Aicardi–Goutières syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis test
Aicardi–Goutières syndrome (AGS) is a rare genetic disorder characterised by progressive encephalopathy, involving microcephaly, intracranial calcification, and cerebrospinal fluid lymphocytosis with increased interferon-α concentrations. The clinical features of AGS overlap with fetal cerebral anom...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-11-01
|
| Series: | Frontiers in Pediatrics |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fped.2022.1048002/full |
| _version_ | 1828100459266572288 |
|---|---|
| author | Chikako Senju Chikako Senju Chikako Senju Chikako Senju Chikako Senju Yuka Nakazawa Yuka Nakazawa Yuka Nakazawa Mayuko Shimada Mayuko Shimada Mayuko Shimada Dai Iwata Dai Iwata Michiko Matsuse Katsumi Tanaka Yasushi Miyazaki Shinichi Moriwaki Norisato Mitsutake Tomoo Ogi Tomoo Ogi Tomoo Ogi |
| author_facet | Chikako Senju Chikako Senju Chikako Senju Chikako Senju Chikako Senju Yuka Nakazawa Yuka Nakazawa Yuka Nakazawa Mayuko Shimada Mayuko Shimada Mayuko Shimada Dai Iwata Dai Iwata Michiko Matsuse Katsumi Tanaka Yasushi Miyazaki Shinichi Moriwaki Norisato Mitsutake Tomoo Ogi Tomoo Ogi Tomoo Ogi |
| author_sort | Chikako Senju |
| collection | DOAJ |
| description | Aicardi–Goutières syndrome (AGS) is a rare genetic disorder characterised by progressive encephalopathy, involving microcephaly, intracranial calcification, and cerebrospinal fluid lymphocytosis with increased interferon-α concentrations. The clinical features of AGS overlap with fetal cerebral anomalies caused by congenital infections, such as TORCH (toxoplasmosis, other, rubella, cytomegalovirus, and herpes), or with those of other genetic disorders showing neonatal microcephaly, including Cockayne syndrome (CS) with transcription-coupled DNA repair deficiency, and Seckel syndrome (SS) showing aberrant cell-cycle checkpoint signaling. Therefore, a differential diagnosis to confirm the genetic cause or a proof of infection should be considered. In this report, we describe an individual who showed primordial dwarfism and encephalopathy, and whose initial diagnosis was CS. First, we conducted conventional DNA repair proficiency tests for the patient derived fibroblast cells. Transcription-coupled nucleotide excision repair (TC-NER) activity, which is mostly compromised in CS cases, was slightly reduced in the patient's cells. However, unscheduled DNA synthesis (UDS) was significantly diminished. These cellular traits were inconsistent with the diagnosis of CS. We further performed whole exome sequencing for the case and identified a compound heterozygous loss-of-function variants in the SAMHD1 gene, mutations in which are known to cause AGS. As SAMHD1 encodes deoxyribonucleoside triphosphate triphosphohydrolase, we reasoned that the deoxyribonucleoside triphosphate (dNTP) pool size in the patient's cells was elevated, and the labeling efficiency of UDS-test was hindered due to the reduced concentration of phosphorylated ethynyl deoxyuridine (EdU), a nucleoside analogue used for the assay. In conclusion, UDS assay may be a useful diagnostic tool to distinguish between AGS with SAMHD1 mutations and other related diseases. |
| first_indexed | 2024-04-11T08:30:04Z |
| format | Article |
| id | doaj.art-74f968cc04b4464687ed046e1824a78b |
| institution | Directory Open Access Journal |
| issn | 2296-2360 |
| language | English |
| last_indexed | 2024-04-11T08:30:04Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pediatrics |
