Biparental and Androgenetic Somatic Mosaicism with Presentation of Non-Syndromic Severe Neonatal Hyperinsulinemia
Por:
Alcántara-Ortigoza M.A., Vela-Amieva M., González-del Angel A., Reyna-Fabián M.E., Fernández-Hernández L., Estandía-Ortega B., Guillén-López S., López-Mejía L., Ibarra-González I., Ruiz-Reyes M.D.L.L., Calzada-de León R., Rojas-Maruri M., Zárate-Mondragón F., Hun-Seo G., Lee H., Fernández-Lainez C.
Publicada:
1 ene 2025
Resumen:
Genome-wide paternal uniparental isodisomy mosaicism (GWpUPIDM) is an extremely rare condition characterized by varying proportions of an androgenetic cell line across different tissues. It is primarily associated with severe congenital hyperinsulinism (CHI), Beckwith–Wiedemann syndrome (BWS) stigmata, a high risk (69–79%) of developing neoplasia and, in some cases, additional manifestations of multilocus paternal imprinting disorders (MPIDs). We herein report the first Mexican/Latin American female patient GWpUPIDM presenting with non-syndromic CHI requiring subtotal pancreatectomy and persistent but unexplained asymptomatic diffuse hepatopathy. When she was 8.5 years old, whole-exome sequencing (WES) in blood revealed an unexpectedly high (~92%) proportion of regions of homozygosity. DNA profiling confirmed a single haploid set of paternal chromosomes in both biparental and androgenetic cell lines, with varying proportions of the androgenetic lineage in leukocytes (84%), resected pancreas (74%), buccal cells (47%), and hair follicles (0.7%). Additional WES trio analysis using gDNA from the patient’s buccal cells and blood samples from both parents revealed an allelic frequency of ~75% for the paternally inherited variant NM_000158.4(GBE1):c.555+1G>T [ClinVar:632422; dbSNP:rs759707498]. At age 8.5, the patient exhibited no clinical features of BWS, MPIDs, or neoplasia. However, she presented persistent hepatic abnormalities that warrant further investigation to rule out an unmasked glycogen storage disease type IV (OMIM#232500). Our findings emphasize the critical need for early diagnosis of GWpUPIDM using SNP-based microarray or WES with further confirmation through DNA profiling in patients presenting with CHI, placental mesenchymal dysplasia, BWS stigmata, or other MPID-related conditions, including neoplasia, to facilitate timely cancer surveillance and management. © 2025 by the authors.
Filiaciones:
Alcántara-Ortigoza M.A.:
Laboratorio de Biología Molecular, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, 04530, Mexico
Vela-Amieva M.:
Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, 04530, Mexico
González-del Angel A.:
Laboratorio de Biología Molecular, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, 04530, Mexico
Reyna-Fabián M.E.:
Laboratorio de Biología Molecular, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, 04530, Mexico
Fernández-Hernández L.:
Laboratorio de Biología Molecular, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, 04530, Mexico
Estandía-Ortega B.:
Laboratorio de Biología Molecular, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, 04530, Mexico
Guillén-López S.:
Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, 04530, Mexico
López-Mejía L.:
Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, 04530, Mexico
Ibarra-González I.:
Unidad de Genética de la Nutrición, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, 04530, Mexico
Ruiz-Reyes M.D.L.L.:
Servicio de Endocrinología, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, 04530, Mexico
Calzada-de León R.:
Servicio de Endocrinología, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, 04530, Mexico
Rojas-Maruri M.:
Departamento de Patología, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, 04530, Mexico
Zárate-Mondragón F.:
Departamento de Gastroenterología y Nutrición, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, 04530, Mexico
Hun-Seo G.:
3billion, Inc., Seoul, 03161, South Korea
Lee H.:
3billion, Inc., Seoul, 03161, South Korea
Fernández-Lainez C.:
Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, 04530, Mexico
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