Delineation of a less than 200 kb minimal deleted region for cardiac malformations on chromosome 7p22

Abstract

Cardiac malformations are commonly seen in individuals with terminal and interstitial deletions involving chromosome band 7p22. Although these malformations represent a significant cause of morbidity, the dosage-sensitive gene(s) that underlie these defects have yet to be identified. In this report, we describe a 16-month-old male with tetralogy of Fallot, bilateral second branchial arch remnants, and mild dysmorphic features. Array comparative genomic hybridization analysis revealed a less than 400 kb interstitial deletion on chromosome 7p22. The deletion was confirmed by real-time quantitative PCR and FISH analyses and was not detected in samples obtained from the child's parents. Molecular data from this de novo deletion, in combination with data from other isolated 7p deletions in the literature, can be used to define a less than 200 kb minimal deleted region for cardiac malformations on 7p22. This minimal deleted region spans all, or portions, of the coding regions of four known genes-MAD1L1, FTSJ2, NUDT1, and SNX8-and may include upstream regulatory elements of EIF3B. It is likely that one or more of these five genes, alone or in combination, plays an important, yet previously uncharacterized, role in cardiac development.

Variable developmental delays and characteristic facial features—A novel 7p22.3p22.2 microdeletion syndrome?

“…Comparison of the deleted regions found in the five patients and those reported by Gallego et al () and Richards et al (). The deletions of the study patients are represented by horizontal red bars while the deletions of the previously reported patients are represented by the horizontal green bars.…”

“…Specifically, the deletion reported by Gallego et al () overlapped with the common region, and the features reported for their patients were similar to those described herein; the proband had a prominent forehead and gross motor delay while the mother was noted to have similar facial dysmorphia (though not further described) and a mild degree of intellectual disability. Furthermore, the slightly telomeric deletion reported by Richards et al () does not include the 0.47 Mb smallest region of overlap nor was the patient reported to have similar dysmorphisms. Development was reported to be normal for their patient although he did have expressive language delay that was attributed to a history of recurrent ear infections.…”

“…(The breakpoints in hg19 are 2223474 and 2400436. Breakpoints were initially reported in hg18 by Richards et al () and were converted with the LiftOver tool in UCSC genome browser.) IQCE is not an OMIM gene.…”

“…His mother was found to carry the same deletion and was reported to have velopharyngeal insufficiency, a mild degree of intellectual disability and similar facial features. Richards, Zaveri, Wolf, Kang, and Scott () identified a 400 kb de novo deletion in a 16 month old boy with tetralogy of Fallot, a small coronary fistula, bilateral branchial remnants, and mild dysmorphic features. However, since these reports, there have been no further studies which describe patients with phenotypes attributed to a deletion within this region.…”

Rare Copy Number Variations in Adults with Tetralogy of Fallot Implicate Novel Risk Gene Pathways

“…Deletion of exons 5–20 in the BBS9 gene was recently reported to have a severe phenotype but this did not include a congenital cardiac defect [58]. The SNX8 gene, coding for sorting nexin 8, lies in the region of overlap of two previously reported 7p22.2 deletions with associated cardiac malformations, including one with TOF [59]. Although the role of SNX8 in development is unknown, sorting nexins have recently been implicated in ciliogenesis [60].…”