Abstract
BackgroundBeckwith-Wiedemann syndrome (BWS) is an imprinting disorder caused by (epi)genetic alterations at 11p15. Because approximately 20% of patients test negative via molecular testing of peripheral blood leukocytes, the concept of Beckwith-Wiedemann spectrum (BWSp) was established to encompass a broader cohort with diverse and overlapping phenotypes. The prevalence of other overgrowth syndromes concealed within molecularly negative BWSp remains unexplored.MethodsWe conducted whole-exome sequencing (WES) on 69 singleton patients exhibiting molecularly negative BWSp. Variants were confirmed by Sanger sequencing or quantitative genomic PCR. We compared BWSp scores and clinical features between groups with classical BWS (cBWS), atypical BWS or isolated lateralised overgrowth (aBWS+ILO) and overgrowth syndromes identified via WES.ResultsTen patients, one classified as aBWS and nine as cBWS, showed causative gene variants for Simpson-Golabi-Behmel syndrome (five patients), Sotos syndrome (two), Imagawa-Matsumoto syndrome (one), glycosylphosphatidylinositol biosynthesis defect 11 (one) or 8q duplication/9p deletion (one). BWSp scores did not distinguish between cBWS and other overgrowth syndromes. Birth weight and height in other overgrowth syndromes were significantly larger than in aBWS+ILO and cBWS, with varying intergroup frequencies of clinical features.ConclusionMolecularly negative BWSp encapsulates other syndromes, and considering both WES and clinical features may facilitate accurate diagnosis.
Funder
Young and Middle-aged Scientific and Technological Innovation Talent Support Project of Shenyang City
Liaoning Province Medical-Industrial Crossover Joint Fund
The Second Clinical College of China Medical University Educational Innovation (Open) Project
Japan Society for the Promotion of Science
345 Talent Project
Japan Agency for Medical Research and Development
Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics
Ministry of Health, Labour and Welfare
Scientific and Technological Innovation Talent Support Project of Shenyang City
Takeda Science Foundation
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