A novel homozygous SLC13A5 whole‐gene deletion generated by Alu/Alu‐mediated rearrangement in an Iraqi family with epileptic encephalopathy

Abstract

Biallelic loss‐of‐function (LoF) of SLC13A5 (solute carrier family 13, member 5) induced deficiency in sodium/citrate transporter (NaCT) causes autosomal recessive developmental epileptic encephalopathy 25 with hypoplastic amelogenesis imperfecta (DEE25; MIM #615905). Many pathogenic SLC13A5 single nucleotide variants (SNVs) and small indels have been described; however, no cases with copy number variants (CNVs) have been sufficiently investigated. We describe a consanguineous Iraqi family harboring an 88.5 kb homozygous deletion including SLC13A5 in Chr17p13.1. The three affected male siblings exhibit neonatal‐onset epilepsy with fever‐sensitivity, recurrent status epilepticus, global developmental delay/intellectual disability (GDD/ID), and other variable neurological findings as shared phenotypical features of DEE25. Two of the three affected subjects exhibit hypoplastic amelogenesis imperfecta (AI), while the proband shows no evidence of dental abnormalities or AI at 2 years of age with apparently unaffected primary dentition. Characterization of the genomic architecture at this locus revealed evidence for genomic instability generated by an Alu/Alu‐mediated rearrangement; confirmed by break‐point junction Sanger sequencing. This multiplex family from a distinct population elucidates the phenotypic consequence of complete LoF of SLC13A5 and illustrates the importance of read‐depth‐based CNV detection in comprehensive exome sequencing analysis to solve cases that otherwise remain molecularly unsolved.

Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder

“…The study was conducted according to the guidelines of the Declaration of Helsinki. Protocol #21-CITI-128, SLC13A5 Deficiency patient study has been determined by the Pearl IRB to be Exempt according to FDA 21 CFR 56.104 and 45CFR46.104(b) (8).…”

“…The SLC13A5 gene and its transcribed protein, NaCT, are highly expressed in the liver at levels thought to be several-fold higher than in the brain [4]. However, the loss of citrate transport, presumably throughout the body, has only been associated with neurologic and dental abnormalities in humans [5][6][7][8][9]. Citrate levels were elevated in the CSF and plasma of the few patients tested [10].…”

Centers for Mendelian Genomics: A decade of facilitating gene discovery

“…A special week-long Genomics course is incorporated into the medical school curriculum at Johns Hopkins and will be developed into an on-line training module. The CMGs have enabled researchers and clinicians investigating rare Mendelian diseases in the US and around the world to access gene discovery techniques, including those in countries where access to research opportunities is limited, such as the Democratic Republic of the Congo, 26 South Africa, Kenya, Egypt, 27, 28 Iraq, 29 Chile 30, 31 , Turkey, 32–34 and Lithuania. For some, this has involved training opportunities within a CMG-affiliated laboratory, while for others learning happened through collaborative meetings to discuss analysis results on teleconferences.…”

Centers for Mendelian Genomics: A decade of facilitating gene discovery

“…The CMGs provided educational and networking opportunities by hosting in-person courses attended by over 300 analysts and researchers, including the Mendelian Data Analysis Workshop (University of Washington), Interpreting Genomes for Rare Disease (Broad), and McKusick Short Course in Human and Mammalian Genetics (Baylor-Hopkins). The CMGs have enabled researchers and clinicians investigating rare Mendelian diseases around the world to access gene discovery techniques, including those in countries where access to research opportunities is limited, such as the Democratic Republic of the Congo, 27 South Africa, Kenya, Egypt, 28,29 Iraq, 30 Chile, 31,32 Turkey, [33][34][35] and Lithuania. For some, this has involved training opportunities within a CMG-affiliated laboratory, whereas for others, learning happened through collaborative meetings to discuss analysis results on teleconferences.…”