Copy-Number Gains of HUWE1 Due to Replication- and Recombination-Based Rearrangements

Abstract

We previously reported on nonrecurrent overlapping duplications at Xp11.22 in individuals with nonsyndromic intellectual disability (ID) harboring HSD17B10, HUWE1, and the microRNAs miR-98 and let-7f-2 in the smallest region of overlap. Here, we describe six additional individuals with nonsyndromic ID and overlapping microduplications that segregate in the families. High-resolution mapping of the 12 copy-number gains reduced the minimal duplicated region to the HUWE1 locus only. Consequently, increased mRNA levels were detected for HUWE1, but not HSD17B10. Marker and SNP analysis, together with identification of two de novo events, suggested a paternally derived intrachromosomal duplication event. In four independent families, we report on a polymorphic 70 kb recurrent copy-number gain, which harbors part of HUWE1 (exon 28 to 3' untranslated region), including miR-98 and let-7f-2. Our findings thus demonstrate that HUWE1 is the only remaining dosage-sensitive gene associated with the ID phenotype. Junction and in silico analysis of breakpoint regions demonstrated simple microhomology-mediated rearrangements suggestive of replication-based duplication events. Intriguingly, in a single family, the duplication was generated through nonallelic homologous recombination (NAHR) with the use of HUWE1-flanking imperfect low-copy repeats, which drive this infrequent NAHR event. The recurrent partial HUWE1 copy-number gain was also generated through NAHR, but here, the homologous sequences used were identified as TcMAR-Tigger DNA elements, a template that has not yet been reported for NAHR. In summary, we showed that an increased dosage of HUWE1 causes nonsyndromic ID and demonstrated that the Xp11.22 region is prone to recombination- and replication-based rearrangements.

A novel splicing mutation in the IQSEC2 gene that modulates the phenotype severity in a family with intellectual disability

“…Regarding clinical features in females, these are less severe due to the presence of a normal X-chromosome, which has been previously described. 9,11 I2 II2 II4 II5 II6 III1 Olson et al 30 Gandomi et al 31 Tran Mau-Them et al 5 Tran Mau-Them et al 5 Gilissen et al 32 33 Moey et al 34 Moey et al 34 Moey et al 34 Moey et al 34 Froyen et al 35 Froyen et al 35 Froyen et al 35 Gedeon et al 36 Froyen et al 37 Froyen et al 37 Froyen et al 37 Froyen et al 37 Patient 1 IQSEC2 splicing mutation and ID I Madrigal et al…”

“…2,5,[30][31][32][33][34][35][36][37][38][39][40][41] Tables 1 and 2 summarize the clinical manifestations of patients with deletions or duplications in the IQSEC2 gene and Table 3 summarizes the clinical manifestations of patients with point variants in this gene. It has been proposed that non-synonymous variants in this gene are responsible for non-syndromic ID, whereas truncating variants may generate a more severe neurodevelopmental phenotype related to the loss of function of IQSEC2.…”

HUWE1 mutation explains phenotypic severity in a case of familial idiopathic intellectual disability

“…Patients with a duplication involving HUWE1 are usually described to have a nonsyndromic mild to moderate ID [13,15]. Few affected individuals are reported to have minor dysmorphic features, but a consistent pattern among all duplication carriers is lacking.…”

“…HUWE1 is a dosage-sensitive gene and copy number variations of this gene have recurrently been linked to ID [13,15]. Here, we would like to emphasize the importance of pathological point mutations in the gene.…”

A novel in-frame deletion affecting the BAR domain of OPHN1 in a family with intellectual disability and hippocampal alterations

“…13 The slides were scanned on an Agilent DNA Microarray Scanner (Agilent Technologies Inc.) and images were extracted using the Feature Extraction software v9.1.3.1 (Agilent Technologies Inc.). The QC report was carefully examined to ensure proper hybridization and grid placement.…”