Abstract
Heterozygous intragenic loss-of-function mutations of ERF, encoding an ETS transcription factor, were previously reported to cause a novel craniosynostosis syndrome, suggesting that ERF is haploinsufficient. We describe six families harboring heterozygous deletionsincluding, or near to, ERF, of which four were characterized by whole-genome sequencing and two by chromosomal microarray. Based on the severity of associated intellectual disability (ID), we identify three categories of ERF-associated deletions. The smallest (32 kb) and only inherited deletion included two additional centromeric genes and was not associated with ID. Three larger deletions (264-314 kb) that included at least five further centromeric genes were associated with moderate ID, suggesting that deletion of one or more of these five genes causes ID. The individual with the most severe ID had a more telomerically extending deletion, including CIC, a known ID gene. Children found to harbor ERF deletions should be referred for craniofacial assessment, to exclude occult raised intracranial pressure.
Highlights
We describe the identification of six smaller (32–314 kb) deletions at the ERF locus, four of them characterized by whole‐genome sequencing (WGS) at base‐pair resolution, and two by array comparative genomic hybridization
As part of a clinical genetics investigation, a further de novo deletion including ERF was identified by array comparative genomic hybridization (aCGH) in Subject 4 (Table 1 and Figure 1a); following informed consent, WGS was carried out using the proband's DNA to characterize the breakpoints, demonstrating a 265 kb deletion (Figure S1D)
Toward a more comprehensive analysis of genotype–phenotype correlations, additional cases harboring heterozygous deletions around ERF that had been identified by aCGH were retrieved from the DECIPHER database (Firth et al, 2009) (Subject 5, ~265 kb; Subject 6, ~51 kb) (Figure 1a), and the respective clinicians/scientists were contacted
Summary
This revealed an apparent heterozygous 314 kb deletion, including ERF, in a proband with syndromic multisuture synostosis (Subject 1; Table 1; Figures 1a and S1A); the deletion was detectable in his clinically unaffected father in a mosaic state; quantification by comparing the numbers of reads within, compared with outside the deletion on chromosome 19 (Figure S1E), indicated that approximately 75% of blood cells harbored the deletion. Previous array CGH in this patient had not detected the chromosome 19 deletion; two other imbalances (one inherited from each parent) had been reported (Table 1; see Supplementary Case Reports for further description of each subject).
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