Deletion of ERF and CIC causes abnormal skull morphology and global developmental delay

• Published in: Cold Spring Harbor molecular case studies 2021-06, Vol.7 (3), p.a005991
• Main Authors: Singh, Ram, Cohen, Ana S A, Poulton, Cathryn, Hjortshøj, Tina Duelund, Akahira-Azuma, Moe, Mendiratta, Geetu, Khan, Wahab A, Azmanov, Dimitar N, Woodward, Karen J, Kirchhoff, Maria, Shi, Lisong, Edelmann, Lisa, Baynam, Gareth, Scott, Stuart A, Jabs, Ethylin Wang
• Format: Article
• Language: English
• Subjects: Adolescent; Cell differentiation; Cell proliferation; Child; Child, Preschool; Chromosome 19; Cranial sutures; Craniosynostosis; Deletion; Developmental Disabilities - genetics; Disabilities; DNA Copy Number Variations; DNA microarrays; Ets-2 protein; Female; Gene Deletion; Genes; Genetic Association Studies; Genetic Predisposition to Disease - genetics; Genetic screening; Genetic Testing; Haploinsufficiency; Heterozygote; Humans; Intellectual disabilities; Intellectual Disability - genetics; Macrocephaly; Male; Membrane Proteins - genetics; Morphology; Neurodevelopmental disorders; Neurodevelopmental Disorders - genetics; Phenotype; Phenotypes; Proto-Oncogene Protein c-ets-2 - genetics; Repressor Proteins - genetics; Research Report; Sequences; Signal transduction; Skull - abnormalities; Skull - growth & development; Skull - pathology; Sodium-Potassium-Exchanging ATPase - genetics; Transcription Factors - genetics
• ISSN: 2373-2865; 2373-2873; 2373-2873
• DOI: 10.1101/mcs.a005991

The ETS2 repressor factor (ERF) is a transcription factor in the RAS-MEK-ERK signal transduction cascade that regulates cell proliferation and differentiation, and pathogenic sequence variants in the gene cause variable craniosynostosis inherited in an autosomal dominant pattern. The reported variants are largely loss-of-function, implying haploinsufficiency as a primary disease mechanism; however, gene deletions have not been reported previously. Here we describe three probands with macrocephaly, craniofacial dysmorphology, and global developmental delay. Clinical genetic testing for fragile X and other relevant sequencing panels were negative; however, chromosomal microarray identified heterozygous deletions (63.7-583.2 kb) on Chromosome 19q13.2 in each proband that together included five genes associated with Mendelian diseases ( , , , , and ). Parental testing indicated that the aberrations were apparently de novo in two of the probands and were inherited in the one proband with the smallest deletion. Deletion of is consistent with the reported loss-of-function variants, prompting clinical copy-number-variant classifications of likely pathogenic. Moreover, the recent characterization of heterozygous loss-of-function sequence variants as a cause of intellectual disability and neurodevelopmental disorders inherited in an autosomal dominant pattern is also consistent with the developmental delays and intellectual disabilities identified among the two probands with deletions. Taken together, this case series adds to the previously reported patients with and/or sequence variants and supports haploinsufficiency of both genes as a mechanism for a variable syndromic cranial phenotype with developmental delays and intellectual disability inherited in an autosomal dominant pattern.