(Epi)genotype-phenotype correlations of Beckwith-Wiedemann syndrome in China

Beckwith-Wiedemann syndrome (BWS) is a rare congenital overgrowth disorder characterized by various clinical features and (epi)genetic defects. The study aims to elaborate on the clinical features, (epi)genetic errors, and (epi)genotype-phenotype correlations in Beckwith-Wiedemann syndrome (BWS) in the past ten years.

A retrospective study was designed on patients with BWS from July 2013 to October 2022 from Children's Hospital of Fudan University. Clinical data, including demographics, clinical features, and molecular testing results, were collected, and the (epi)genotype-phenotype correlations were systematically analyzed. The clinical diagnosis standard and scoring were referred to the international experts' consensus (2018 version). Patients suspected or clinically diagnosed with BWS underwent MS-MLPA testing for (epi)genotyping.

242 BWS patients (119 males and 123 females) aged from 0 to 69 months were in the study. The most common clinical features were macroglossia (96.3%), followed by lateralized overgrowth (63.6%) and ear creases/pits (50.4%). Two hepatoblastomas and one Wilms tumor were found in the cohort. The average BWS clinical score was 5.74 ± 1.73 points. The (epi)genotyping results identified the three most common (epi)genetics errors: IC2 LOM, pUPD11, and IC1 GOM accounted for 52.3%, 19.2%, and 9.3%, respectively, of all patients who underwent MS-MLPA testing. A characteristic pattern was found in the three different molecular groups. Macroglossia, exomphalos, and facial naevus simplex were more common in IC2 LOM than in IC1 GOM and pUPD11 (p < 0.05). Lateralized overgrowth was more common in pUPD11 than in IC2 LOM and IC1 GOM group (p < 0.001). Nephromegaly or hepatomegaly was more common in IC1 GOM than in IC2 LOM and pUPD11 (p < 0.001).

The (epi)genotype-phenotype correlations delineate different phenotypic profiles. Molecular testing and standardization of BWS diagnostic procedures are of great significance for the early diagnosis and surveillance of BWS.