Dissection of contiguous gene effects for deletions around ERF on chromosome 19

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 deletions including, 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.

Evaluating the performance of a clinical genome sequencing program for diagnosis of rare genetic disease, seen through the lens of craniosynostosis

“…Three researcher-only RIPDs (Cases 20-22) were untiered SV/CNV, comprising a complex inversion involving TWIST1 (case 20), deletion including ERF (case 21) 31 and duplication involving the HOXC gene cluster (case 22), each of which was detected by the CGG using overlapping Canvas 24 and Manta 32 calls ( Table 1 , Table S4 , and Supplementary Information). Whilst analysis of CNVs using the Canvas caller is now incorporated into the GE/GMC pipeline, cases analysed before January 2019 did not have tiered CNVs.…”

“…Identification of several of the variants has led to new molecular diagnostic insights, as illustrated by publications on SMAD6 18 , SOX6 28 and ERF ; 31 additionally, the duplication of the HOXC cluster (case 22) gives rise to an apparently novel combination of phenotypes. Many other discoveries from the combined clinical-research approach have been reported in other disease domains of 100kGP.…”

DECIPHER: Supporting the interpretation and sharing of rare disease phenotype‐linked variant data to advance diagnosis and research

“…The data set also enables the extension of phenotypes for new syndromes to be uncovered (e.g., Witteveen-Kolk syndrome a SIN3Arelated disorder; Balasubramanian et al, 2021), in addition to wellestablished syndromes (e.g., ALG13 congenital disorder of glycosylation; Alsharhan et al, 2021). It also permits the understanding of contiguous gene effects, such as that around ERF which causes a novel craniosynostosis syndrome with varying degrees of intellectual disability (Calpena et al, 2021). | 693 Kaplanis et al (2020).…”