title: A homozygous splicing mutation in ELAC2 suggests phenotypic variability including intellectual disability with minimal cardiac involvement.
abstract: The group of ELAC2-related encephalomyopathies is a recent addition to the rapidly growing heterogeneous mitochondrial disorders.
  
  
  
  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) in ELAC2 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.
  
  
  
  The only three previously reported families with defects in ELAC2 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 of ELAC2- 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.
authors: Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.|Present address: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors: Nadia A
authors: NA
authors: Akawi
authors: Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
authors: Salma
authors: S
authors: Ben-Salem
authors: Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.|Department of Paediatrics, Tawam Hospital, Al-Ain, United Arab Emirates.
authors: Jozef
authors: J
authors: Hertecant
authors: Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
authors: Anne
authors: A
authors: John
authors: Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al-Ain, United Arab Emirates.
authors: Thachillath
authors: T
authors: Pramathan
authors: Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
authors: Praseetha
authors: P
authors: Kizhakkedath
authors: Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
authors: Bassam R
authors: BR
authors: Ali
authors: Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al-Ain, United Arab Emirates. algazali@hotmail.com.
authors: Lihadh
authors: L
authors: Al-Gazali
mesh_terms: D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; C421605:ELAC2 protein, human; D009363:Neoplasm Proteins; D022821:RNA Splice Sites
keywords: 5′ end unprocessed mt-RNAs; ELAC2; Intellectual disability; Mitochondrial disorder; Respiratory chain complex I (RCCI) deficiency; Splice site mutation