A homozygous splicing mutation in ELAC2 suggests phenotypic variability including intellectual disability with minimal cardiac involvement

Abstract

BackgroundThe group of ELAC2-related encephalomyopathies is a recent addition to the rapidly growing heterogeneous mitochondrial disorders.ResultsWe 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-016-0526-8) contains supplementary material, which is available to authorized users.

Mutations inELAC2associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3′‐end processing

“…All remaining patients of the analyzed cohort harbored novel missense ( n = 10), frameshift ( n = 2) or splice site ( n = 4) mutations (Figure and Table ). P2 harbored a novel consensus splice variant (c.1423 + 1 G>A) in the same splice site as previously reported patients of Pakistani origin (c.1423 + 2 T>A; Akawi et al, ). All these variants were extremely rare or not reported in public databases and predicted damaging using Polyphen‐2 (Adzhubei et al, ).…”

“…However, one case (P2), who harbors a c.1423 + 1 G>A ELAC2 variant affecting a consensus splice site (in compound heterozygosity with a truncating c.2009del; p.Cys670Serfs*14 variant), was the only patient in our cohort who did not present with cardiomyopathy. Interestingly, five patients from a consanguineous Arabic family harboring another homozygous ELAC2 mutation involving the same consensus splice site (homozygous c.1423 + 2 T>A) predominantly presented with intellectual disability without prominent cardiac involvement (Akawi et al, ). Both of these variants affect the same consensus donor sequence (exon 15), and it would be interesting to further explore the features of pre‐mRNA splice site selection of this particular donor site in cardiac tissue.…”

“…One of these, the variant coding for p.Phe154Leu, was also recently reported as prevalent in consanguineous Arabian families affected by infantile cardiomyopathy (Shinwari et al, ). In contrast, a homozygous splice site mutation (c.1423 + 2 T>A) in ELAC2 has been associated with developmental delay and minimal cardiac involvement in a consanguineous Pakistani family (Akawi et al, ). A single heterozygous ELAC2 variant coding for p.Pro32Arg was recently reported in an infant presenting with encephalopathy, epilepsy, and growth and developmental retardation (Kim, Kim, Lee, & Cheon, ).…”

“…The patient also developed Tetralogy of Fallot, however, without evidence of cardiomyopathy. Since the transmission pattern of ELAC2-related disease in the families reported previously (Akawi et al, 2016;Haack et al, 2013;Shinwari et al, 2017) was consistent with recessive inheritance, the relevance of this variant remains unclear. Finally, an Assyrian patient presenting with chorea, psychosis, acanthocytosis, and displaying a prolonged survival has been identified to carry compound heterozygous ELAC2 variants coding for p.Gly132Arg and p.Ser347Phe.…”

Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3’-end processing

“…One of these, the variant coding for p.Phe154Leu, was also recently reported as prevalent in consanguineous Arabian families affected by infantile cardiomyopathy [16]. In contrast, a homozygous splice site mutation (c.1423+2T>A) in ELAC2 has been associated with developmental delay and minimal cardiac involvement in a consanguineous Pakistani family [17]. Finally, a single heterozygous ELAC2 variant coding for p.Pro32Arg was recently reported in an infant presenting with encephalopathy, epilepsy, and growth and developmental retardation [18].…”