Aberrant splicing induced by the most common EPG5 mutation in an individual with Vici syndrome.

Abstract

Sir, Recently, a study describing the clinical and genetic data of 50 patients (30 families) with Vici syndrome (OMIM 242840) was published in Brain (Byrne et al. , 2016 b ). Vici syndrome is a severe autosomal recessive condition recently found to be caused by mutations in the EPG5 gene (NG_042838.1) (Cullup et al. , 2013). Principal features of Vici syndrome include neurological sequelae (agenesis of the corpus callosum, profound developmental delay, and progressive microcephaly), neonatal cataracts, hypopigmentation involving both skin and hair, progressive dilated or hypertrophic cardiomyopathy, and both B and T cell-related immunodeficiency (Byrne et al. , 2016 a , b ). The most common mutation identified in Vici syndrome patients is EPG5 NM_020964.2; c.1007A>G p.Gln336Arg. Based on the two large cohorts of patients recently studied (Cullup et al. , 2013; Byrne et al. , 2016 b ), this mutation accounts for >10% (9/86) of mutations. Ancestry data from previous studies show that this mutation may be associated with Ashkenazi descent (Byrne et al. , 2016 a , b ). This variant was not detected in whole genome sequencing data from our cohort of 4456 unrelated adults seen at the Inova Translational Medicine Institute (Bodian et al. , 2014, 2016). This variant is seen with a frequency of 3.129 ×10−5 in the European (non-Finnish) population of Exome Aggregation Consortium (ExAC) and has thus far never been reported in other ExAC populations (ExAC, 2016; http://exac.broadinstitute.org). The EGP5 c.1007A>G mutation has been suggested to affect splicing through in silico prediction models, though multiple predictions are contradictory [Human Splicing Finder (Desmet et al. , 2009; http://www.umd.be/HSF3/HSF.html: −6%) and NNSPLICE (Reese et al. , 1997; http://www.fruitfly.org/seq_tools/splice.html: −100%)]. Likewise, in silico predictions of the missense mutation are in disagreement with regards to its pathogenicity [PolyPhen-2 (Adzhubei et al. , …