Correlation between Phenotype and Genotype in CTNNB1 Syndrome: A Systematic Review of the Literature

Abstract

The CTNNB1 Syndrome is a rare neurodevelopmental disorder associated with developmental delay, intellectual disability, and delayed or absent speech. The aim of the present study is to systematically review the available data on the prevalence of clinical manifestations and to evaluate the correlation between phenotype and genotype in published cases of patients with CTNNB1 Syndrome. Studies were identified by systematic searches of four major databases. Information was collected on patients’ genetic mutations, prenatal and neonatal problems, head circumference, muscle tone, EEG and MRI results, dysmorphic features, eye abnormalities, early development, language and comprehension, behavioral characteristics, and additional clinical problems. In addition, the mutations were classified into five groups according to the severity of symptoms. The study showed wide genotypic and phenotypic variability in patients with CTNNB1 Syndrome. The most common moderate-severe phenotype manifested in facial dysmorphisms, microcephaly, various motor disabilities, language and cognitive impairments, and behavioral abnormalities (e.g., autistic-like or aggressive behavior). Nonsense and missense mutations occurring in exons 14 and 15 were classified in the normal clinical outcome category/group because they had presented an otherwise normal phenotype, except for eye abnormalities. A milder phenotype was also observed with missense and nonsense mutations in exon 13. The autosomal dominant CTNNB1 Syndrome encompasses a wide spectrum of clinical features, ranging from normal to severe. While mutations cannot be more generally categorized by location, it is generally observed that the C-terminal protein region (exons 13, 14, 15) correlates with a milder phenotype.

Familial Exudative Vitreoretinopathy and Systemic Abnormalities in Patients With CTNNB1 Mutations

“… 11 , 24 , 25 , 36 These findings indicate that there is no mutation hotspot in CTNNB1 specifically associated with the FEVR phenotype. Furthermore, a study demonstrated that patients with nonsense and missense mutations in exons 14 and 15 had only ocular abnormalities, 39 whereas those with frameshift mutations had severe disease phenotypes. Panagiotou indicated that non-syndromic FEVR is a milder phenotype caused by mutations in the CTD of β-catenin.…”

Congenital heart defects in CTNNB1 syndrome: Raising clinical awareness

“…Six articles reporting CHDs in CTNNB1 patients were found in the literature, 3,[13][14][15][16][17] four being included in the paper by Kayumi et al 3,[13][14][15][16] Two main clinical reviews about CTNNB1syndrome were published to date and considered in the present report. 3,6 In the paper by Kayumi et al, 3 120/404 genetically diagnosed individuals having an adequate phenotype description were revised in detail. Accordingly, 10/120 (8.3%) cases had a CHD diagnosis (Table 1).…”

“…When considering only the more severe cardiac malformations (APV with IVS, ToF, AVC), the prevalence was higher than 15% (3/19). Six articles reporting CHDs in CTNNB1 patients were found in the literature, 3,13–17 four being included in the paper by Kayumi et al 3,13–16 Two main clinical reviews about CTNNB1 ‐syndrome were published to date and considered in the present report 3,6 . In the paper by Kayumi et al, 3 120/404 genetically diagnosed individuals having an adequate phenotype description were revised in detail.…”

“…CTNNB1 encodes β‐catenin, an integral part of the cadherin/catenin complex connected to the activation of the Wnt signaling pathway. B‐catenin acts both as a transcriptional effector of Wnt signaling, and as structural protein mediating intracellular cell connections and adhesion 6 …”

“…Such observations testify to a polyhedric action of CTNNB1 both in development and cell physiology. CTNNB1 comprises 16 exons, with exons 2–15 (2346 bp) encoding the central, mainly active part of the protein consisting of 781 amino acids related to the armadillo structural proteins 6 . CTNNB1 encodes β‐catenin, an integral part of the cadherin/catenin complex connected to the activation of the Wnt signaling pathway.…”