Whole exome sequencing revealed a novel homozygous variant in the DGKE catalytic domain: a case report of familial hemol
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(2020) 21:169
CASE REPORT
Open Access
Whole exome sequencing revealed a novel homozygous variant in the DGKE catalytic domain: a case report of familial hemolytic uremic syndrome Soraya Gholizad-kolveiri1, Nakysa Hooman2, Rasoul Alizadeh1, Rozita Hoseini2, Hasan Otukesh2, Saeed Talebi1* and Mansoureh Akouchekian1*
Abstract Background: Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by microangiopathic hemolytic anemia caused by small vessel thrombosis, thrombocytopenia, and renal failure. The common cause of aHUS is a dysregulation in the alternative complement pathway. Mutations in none complement genes such as diacylglycerol kinase epsilon (DGKE) can also result in this syndrome. Case presentation: Here, we report on a 19-year-old female with the clinical diagnosis of aHUS, who has unaffected consanguineous parents and an older sibling who was deceased from aHUS when she was seven months old. We performed whole exome sequencing (WES) followed by evaluation of detected variants for functional significance, using several online prediction tools. Next, in order to confirm the detected pathogenic variant in proband and segregation analysis in her family, Sanger sequencing was done. The novel variant was analyzed in terms of its impact on the protein 3-dimensional structure by computational structural modeling. The results revealed that the proband carried a novel homozygous missense variant in DGKE located in exon 6 of the gene (NM_003647.3, c.942C > G [p.Asn314Lys]), and in silico analysis anticipated it as damaging. Protein computational study confirmed the influence of potential pathogenic variant on structural stability and protein function. Conclusion: We suggest that some variations in the catalytic domain of DGKE like p.Asn314Lys which can cause alterations in secondary and 3-D structure of protein, might lead to aHUS. Keywords: Hemolytic-uremic syndrome, DGKE, Protein computational analysis, Whole exome sequencing
Background Thrombotic microangiopathies (TMA) are a spectrum of disorders which are characterized by hemolytic anemia, low platelets, and organ damage [1]. Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are two types of TMA * Correspondence: [email protected]; [email protected] 1 Department of Medical Genetics and Molecular Biology, school of medicine, Iran University of Medical Sciences, P.O.Box: 1449614525, Tehran, Iran Full list of author information is available at the end of the article
which can be differentiated by measuring ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type1 motif, member13 or von Willebrand factor-cleaving protease) activity, which in case of TTP, is less than 10% [2, 3]. HUS is a rare disease characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and kidney failure. The most common cause of HUS in children is bacterial Shiga-like toxin produced e.g. by Escherichia coli. (E. coli) O: 157 and O: 104 serotypes [4]
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