Novel clinical and genetic insight into CXorf56-associated intellectual disability
| Autor: | Tainá Regina Damaceno Silveira, Aida M. Bertoli-Avella, Arndt Rolfs, Daíse Moreno Sás, Willie Reardon, Peter Bauer, Charles Marques Lourenço, Maria Eugenia Rocha, Erina Sasaki, Christian Beetz, Krishna Kumar Kandaswamy |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male Genetics of the nervous system Developmental Disabilities Nerve Tissue Proteins Neurological disorder Disease Article 03 medical and health sciences Loss of Function Mutation X Chromosome Inactivation Intellectual Disability Genetics research Intellectual disability Genetics medicine Humans Family history Genetics (clinical) Exome sequencing 030304 developmental biology Hemizygote 0303 health sciences Genetic heterogeneity business.industry Neurodevelopmental disorders 030305 genetics & heredity Nuclear Proteins Middle Aged medicine.disease Molecular diagnostics Pedigree 3. Good health Phenotype Female business |
| Zdroj: | European Journal of Human Genetics |
| ISSN: | 1476-5438 1018-4813 |
| DOI: | 10.1038/s41431-019-0558-3 |
| Popis: | Intellectual disability (ID) is one of most frequent reasons for genetic consultation. The complex molecular anatomy of ID ranges from complete chromosomal imbalances to single nucleotide variant changes occurring de novo, with thousands of genes identified. This extreme genetic heterogeneity challenges the molecular diagnosis, which mostly requires a genomic approach. CXorf56 is largely uncharacterized and was recently proposed as a candidate ID gene based on findings in a single Dutch family. Here, we describe nine cases (six males and three females) from three unrelated families. Exome sequencing and combined database analyses, identified family-specific CXorf56 variants (NM_022101.3:c.498_503del, p.(Glu167_Glu168del) and c.303_304delCTinsACCC, p.(Phe101Leufs*20)) that segregated with the ID phenotype. These variants are presumably leading to loss-of-function, which is the proposed disease mechanism. Clinically, CXorf56-related disease is a slowly progressive neurological disorder. The phenotype is more severe in hemizygote males, but might also manifests in heterozygote females, which showed skewed X-inactivation patterns in blood. Male patients might present previously unreported neurological features such as epilepsy, abnormal gait, tremor, and clonus, which extends the clinical spectrum of the disorder. In conclusion, we confirm the causative role of variants in CXorf56 for an X-linked form of intellectual disability with additional neurological features. The gene should be considered for molecular diagnostics of patients with ID, specifically when family history is suggestive of X-linked inheritance. Further work is needed to understand the role of this gene in neurodevelopment and intellectual disability. |
| Databáze: | OpenAIRE |
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