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

• Published in: American journal of medical genetics. Part A Vol. 185; no. 7; pp. 1972 - 1980
• Main Authors: Duan, Ruizhi, Saadi, Nebal Waill, Grochowski, Christopher M., Bhadila, Ghalia, Faridoun, Afnan, Mitani, Tadahiro, Du, Haowei, Fatih, Jawid M., Jhangiani, Shalini N., Akdemir, Zeynep C., Gibbs, Richard A., Pehlivan, Davut, Posey, Jennifer E., Marafi, Dana, Lupski, James R.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-07-2021; Wiley Subscription Services, Inc
• Subjects: Alu Elements - genetics; Alu/Alu‐mediated rearrangement; Amelogenesis imperfecta; Child, Preschool; Chromosomes, Human, Pair 17 - genetics; Citric acid; CNV alleles; Copy number; Dentition; developmental and epileptic encephalopathy; DNA Copy Number Variations - genetics; Encephalopathy; Epilepsy; Epilepsy, Generalized - genetics; Epilepsy, Generalized - pathology; Female; Fever; Gene deletion; Gene rearrangement; Genomic instability; Homozygote; homozygous deletion; Humans; Infant; Intellectual disabilities; Intellectual Disability - genetics; Intellectual Disability - pathology; Male; Mutation - genetics; Neonates; Pedigree; Sequence analysis; Sequence Deletion - genetics; SLC13A5; Symporters - genetics; Teeth; Whole Exome Sequencing; Iraq; developmental and epileptic encephalopathy; Alu/Alu-mediated rearrangement; SLC13A5; genomic instability; homozygous deletion; CNV alleles
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.62192

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.