A novel de novo truncating variant in a Hungarian patient with CTNNB1 neurodevelopmental disorder.

Purpose: We aimed to elucidate the underlying disease in a Hungarian family, with only one affected family member, a 16-year-old male Hungarian patient, who developed global developmental delay, cognitive impairment, behavioral problems, short stature, intermittent headaches, recurrent dizziness, strabismus, hypermetropia, complex movement disorder and partial pituitary dysfunction. After years of detailed clinical investigations and careful pediatric care, the exact diagnosis of the patient and the cause of the disease was still unknown. Methods: We aimed to perform whole exome sequencing (WES) in order to investigate whether the affected patient is suffering from a rare monogenic disease. Results: Using WES, we identified a novel, de novo frameshift variant (c.1902dupG, p.Ala636SerfsTer12) of the catenin beta-1 (CTNNB1) gene. Assessment of the novel CTNNB1 variant suggested that it is a likely pathogenic one and raised the diagnosis of CTNNB1 neurodevelopmental disorder (OMIM 615,075). Conclusions: Our manuscript may contribute to the better understanding of the genetic background of the recently discovered CTNNB1 neurodevelopmental disorder and raise awareness among clinicians and geneticists. The affected Hungarian family demonstrates that based on the results of the clinical workup is difficult to establish the diagnosis and high-throughput genetic screening may help to solve these complex cases. What is known: • CTNNB1 neurodevelopmental disorder is featured by two main symptoms: cognitive impairment and exudative vitreoretinopathy. Additional manifestations include truncal hypotonia, peripheral spasticity, dystonia, behavioral problems, microcephaly, refractive errors, strabismus, intrauterine growth restriction, feeding difficulties, and scoliosis. • CTNNB1 neurodevelopmental disorder develops as a consequence of de novo germline loss-of-function pathogenic variants of the catenin beta-1 (CTNNB1) gene. The CTNNB1 protein is a component of adherens junctions and contributes to the establishment and maintenance of epithelial layers and adhesion between cells. CTNNB1 is also involved in the WNT signaling pathway regulating several biological processes including cell proliferation or cell fate determination. What is new • The c.1902dupG, p.Ala636SerfsTer12 is a novel heterozygous frameshift variant in the 12th exon of the CTNNB1 gene. Based on the ACMG variant classification guideline, this variant could be classified as a likely pathogenic one, since null variants (frameshift) in gene CTNNB1 are predicted to cause loss-of-function, which is a known mechanism of the disease. • The c.1902dupG, p.Ala636SerfsTer12 variant affects the 10th amino acid of the last 40 amino acid–long ARM domain of the encoded protein, and after 12 amino acids it results in the formation of a premature termination codon, which may either cause a nonsense-mediated RNA decay or a severely mutated protein with a largely truncated ARM domain and a missing 3' end of the protein. ARM domains may mediate the interaction of CTNNB1 with its ligands; therefore, we hypothesized that the identified novel variant has a severe loss-of-function impact on protein functions. [ABSTRACT FROM AUTHOR]