Clinical and genetic characteristics of Cornelia de Lange syndrome in pediatric patients

ABSTRACT Importance Cornelia de Lange syndrome (CdLS) is a rare genetic disorder characterized by a spectrum of developmental and physical anomalies. Understanding the clinical and genetic landscape of CdLS in pediatric patients is crucial for improving diagnosis and management. Objective To investigate the clinical and genetic characteristics of 19 pediatric patients with CdLS in China, with a focus on identifying the association between genetic variants and clinical severity. Methods We performed whole exome sequencing on 19 patients with CdLS and compared their clinical characteristics based on the presence of null variants. Results Among the 19 patients, 16 (84.2%) showed global developmental delays and 14 (73.7%) experienced prenatal growth retardation and short stature. Craniofacial anomalies–short noses and anteverted nares were observed in 94.7% (18/19) of patients. Small hands and/or feet were present in 16 patients, skin manifestations (hirsutism or mottled skin) in six, and hearing loss in four. Genetic testing identified 19 variants in NIPBL (78.9%, 15/19), SMC1A (10.5%, 2/19), and RAD21 (10.5%, 2/19), including 13 novel variants. NIPBL null variants correlated significantly with more severe growth impairments (P = 0.016) and microcephaly (P = 0.004). Although complete protein function loss often correlated with more severe clinical presentations, no significant difference in clinical scoring was observed (P = 0.600). Three patients treated with recombinant human growth hormone showed heterogeneous responses. Interpretation This study highlights the clinical heterogeneity of CdLS and suggests a potential link between specific genetic variants and disease severity. These findings warrant further research to optimize treatments and better understand the functional impact of these genetic variants.