Abstract
Mutations in early B cell factor 3 (EBF3) were recently described in patients with a neurodevelopmental disorder (NDD) that includes developmental delay/intellectual disability, ataxia, hypotonia, speech impairment, strabismus, genitourinary abnormalities, and mild facial dysmorphisms. Several large 10q terminal and interstitial deletions affecting many genes and including EBF3 have been described in the literature. However, small deletions (<1 MB) affecting almost exclusively EBF3 are not commonly reported. We performed array comparative genomic hybridization (aCGH) (Agilent 180K) and quantitative PCR analysis in a female patient with intellectual disability. A clinical comparison between our patient and overlapping cases reported in the literature was also made. The patient carries a de novo 600 Kb deletion at 10q26.3 affecting the MGMT, EBF3, and GLRX genes. The patient has severe intellectual disability, language impairment, conductive hearing loss, hypotonia, vision alterations, triangular face, short stature, and behavior problems. This presentation overlaps that reported for patients carrying EBF3 heterozygous point mutations, as well as literature reports of patients carrying large 10qter deletions. Our results and the literature review suggest that EBF3 haploinsufficiency is a key contributor to the common aspects of the phenotype presented by patients bearing point mutations and indels in this gene, given that deletions affecting the entire gene (alone or in addition to other genes) are causative of a similar syndrome, including intellectual disability (ID) with associated neurological symptoms and particular facial dysmorphisms.
Highlights
Intellectual disability (ID) affects nearly 1–2% of the population and is the most common neurodevelopmental disorder (NDD)
Genome-wide analysis techniques currently used for investigation of etiology often lead to the identification of very rare almost private variants, the collection of patients with alterations in the same gene being a crucial aspect of the definition of a new clinical entity
The intellectual impairment, central nervous system and genitourinary anomalies observed in patient with both mutations in early B cell factor 3 (EBF3) and ARX might reflect the contribution of both proteins to the same molecular and cellular processes (Chao et al, 2017)
Summary
Intellectual disability (ID) affects nearly 1–2% of the population and is the most common neurodevelopmental disorder (NDD). Genome-wide analysis techniques currently used for investigation of etiology often lead to the identification of very rare almost private variants, the collection of patients with alterations in the same gene being a crucial aspect of the definition of a new clinical entity. Earlier this year, patients harboring mutations in EBF3 gene have been described, presenting a neurodevelopmental syndrome including ID, ataxia, hypotonia, mild facial dysmorphisms, and genitourinary abnormalities (OMIM 617330) (Chao et al, 2017; Harms et al, 2017; Sleven et al, 2017). The exact pathogenic mechanisms of EBF3 mutations is not yet fully elucidated but the type of variants described so far [copy number variations (CNVs), missense, nonsense, and splice site altering] suggest that haploinsufficiency, gain of function, and dominant negative are possible pathogenic mechanisms for the variants described (Chao et al, 2017; Sleven et al, 2017)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
