Missense variants in <i>CTNNB1</i> can be associated with vitreoretinopathy—Seven new cases of <i>CTNNB1</i>‐associated neurodevelopmental disorder including a previously unreported retinal phenotype

Rossetti, Linda; Bekheirnia, Mir Reza; Lewis, Andrea M.; Mefford, Heather C; Golden‐Grant, Katie; Tarczy-Hornoch, Kristina; Briere, Lauren C.; Sweetser, David A.; Walker, Melissa; Kravets, Elijah; Stevenson, David A.; Bruenner, Georgette; Sebastian, Jessica; Knapo, Julia; Rosenfeld, Jill A.; Marcogliese, Paul C.; Wangler, Michael F.

doi:10.1002/mgg3.1542

Cited by 20 publications

(33 citation statements)

References 24 publications

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“…While all our patients with mutations in the CTNNB1 gene had a similar phenotype with microcephaly (−2.3 to −4.3 SD), DD and abnormal muscle tone, patient S87 presented with uncommon finding of delayed myelination as evidenced on brain MRI studies. Three patients were found with strabismus, which supports the observation that ocular abnormalities are frequent findings in patients with CTNNB1 -associated neurodevelopmental disorder [ 34 ].…”

Section: Discussionsupporting

confidence: 80%

“…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 ]. In one case (S87) we identified a frameshift variant NM_001904.4: c.1665del: p.(Thr556HisfsTer14) that had been reported only once in the literature, while the other three (S42, S63, S145) were harboring more common pathogenic variants already reported in the ClinVar database.…”

Section: Discussionmentioning

confidence: 50%

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

Dawidziuk¹,

Gambin²,

Bukowska‐Olech

et al. 2021

Genes

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Congenital microcephaly causes smaller than average head circumference relative to age, sex and ethnicity and is most usually associated with a variety of neurodevelopmental disorders. The underlying etiology is highly heterogeneous and can be either environmental or genetic. Disruption of any one of multiple biological processes, such as those underlying neurogenesis, cell cycle and division, DNA repair or transcription regulation, can result in microcephaly. This etiological heterogeneity manifests in a clinical variability and presents a major diagnostic and therapeutic challenge, leaving an unacceptably large proportion of over half of microcephaly patients without molecular diagnosis. To elucidate the clinical and genetic landscapes of congenital microcephaly, we sequenced the exomes of 191 clinically diagnosed patients with microcephaly as one of the features. We established a molecular basis for microcephaly in 71 patients (37%), and detected novel variants in five high confidence candidate genes previously unassociated with this condition. We report a large number of patients with mutations in tubulin-related genes in our cohort as well as higher incidence of pathogenic mutations in MCPH genes. Our study expands the phenotypic and genetic landscape of microcephaly, facilitating differential clinical diagnoses for disorders associated with most commonly disrupted genes in our cohort.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 50%

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

Dawidziuk¹,

Gambin²,

Bukowska‐Olech

et al. 2021

Genes

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“…After evaluating CTNNA1 mutations in the FEVR population, no potential pathogenic mutations have been found in our FEVR cohort (Zhu et al, 2021 ). Another CTNNB1 was reported to cause FEVR, but it was not included in our detection panel list (Dixon et al, 2016 ; Rossetti et al, 2021 ). In the future, we will further improve and update the range of genes covered by our panel.…”

