Genetic and clinical characteristics of 24 mainland Chinese patients with CTNNB1 loss‐of‐function variants

Abstract

Background: Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV) is a rare autosomal dominant syndrome, which is caused by the heterozygous germline loss-of-function variants in CTNNB1. Methods:We evaluated the clinical and genetic findings of 24 previously undescribed Chinese patients affected by CTNNB1-related disorders and explored the possible ethnicity-related phenotypic variations.Results: Twenty-one loss-of-function variants were identified within these 24 NEDSDV patients, including 14 novel CTNNB1 variants and 7 recurrent ones.The prominent clinical manifestations in our cohort are developmental delay/intellectual disability (100%), motor delay (100%), speech impairment (100%), dystonia (87.5%) and microcephaly (69.6%). The common facial dysmorphisms were consistent with previous reports, including wide nasal bridge (58.3%), bulbous nose (45.8%), long philtrum (45.8%) and thin upper lip (45.8%). In addition, 19 patients (79.2%) in our cohort had mild visual defects, while one affected individual (4.2%) had familial exudative vitreoretinopathy. Notably, we discovered that 20 patients (83.3%) exhibited various behavioral abnormalities, which is described in Chinese patients for the first time. Conclusion:We provided the largest known Chinese cohort with pathogenic CTNNB1 variants, which not only helps to expand the variant spectrum of CTNNB1 gene, but further delineates the typical phenotype of this disorder in Chinese population.

Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder

“…One large autism genetic study 38 identified CTNNB1 as a risk gene for autism. In our study, caregivers reported an autism diagnosis in 34%, which is higher than the previous studies 1,23 . The report of autism is supported by the results from the SCQ, which found that 33% of individuals had a risk of social communication impairment.…”

“…However, Kayumi et al 1 reported a higher frequency of microcephaly (79.8%) and lower frequency of dystonia (7.5%) and tethered cord (9.3%) compared to our study. The Yan et al series 23 reported a similar frequency of microcephaly (69.6%) and higher frequency of dystonia (87.5%) compared to our series.…”

“…In our study, caregivers reported an autism diagnosis in 34%, which is higher than the previous studies. 1,23 The report of autism is supported by the results from the SCQ, which found that 33% of individuals had a risk of social communication impairment. The higher frequency of autism in our study may be due to the method of data collection (specifically asking parents about autism) and the older age of our cohort.…”

CTNNB1 in neurodevelopmental disorders

“…A summary of recent publications related to the clinical phenotypes of patients with CTNNB1 mutation is presented in Table 1 . Multiple case reports have described the complicated abnormalities caused by different mutations in CTNNB1, including de novo nonsense mutation ( 47 ), haploinsufficiency ( 42 ), small de novo deletions ( 51 ), with behavioral anomalies, anxiety, impaired motor performance, cognitive impairment as major phenotypes.…”

A case report of familial exudative vitreoretinopathy in a Chinese Family

“…Dixon et al [22] rst reported the relationship between CTNNB1 haploid dysfunction and FEVR in 2016, a few cases have been reported, and the majority of patients are of Asian ethnicity [23,24] . In the study of Yan et al [25] , the clinical characteristics and genetic results of 24 patients with CTNNB1 pathogenic variation in the Chinese Mainland were reported. This is currently the largest case series of NEDSDV caused by CTNNB1 mutation in China.…”