Deletion of REXO1L1 locus in a patient with malabsorption syndrome, growth retardation, and dysmorphic features: a novel recognizable microdeletion syndrome?

Abstract

BackgroundCopy number variations (CNVs) can contribute to genetic variation among individuals and/or have a significant influence in causing diseases. Many studies consider new CNVs’ effects on protein family evolution giving rise to gene duplicates or losses. “Unsuccessful” duplicates that remain in the genome as pseudogenes often exhibit functional roles. So, changes in gene and pseudogene number may contribute to development or act as susceptibility alleles of diseases.Case presentationWe report a de novo heterozygous 271 Kb microdeletion at 8q21.2 region which includes the family of REXO1L genes and pseudogenes in a young man affected by global development delay, progeroid signs, and gastrointestinal anomalies. Molecular and cellular analysis showed that the REXO1L1 gene hemizygosity in a patient’s fibroblasts induces genetic instability and increased apoptosis after treatment with different DNA damage-induced agents.ConclusionsThe present results support the hypothesis that low copy gene number within REXO1L1 cluster could play a significant role in this complex clinical and cellular phenotype.

Copy number variation of the REXO1L1 gene cluster; euchromatic deletion variant or susceptibility factor?

“…1 These simple~2:1 ratios suggest that the extreme high and low ends of the otherwise continuous REXO1L1 copy number distribution might be due to large reciprocal duplications and deletions of the REXO1L1 cluster that are cytogenetically visible as EVs (Supplementary Figure 2). As gains of RP11-96G1 were far more frequent than losses in the healthy populations analysed by Redon et al, 8 D'Apice et al 2 may have found a rare benign euchromatic deletion variant of 8q21.2 rather than a novel microdeletion. If not due to dosage, any possible effects of a deletion would require alternative mechanisms such as enhancer adoption by genes flanking the REXO1L1 cluster 7 or the release of other genes from epigenetic control.…”

“…If the patient studied by D'Apice et al 2 had half the lowest observed diploid copy number of 97, the remaining copies on the homologous chromosome 8 would be expected to compensate for the loss of the cluster from the chromosome 8 carrying the deletion. Using the less accurate method of real-time quantitative PCR 7 with calibrator plasmids as controls, D'Apice et al 2 reported diploid copy numbers that were in an order of magnitude lower with 16-24 diploid copies in 60 controls and 8 in their deleted patient.…”

“…3 D'Apice et al 2 used loss of hybridisation signal from a single bacterial artificial chromosome (BAC) to imply that the whole REXO1L1 cluster had been deleted but their BAC (RP11-96G1) only partially overlaps this region (Supplementary Figure 1) and residual copies of the 12 kb repeat might not have been detected using FISH. BAC RP11-96G1 is also one of the commonest benign CNVs found using BAC aCGH 4 and subject to loss, gain and inversion in the database of genomic variants.…”

“…7 As immunological reaction against the human REXO1L1 gene product is a marker of HCV infection, a role for REXO1L1 copy number in HCV infection was suggested. 1 D'Apice et al 2 found increased genetic instability and apoptosis in their patient fibroblasts after treatment with DNA-damaging agents and, as REXO1L1 is a 3′-5' exonuclease member of the DEDD superfamily which might control HBV and RNA virus infections, speculated that low REXO1L1 copy number might predispose and high numbers protect against viral infection.…”

“…1 In contrast, it has been proposed that de novo heterozygous deletion of the REXO1L1 cluster in a single patient is responsible for a new microdeletion syndrome including dysmorphic features, cleft palate, incomplete spina bifida, dyspraxia, global developmental delay, growth retardation and gastrointestinal malabsorption. 2 Here we argue that determining the possible clinical significance of large-scale CNV requires the application of accurate quantitative techniques to both individual families and large cohorts of affected and unaffected individuals.…”