Section: Discussionmentioning

confidence: 99%

Mutation spectrum in a cohort with familial exudative vitreoretinopathy

Han

et al. 2022

Molec Gen & Gen Med

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To expand the mutation spectrum of patients with familial exudative vitreoretinopathy (FEVR) disease. Participants: 74 probands (53 families and 21 sporadic probands) with familial exudative vitreoretinopathy (FEVR) disease and their available family members (n = 188) were recruited for sequencing. Methods: Panel-based targeted screening was performed on all subjects. Before sanger sequencing, variants of LRP5, NDP, FZD4, TSPAN12, ZNF408, KIF11, RCBTB1, JAG1, and CTNNA1 genes were verified by a series of bioinformatics tools and genotype-phenotype co-segregation analysis.Results: 40.54% (30/74) of the probands were sighted to possess at least one etiological mutation of the nine FEVR-causative genes. The etiological mutation detection rate was 37.74% (20/53) in family-attainable probands while 47.62% (10/21) in sporadic cases. The diagnosis rate of patients in the early-onset subgroup (≤5 years old, 45.4%) is higher than that of the children or adolescence-onset subgroup (6-16 years old, 42.1%) and the late-onset subgroup (≥17 years old, 39.4%). A total of 36 etiological mutations were identified in this study, comprising 26 novel mutations and 10 reported mutations. LRP5 was the most prevalent mutant gene among the 36 mutation types with a percentage of 41.67% (15/36). Followed by FZD4 (10/36, 27.78%), TSPAN12 (5/36, 13.89%), NDP (4/36, 11.11%), KIF11 (1/36, 2.78%), and RCBTB1 (1/36, 2.78%). Among these mutations, 63.89% (23/36) were missense mutations, 25.00% (9/36) were frameshift mutations, 5.56% (2/36) were splicing mutations, 5.56% (2/36) were nonsense mutations. Moreover, the clinical pathogenicity of these variants was defined according to American College of Medical Genetics (ACMG) and genomics guidelines: 41.67% (15/36) were likely

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“…Pathogenic variants in the CTNNB1 gene have been associated with non‐syndromic exudative vitreoretinopathy (OMIM #617572) and NEDSDV (#615075). This latter is characterized by the association of intellectual disability, microcephaly, limited‐to‐absent speech, spasticity in the lower extremities, and possibly extrapyramidal (bradykinesia, choreiform movements, and dystonia) (Rossetti et al, 2021; Wirth et al, 2020) or cerebellar (intention tremor) (Rossetti et al, 2021) signs. Failure‐to‐thrive and self‐injurious behaviors have also been documented.…”

Section: Discussionmentioning

confidence: 99%

“…Failure‐to‐thrive and self‐injurious behaviors have also been documented. The ocular phenotype ranges from exudative vitreoretinopathy to strabismus, hyperopia, astigmatism, and retinal detachment, without clear genotype–phenotype correlations (Rossetti et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Novel CTNNB1 variant leading to neurodevelopmental disorder with spastic diplegia and visual defects plus peripheral neuropathy: A case report

Spagnoli

Salerno

Rizzi

et al. 2022

American J of Med Genetics Pt A

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Pathogenic variants in the β1-catenin (CTNNB1) gene have been identified in patients with various diseases, including syndromic intellectual disability, autism spectrum disorder, familial exudative vitreoretinopathy, and neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV). We report on the clinical, genetic, neuroimaging, and neurophysiological data of a 15-year-old patient with complex hereditary spastic paraplegias with exotropia, dyskinesia, and cerebellar signs and a so-far unreported demyelinating (mainly sensory) polyneuropathy in her lower limbs. She carries the novel, de novo, likely pathogenic heterozygous c.603_605delinsAATA, p.(Met202Ilefs*6) frameshift variant in the CTNNB1 gene. Although peripheral neuropathy was not previously associated with NEDSDV, in light of the role of β1-catenin as a junction protein in the peripheral as well as in the central nervous system documented in experimental studies, it might represent a causally linked and underreported finding to be further explored.

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Missense variants in CTNNB1 can be associated with vitreoretinopathy—Seven new cases of CTNNB1‐associated neurodevelopmental disorder including a previously unreported retinal phenotype

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 20 publications

References 24 publications

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

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

Mutation spectrum in a cohort with familial exudative vitreoretinopathy

Novel CTNNB1 variant leading to neurodevelopmental disorder with spastic diplegia and visual defects plus peripheral neuropathy: A case report

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