Abstract
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.
Highlights
Intellectual disability (ID) is a neurodevelopmental disorder affecting 1% of the population worldwide
Via linkage analysis followed by whole genome sequencing, the authors uncovered a frameshift variant in exon 2 of CXorf56 (NM_022101.3c.159_160insTA) that leads to nonsensemediated decay (NMD) with reduced mRNA expression in the affected individuals
By Whole exome sequencing (WES) and combined database analyses, we identified two novel disease-causing variants in the CXorf56 gene in three unrelated families with nine cases of X-linked, nonsyndromic ID
Summary
Intellectual disability (ID) is a neurodevelopmental disorder affecting 1% of the population worldwide. Verkerk et al [5], described CXorf as a new candidate gene for ID in a large family with mild X-linked ID (four males and one female). These five patients presented with nonsyndromic ID and behavioral issues. No other patients with CXorf causative variants were identified among 413 unrelated individuals with ID without specific diagnosis [5]. This article describes the clinical and genetic features of three unrelated families, expanding the related phenotype and confirming the causative role of CXorf variants in a nonsyndromic form of ID. The androgen receptor (AR) was studied by fluorescent PCR in the presence or absence of the methylation sensitive enzyme HpaII as previously described [8]
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