Alcántara-Ortigoza Miguel Angel, Vela-Amieva Marcela, González-Del Angel Ariadna, Reyna-Fabián Miriam Erandi, Fernández-Hernández Liliana, Estandía-Ortega Bernardette, Guillén-López Sara, López-Mejía Lizbeth, Ibarra-González Isabel, Ruiz-Reyes María de la Luz, Calzada-de León Raúl, Rojas-Maruri Mauricio, Zárate-Mondragón Flora, Hun-Seo Go, Lee Hane, Fernández-Lainez Cynthia
Laboratorio de Biología Molecular, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City 04530, Mexico.
Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City 04530, Mexico.
Int J Mol Sci. 2025 Aug 19;26(16):7985. doi: 10.3390/ijms26167985.
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():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.
全基因组父源单亲二体嵌合体（GWpUPIDM）是一种极其罕见的病症，其特征是不同组织中存在不同比例的孤雄细胞系。它主要与严重先天性高胰岛素血症（CHI）、贝克威思-维德曼综合征（BWS）体征、发生肿瘤的高风险（69 - 79%）相关，并且在某些情况下，还与多位点父源印记障碍（MPIDs）的其他表现有关。我们在此报告首例墨西哥/拉丁裔女性GWpUPIDM患者，该患者表现为非综合征性CHI，需要进行次全胰腺切除术，且存在持续但原因不明的无症状弥漫性肝病。患者8.5岁时，血液中的全外显子组测序（WES）显示纯合区域比例意外地高（约92%）。DNA分析证实双亲细胞系和孤雄细胞系中均存在单倍体父源染色体组，白细胞中孤雄谱系比例为84%，切除的胰腺中为74%，颊细胞中为47%，毛囊中为0.7%。使用患者颊细胞的基因组DNA（gDNA）和双亲的血液样本进行的额外WES三联体分析显示，父源遗传变异NM_000158.4():c.555 + 1G>T [ClinVar:632422；dbSNP:rs759707498]的等位基因频率约为75%。8.5岁时，患者没有BWS、MPIDs或肿瘤的临床特征。然而，她存在持续的肝脏异常，需要进一步检查以排除未被发现的IV型糖原贮积病（OMIM#232500）。我们的研究结果强调，对于患有CHI、胎盘间充质发育异常、BWS体征或其他与MPID相关病症（包括肿瘤）的患者，迫切需要使用基于单核苷酸多态性（SNP）的微阵列或WES进行GWpUPIDM的早期诊断，并通过DNA分析进一步确认，以便及时进行癌症监测和管理。
