Linda Z Rossetti1, Mir Reza Bekheirnia1, Andrea M Lewis1, Heather C Mefford2, Katie Golden-Grant2, Kristina Tarczy-Hornoch3, Lauren C Briere4, David A Sweetser4, Melissa A Walker5, Elijah Kravets6, David A Stevenson6, Georgette Bruenner7, Jessica Sebastian8, Julia Knapo8, Jill A Rosenfeld1, Paul C Marcogliese1,9, Michael F Wangler1,9. 1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. 2. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA. 3. Department of Ophthalmology, University of Washington, Seattle, WA, USA. 4. Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. 5. Department of Neurology, Division of Neurogenetics, Child Neurology, Massachusetts General Hospital, Boston, MA, USA. 6. Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA, USA. 7. Division of Medical Genetics, Department of Pediatrics, Cohen Children's Medical Center, Queens, NY, USA. 8. Division of Medical Genetics, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. 9. Jan and Dan Duncan Texas Children's Neurological Research Institute, Houston, TX, USA.
Abstract
BACKGROUND: CTNNB1 (MIM 116806) encodes beta-catenin, an adherens junction protein that supports the integrity between layers of epithelial tissue and mediates intercellular signaling. Recently, various heterozygous germline variants in CTNNB1 have been associated with human disease, including neurodevelopmental disorder with spastic diplegia and visual defects (MIM 615075) as well as isolated familial exudative vitreoretinopathy without developmental delays or other organ system involvement (MIM 617572). From over 40 previously reported patients with CTNNB1-related neurodevelopmental disorder, many have had ocular anomalies including strabismus, hyperopia, and astigmatism. More recently, multiple reports indicate that these abnormalities are associated with the presence of vitreoretinopathy. METHODS: We gathered a cohort of three patients with CTNNB1-related neurodevelopmental disorder, recruited from both our own clinic and referred from outside providers. We then searched for a clinical database comprised of over 12,000 exome sequencing studies to identify and recruit four additional patients. RESULTS: Here, we report seven new cases of CTNNB1-related neurodevelopmental disorder, all harboring de novo variants, six of which were previously unreported. All patients but one presented with a spectrum of ocular abnormalities and one patient, who was found to carry a missense variant in CTNNB1, had notable vitreoretinopathy. CONCLUSIONS: Our findings suggest ophthalmologic screening should be performed in all patients with CTNNB1 variants.
BACKGROUND:CTNNB1 (MIM 116806) encodes beta-catenin, an adherens junction protein that supports the integrity between layers of epithelial tissue and mediates intercellular signaling. Recently, various heterozygous germline variants in CTNNB1 have been associated with human disease, including neurodevelopmental disorder with spastic diplegia and visual defects (MIM 615075) as well as isolated familial exudative vitreoretinopathy without developmental delays or other organ system involvement (MIM 617572). From over 40 previously reported patients with CTNNB1-related neurodevelopmental disorder, many have had ocular anomalies including strabismus, hyperopia, and astigmatism. More recently, multiple reports indicate that these abnormalities are associated with the presence of vitreoretinopathy. METHODS: We gathered a cohort of three patients with CTNNB1-related neurodevelopmental disorder, recruited from both our own clinic and referred from outside providers. We then searched for a clinical database comprised of over 12,000 exome sequencing studies to identify and recruit four additional patients. RESULTS: Here, we report seven new cases of CTNNB1-related neurodevelopmental disorder, all harboring de novo variants, six of which were previously unreported. All patients but one presented with a spectrum of ocular abnormalities and one patient, who was found to carry a missense variant in CTNNB1, had notable vitreoretinopathy. CONCLUSIONS: Our findings suggest ophthalmologic screening should be performed in all patients with CTNNB1 variants.
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