Case Report: A de novo CTNNB1 Nonsense Mutation Associated With Neurodevelopmental Disorder, Retinal Detachment, Polydactyly

Abstract

CTNNB1 gene mutation was firstly reported related to intellectual disability in 2012, to explore the clinical phenotype and genotype characteristics of CTNNB1 mutation, we collected and analyzed the clinical data of a child with a neurodevelopmental disorder caused by a mutation of CTNNB1. The child had dysmorphic features, microcephaly, hypotonia, polydactyly, retinal detachment, and neurodevelopmental disorder, with a de novo mutation of CTNNB1 c.1603C > T, p.R535X. The patient was diagnosed as Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV) and was given rehabilitation training. After 4 months of rehabilitation training, she improved in gross motor function. We found that CTNNB1 mutation can cause neurodevelopmental disorder, which could be accompanied by retinal detachment and polydactyly. The retinal detachment had only been reported in two Asian patients, and we firstly reported the phenotype of polydactyly in the CTNNB1 mutation. This report not only helps to expand the clinical phenotype spectrum of the CTNNB1 gene mutation but also prompts a new insight into genetic diagnosis in patients with a neurodevelopmental disorder, retinal detachment, and polydactyly.

Exome Sequencing Reveals Novel Variants and Expands the Genetic Landscape for Congenital Microcephaly

“…Our study allows for the further delineation of phenotype of microcephalic patients, especially in the case of several genes in which mutations were identified in more than one patient. Our findings seem to confirm the existence of sex bias in the neurodevelopmental disorder with spastic diplegia and visual defects caused by variants in CTNNB1 , as all our patients are females [ 33 ]. With recent reports of eight additional patients, five of whom were male, and four patients from our study the sex ratio in this disorder is approximately 63% females to 37% males [ 34 , 35 ].…”

The extended clinical and genetic spectrum of CTNNB1-related neurodevelopmental disorder

“…The association between seizure and developmental delay or intellectual disability has been well established, and one study reported the prevalence of epilepsy in global developmental delay patients as high as 56% (31-33). Among the 69 patients with CTNNB1-related neurodevelopmental disorder we reviewed, none of them had apparent seizure history or abnormal electroencephalogram results (1,(3)(4)(5)(6)(7)(8)(9)(10)(11)(13)(14)(15). In addition, while structural brain abnormalities have been detected in around 30% of developmental delay patients (34, 35), there were only three patients (5.4%) showing remarkable brain abnormalities among 56 patients.…”

“…In addition, none of our patients had any seizure history during follow-up. As shown in Figure 2A, we reviewed a total of 69 patients with CTNNB1-related neurodevelopmental disorder reported in the literature, including our patients, and found that only one (1.4%) and three (5.4%) patients had seizure history and brain abnormalities, respectively (1,(3)(4)(5)(6)(7)(8)(9)(10)(11)(13)(14)(15). The patient with seizure history was suspected as having absence seizure in early childhood.…”

“…Interestingly, all three patients with autistic features were female in this study. Autistic features have been reported frequently (1,(3)(4)(5)(6)(7)(8)(9)(10)(11)(13)(14)(15), shown in around 30% of patients with CTNNB1-related neurodevelopmental disorder (Figure 2A). Consistent with our study, autistic features were significantly more frequent in female patients (54.3%, 19 out of 35) than in male patients (5.9%, 2 out of 34) with a P-value = 1.3 × 10 −5 by Fisher's exact test (Figure 2B).…”

“…This is an autosomal dominant disorder, mostly caused by loss-offunction mutations resulting in disruption of normal molecular function. Although several studies had reported additional cases of NEDSDV, their clinical presentations are different from each other (1,(3)(4)(5)(6)(7)(8)(9)(10)(11).…”