A de novo CTNNB1 Novel Splice Variant in an Adult Female with Severe Intellectual Disability

• Main Authors: Verhoeven WMA, Egger JIM, Jongbloed RE, Meijer van Putten M, de Bruin-van Zandwijk M, Zwemer AS, Pfundt R, Willemsen MH
• Format: Article
• Language: English
• Published: Dove Medical Press 2020-10-01
• Series: International Medical Case Reports Journal
• Subjects: heterozygous splice site variant; ctnnb1; nedsdv; autism; intellectual disability; distal spastic tetraparesis
• Online Access: https://www.dovepress.com/a-de-novo-ctnnb1-novel-splice-variant-in-an-adult-female-with-severe-i-peer-reviewed-article-IMCRJ

Willem MA Verhoeven,1– 3 Jos IM Egger,3– 5 Rob E Jongbloed,6 Marloes Meijer van Putten,6 Marieke de Bruin-van Zandwijk,7 Anne-Suus Zwemer,7 Rolph Pfundt,4,8 Marjolein H Willemsen8 1Department of Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands; 2Centre for Consultation and Expertise, Utrecht, the Netherlands; 3Vincent van Gogh Centre of Excellence for Neuropsychiatry, Venray, the Netherlands; 4Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands; 5Stevig, Specialized and Forensic Care for People with Intellectual Disabilities, Dichterbij, Oostrum, the Netherlands; 6Raphael Institute Scorlewald, Centre for People with Intellectual Disabilities, Schoorl, the Netherlands; 7ASVZ, Centre for People with Intellectual Disabilities, Sliedrecht, the Netherlands; 8Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the NetherlandsCorrespondence: Willem MA VerhoevenVincent Van Gogh Centre of Excellence for Neuropsychiatry, Stationsweg 46, 5803 AC, Venray, the NetherlandsTel [phone]Fax [phone]Email [e-mail]: The catenin beta-1 (CTNNB1) gene, encoding a sub-unit of the cadherin/catenin protein complex that is involved in the Wnt signalling pathway important for proper interneuron development, is considered to be causative for the rare autosomal dominant mental retardation syndrome, formerly called MRD19 but later renamed neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV). Its main characteristics are moderate to severe intellectual disability (ID), disruptive autistic behaviours, microcephaly, absent or limited speech, facial dysmorphisms, peripheral hypertonia/spasticity, motor delay and visual defects. So far, 35 patients have been reported with a de novo loss-of-function variant in CTNNB1. In two other patients, a deletion comprising the full gene was found. Four out of the 37 patients were of adult age (range: 27– 51 years), while the majority was infant or adolescent (range: 0– 20 years). Here, a 32-year-old severely intellectually disabled female patient is described in whom exome sequencing disclosed a de novo heterozygous splice site variant in the CTNNB1 gene [Chr3(GRCh37): g.41267064G>T; NM_001904.3: 23. c.734+1G>T; r. spl?]. Somatic investigation disclosed significant microcephaly and minor facial dysmorphisms. Neurological examination demonstrated severe kyphoscoliosis, distal spastic tetraparesis, especially of the legs with increased tendon reflexes and bilateral Babinski sign, resulting in severely impaired walking capability with a broad-based gait. Apart from strabismus, no ophthalmological abnormalities were found. Here, the reported variant in the CTNNB1 gene was not published earlier nor is included in the international databases. This specific variant is considered to be causative for the severe ID, autism and the somato-neurological phenotype of the patient and corresponds with a diagnosis of NEDSDV.Keywords: heterozygous splice site variant, CTNNB1, NEDSDV, autism, intellectual disability, distal spastic tetraparesis