Novel clinical and genetic insight into CXorf56-associated intellectual disability.
Authors
Rocha, Maria EugeniaSilveira, Tainá Regina Damaceno
Sasaki, Erina
Sás, Daíse Moreno
Lourenço, Charles Marques
Kandaswamy, Krishna K
Beetz, Christian
Rolfs, Arndt
Bauer, Peter
Reardon, Willie
Bertoli-Avella, Aida M
Issue Date
2019-12-10Keywords
INTELLECTUAL DISABILITIESGENETIC FACTORS
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European journal of human genetics : EJHGDOI
10.1038/s41431-019-0558-3PubMed ID
31822863Abstract
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.Item Type
ArticleOther
Language
enEISSN
1476-5438ae974a485f413a2113503eed53cd6c53
10.1038/s41431-019-0558-3
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