Loss-of-function variants in ERF are associated with a Noonan syndrome-like phenotype with or without craniosynostosis

2024-08-06 Tue
ERF gene Noonan syndrome craniosynostosis developmental delay facial features
Correlation between Erf Gene Loss-of-Function Variants and Noonan Syndrome-like Phenotype - With or Without CraniosynostosisResearch BackgroundMembers of the ETS transcription factor family play a crucial role in RAS-MAPK signal transduction, regulating the expression of “early response” genes and other functionally related genes. Among them, ETS2 repressor factor (Erf) is a transcriptional regulator responsible for modulating RAS-MAPK signaling. Extensive truncating variants of the Erf gene have been associated with various craniosynostosis syndromes and the extremely rare Chitayat syndrome. Researchers here discovered a case resembling Noonan syndrome (NS), suggesting that Erf gene loss-of-function variants are related to NS phenotypes. This study aims to further explore the relationship between Erf gene loss-of-function variants and Noonan syndrome-like phenotypes.
Research SourceThe author team of this paper includes Maria Lisa Dentici, Marcello Niceta, and other researchers from Bambino Gesù Children’s Hospital in Rome, along with other collaborators. The paper was published in the European Journal of Human Genetics in 2024.
Research MethodsStudy SubjectsA total of 26 individuals from 15 unrelated families carrying different heterozygous Erf gene variants were collected, all showing phenotypes similar to NS.
Research WorkflowThis study included clinical evaluation of cases, genomic analysis, and related data processing. Particular attention was paid to subjects showing global developmental and/or language delay, as well as shared facial features.
Experimental MethodsExome sequencing (ES), clinical exome sequencing (CES), and RAS-pathology targeted sequencing were used for genomic analysis of patients. Variants were classified according to ACMG guidelines.
Research ResultsThe main results indicate that individuals carrying heterozygous loss-of-function variants in the Erf gene exhibit NS-like phenotypes.
Common facial features among these individuals include absolute/relative macrocephaly, high forehead, hypertelorism, ptosis, broad nasal bridge, and low-set/posteriorly rotated ears.
Two-thirds of the individuals had height below the 3rd percentile, while no subjects showed typical NS cardiac involvement.
The causative variants were primarily nonsense and frameshift mutations, supporting the Erf gene haploinsufficiency hypothesis.
Conclusion and SignificanceThe study suggests that phenotypes caused by heterozygous loss-of-function variants in the Erf gene may be a “Rasopathy” with phenotypes similar to NS, with or without craniosynostosis. This helps to further understand the contribution of MAPK signaling diversity to molecular cycling.
Research HighlightsThe most important finding of this study is the association between Erf gene loss-of-function variants and NS-like phenotypes, as well as the role of the Erf gene in development and other neurodevelopmental disorders.