A homozygous splicing mutation in ELAC2 suggests phenotypic variability including intellectual disability with minimal cardiac involvement. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Akawi, Nadia; Ben-Salem, Salma; Hertecant, Jozef; John, Anne; Pramathan, Thachillath; Kizhakkedath, Praseetha; Ali, Bassam; Al-Gazali, Lihadh
• Is Part Of: Orphanet journal of rare diseases. Volume 11:Issue 1(2016)
• Page Start: 1
• Page End: 9
• Publication Date: 2016-12
• Subjects: ELAC2 -- Mitochondrial disorder -- 5′ end unprocessed mt-RNAs -- Splice site mutation -- Intellectual disability -- Respiratory chain complex I (RCCI) deficiency; Rare diseases -- Periodicals; Genetic disorders -- Periodicals; Orphan drugs -- Periodicals; 616
• DOI: 10.1186/s13023-016-0526-8
• Languages: English
• ISSNs: 1750-1172

Abstract

Abstract Background The group ofELAC2 -related encephalomyopathies is a recent addition to the rapidly growing heterogeneous mitochondrial disorders. Results We describe a highly inbred consanguineous Pakistani family with multiple affected children in 2 branches exhibiting moderately severe global developmental delay. Using homozygosity mapping, we mapped the phenotype in this family to a single locus on chromosome 17. In addition, whole-exome sequencing identified a homozygous splicing mutation (c.1423 + 2 T > A) inELAC2 gene that disrupted the canonical donor splice site of intron 15 of all known isoforms. A noticeable reduction in ELAC2 expression was observed in patients compared to controls. In addition, patients exhibited significantly increased levels of 5′ end unprocessed mt-RNAs compared to the control fibroblast cells. Conclusions The only three previously reported families with defects inELAC2 gene exhibited infantile hypertrophic cardiomyopathy and complex I deficiency. In contrast, our patients exhibited intellectual disability as the main feature with minimal cardiac involvement. Therefore our findings expand the phenotypic spectrum ofELAC2 - associated disorders illustrating clinical heterogeneity of mutations in this gene. In addition, ELAC2 mutations should be considered when evaluating patient with mainly intellectual disability phenotypes.