in Pediatric Patients by Targeted NGS

Luis Salamanca1, Maria Al Kadaoui2, Julio Guerrero1, Atilano Carcavilla1, Nerea Itza1, Cristina Mora1, Ana Coral Barreda1, Jesús Dominguez1, Elena Vallespín3, Angela Del Pozo3, Mario Solis3, Angel Aragonés4, Florinda Hermoso5, Joaquín Ramirez6, Maria Teresa Muñoz7, Lucía Garzón8, Amparo Rodriguez9, Arantxa Escribano10, Isabel Gonzalez11, Angel Campos3


1Pediatric Endocrinology. La Paz University Hospital., Madrid, Spain. 2Institute of Medical and Molecular Genetics. La Paz University Hospital, Madrid, Spain. 3Institute of Medical and Molecular Genetics (INGEMM), IdiPAZ, CIBERER U753, ISCIII. La Paz University Hospital, Madrid, Spain. 4Pediatric Endocrinology. Toledo Hospital., Toledo, Spain. 5Pediatric Endocrinology. Campo Grande Hospital, Valladolid, Spain. 6Pediatric Endocrinology. Principe de Asturias Hospital, Madrid, Spain. 7Pediatric Endocrinology. Niño Jesus Hospital, Madrid, Spain. 8Pediatric Endocrinology. 12 de Octubre Hospital, Madrid, Spain. 9Pediatric Endocrinology. Gregorio Marañon General Hospital, Madrid, Spain. 10Pediatric Endocrinology. Virgen de la Arrixaca Hospital, Murcia, Spain. 11Pediatric Endocrinology. La Paz University Hospital, Madrid, Spain


Though up to fourteen different MODY subtypes have been so far described, there are no studies in the literature which have determined their actual frequency and prevalence in pediatric patients.

Objectives: To identify the underlying molecular basis in a cohort of pediatric patients with a suspected clinical diagnosis of MODY by targeted NGS.

Materials/Methods: Cohort of 60 patient fulfilling MODY clinical criteria (presentation before age 25 years, autosomal dominant inheritance, no obesity, negative autoimmunity and partial beta cell function preservation), and 2 neonatal diabetes patients (26 days and 6 months old, respectively). Molecular analysis by targeted NGS with a custom panel (MonDIAB_V1; 173 genes implicated in glucose homeostasis or associated with dysglycemia, including the 14 known MODY genes). Average coverage >100x, % bases with coverage >20x=>90%; variant priorization using VarSeqV2.1.0. (Golden Helix).

Results: We identified 33 potentially pathogenic heterozygous variants (bioinformatic predictors: CADD>20; DANN >0.98) in 26/60 (43.3%) patients (mean age: 10 + 3.7 years; range 1-16 years). Seven patients 26.9%) presented digenic inheritance with 2 relevant variants in two different MODY genes. Regarding the prevalent subtypes, 14/33 (42.4%) were identified in GCK (4 missense, 1 frameshift, and 9 missense variants; 2 of which are novel); 7/33 (21.2%) in HNF1A (1 frameshift and 6 missense variants, 1 non previously described); 4/33 (12.1%) in ABCC8 (1 proximal promotor variant in 2 patients and 2 missense variants, 1 non previously described); 2/33 (6.1%) in BLK (2 novel missense variants); and one missense variants in HNF1b, HNF4A, PDX1, PAX4, KCNJ11, and NEUROD1, respectively, all novel. The seven patients with an apparent digenic inheritance presented the following variants combinations: HN4A + PAX4, GCK + ABCC8, HNF1A + ABCC8 (n=3), and GCK+KCNJ11. The 2 patients with neonatal diabetes presented with a previously described heterozygous pathogenic nonsense mutation in KCNJ11 and a novel missense variant in NKX6-2, respectively.

Conclusions: Targeted NGS analysis identified potentially pathogenic variants in known MODY genes in 43.3% of the examined patients.

Up to 26.9% of the patients with relevant variants in MODY genes (11.7% of the examined cohort) presented an apparent digenic inheritance. This represents a much larger proportion than that initially estimated by traditional screening techniques of candidate genes.

56.7% of the examined patients, did not present relevant variants in the 14 known MODY genes, which suggests the implication of other unknown genes in the etiology of MODY.

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