A Novel Missense Mutation in SRD5A3 Causes Congenital Disorder of Glycosylation Type I (Cerebello-Ocular Syndrome)

Abstract

A consanguineous Qatari family having an autosomal recessive disorder characterized by severe mental retardation, cerebellar vermis hypoplasia, retinal degeneration, optic nerve atrophy, ataxic gait, and seizures was studied for identification of the offending gene and mutation. Homozygosity mapping identified an 11.4 Mb critical interval at 4q12 to q13.2 that would contain the gene responsible for the disorder. Ten positional candidate genes were screened for pathogenic mutations, but none were identified. Next-generation exome sequencing in one affected individual identified a novel SRD5A3 missense mutation c.T744G/p.F248L, which was subsequently confirmed by Sanger sequencing, suggesting a congenital disorder of glycosylation type IQ defect. Isoelectric focusing of serum transferrin showed a type I pattern indicative of an N-glycan assembly defect. This is a novel pathogenic mutation and the first SRD5A3 missense mutation as all others are protein-truncating mutations.

SRD5A3‐CDG: 3D structure modeling, clinical spectrum, and computer‐based dysmorphic facial recognition

“…Severe intellectual disability was observed in all SRD5A3‐CDG patients whereas lower normal intelligence was exceptional (Kara et al, 2014). Epilepsy which is a main concern in other forms of CDG was uncommon in SRD5A3‐CDG cases and was noticed in 7/38 patients with absence, generalized tonic–clonic seizures and west syndrome (Al‐Sarraj et al, 2014; Gupta et al, 2018; Wheeler et al, 2016). It is worth notably to mention that none of our patients had seizures at all.…”

“…We have customized a recognition system based on deep learning of residual CNN Architecture (ResNet) to extract the most relevant facial features from frontal 2D images of SRD5A3‐CDG cases. In addition to our patient's photos, all images from published SRD5A3‐CDG cases were used for this purpose (Al‐Gazali, Hertecant, Algawi, El Teraifi, & Dattani, 2008; Al‐Sarraj et al, 2014; Bastaki et al, 2018; Chang, He, & Lam, 2018; Gupta et al, 2018; Kahrizi et al, 2009; Kasapkara et al, 2012; Medrano et al, 2019; Eva Morava et al, 2010; Taylor et al, 2017; Tuysuz et al, 2015; Wheeler et al, 2016). Given the limited number of available photos in our database, data augmentation approach was adopted where each image was randomly augmented through rotation with a range of −10 to 10°.…”

“…Cantagrel et al (2010) identified the first SRD5A3 homozygous pathogenic variant in a large Emirati family. Subsequently, 17 SRD5A3‐CDG‐causing variants were identified in 26 families (Al‐Sarraj et al, 2014; Bastaki et al, 2018; Gründahl et al, 2012; Gupta, Verma, Kabra, Bijarnia‐Mahay, & Ganapathy, 2018; Kahrizi et al, 2009, 2011; Kara, Ayhan, Gökçay, Başboğaoğlu, & Tolun, 2014; Kasapkara et al, 2012; Kousal et al, 2019; Medrano et al, 2019; E. Morava et al, 2008; Eva Morava et al, 2010; Najmabadi et al, 2011; Taylor et al, 2017; Tuysuz et al, 2015; Wheeler et al, 2016). Most of those variants are either of nonsense or frameshift.…”