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. 2022 Oct 19;23(20):12564.
doi: 10.3390/ijms232012564.

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

Špela Miroševič  1 , Shivang Khandelwal  2 , Petra Sušjan  3 , Nina Žakelj  4   5 , David Gosar  5 , Vida Forstnerič  3 , Duško Lainšček  3 , Roman Jerala  3   6 , Damjan Osredkar  5   7
Affiliations

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

Špela Miroševič et al. Int J Mol Sci. .

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.

Keywords: beta-catenin; eye movement disorders; hypotonia; intellectual disability; loss of function mutation; microcephaly.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Flow diagram of the systematic review.
Figure 2
Figure 2
A 2-D bar chart representing clinical manifestations categorized based on the primary and secondary criteria.
Figure 3
Figure 3
A column chart representing percentages of facial dysmorphism, eye abnormalities, speech development, and behavioral problems found in reported CTNNB1 patients.
Figure 4
Figure 4
Schematic representation of the β catenin coding region; exon structure in correspondence to encoded protein domains.
Figure 5
Figure 5
Three-dimensional model of human β-catenin protein generated by I-Tasser. Annotation was performed according to Huber et al., 1997. The model shows the N-terminus (red), armadillo repeat arms 1–12, and a helix and unstructured region of the C-terminal domain.
Figure 6
Figure 6
Distribution of mutation causative of CTNNB1 Syndrome throughout the protein coding region in accordance with exon location and subsequent encoded protein domains. Most mutations reside within the armadillo repeat region of the protein. Asterisk indicates a nonsense mutation and number in parenthesis indicates the number of cases reported the mutation.
Figure 7
Figure 7
Distribution of CTNNB1 mutation types.
Figure 8
Figure 8
Number of mutations detected in individual intron or exon regions or whole gene deletions of analyzed samples in this study (n = 84).
See this image and copyright information in PMC

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