| spelling | doaj.art-74f968cc04b4464687ed046e1824a78b2022-12-22T04:34:34ZengFrontiers Media S.A.Frontiers in Pediatrics2296-23602022-11-011010.3389/fped.2022.10480021048002Aicardi–Goutières syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis testChikako Senju0Chikako Senju1Chikako Senju2Chikako Senju3Chikako Senju4Yuka Nakazawa5Yuka Nakazawa6Yuka Nakazawa7Mayuko Shimada8Mayuko Shimada9Mayuko Shimada10Dai Iwata11Dai Iwata12Michiko Matsuse13Katsumi Tanaka14Yasushi Miyazaki15Shinichi Moriwaki16Norisato Mitsutake17Tomoo Ogi18Tomoo Ogi19Tomoo Ogi20Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JapanDepartment of Plastic and Reconstructive Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JapanDepartment of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, JapanDepartment of Human Genetics and Molecular Biology, Graduate School of Medicine, Nagoya University, Nagoya, JapanDepartment of Genome Repair, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, JapanDepartment of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, JapanDepartment of Human Genetics and Molecular Biology, Graduate School of Medicine, Nagoya University, Nagoya, JapanDepartment of Genome Repair, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, JapanDepartment of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, JapanDepartment of Human Genetics and Molecular Biology, Graduate School of Medicine, Nagoya University, Nagoya, JapanDepartment of Genome Repair, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, JapanDepartment of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, JapanDepartment of Human Genetics and Molecular Biology, Graduate School of Medicine, Nagoya University, Nagoya, JapanDepartment of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, JapanDepartment of Plastic and Reconstructive Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JapanDepartment of Hematology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JapanDepartment of Dermatology, Osaka Medical and Pharmaceutical University, Takatsuki, JapanDepartment of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, JapanDepartment of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, JapanDepartment of Human Genetics and Molecular Biology, Graduate School of Medicine, Nagoya University, Nagoya, JapanDepartment of Genome Repair, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, JapanAicardi–Goutières syndrome (AGS) is a rare genetic disorder characterised by progressive encephalopathy, involving microcephaly, intracranial calcification, and cerebrospinal fluid lymphocytosis with increased interferon-α concentrations. The clinical features of AGS overlap with fetal cerebral anomalies caused by congenital infections, such as TORCH (toxoplasmosis, other, rubella, cytomegalovirus, and herpes), or with those of other genetic disorders showing neonatal microcephaly, including Cockayne syndrome (CS) with transcription-coupled DNA repair deficiency, and Seckel syndrome (SS) showing aberrant cell-cycle checkpoint signaling. Therefore, a differential diagnosis to confirm the genetic cause or a proof of infection should be considered. In this report, we describe an individual who showed primordial dwarfism and encephalopathy, and whose initial diagnosis was CS. First, we conducted conventional DNA repair proficiency tests for the patient derived fibroblast cells. Transcription-coupled nucleotide excision repair (TC-NER) activity, which is mostly compromised in CS cases, was slightly reduced in the patient's cells. However, unscheduled DNA synthesis (UDS) was significantly diminished. These cellular traits were inconsistent with the diagnosis of CS. We further performed whole exome sequencing for the case and identified a compound heterozygous loss-of-function variants in the SAMHD1 gene, mutations in which are known to cause AGS. As SAMHD1 encodes deoxyribonucleoside triphosphate triphosphohydrolase, we reasoned that the deoxyribonucleoside triphosphate (dNTP) pool size in the patient's cells was elevated, and the labeling efficiency of UDS-test was hindered due to the reduced concentration of phosphorylated ethynyl deoxyuridine (EdU), a nucleoside analogue used for the assay. In conclusion, UDS assay may be a useful diagnostic tool to distinguish between AGS with SAMHD1 mutations and other related diseases.https://www.frontiersin.org/articles/10.3389/fped.2022.1048002/fullAicardi-Goutières syndrome (AGS)SAMHD1unscheduled DNA synthesis (UDS)cockayne syndrome (CS)transcription coupled repair (TCR) |
| spellingShingle | Chikako Senju Chikako Senju Chikako Senju Chikako Senju Chikako Senju Yuka Nakazawa Yuka Nakazawa Yuka Nakazawa Mayuko Shimada Mayuko Shimada Mayuko Shimada Dai Iwata Dai Iwata Michiko Matsuse Katsumi Tanaka Yasushi Miyazaki Shinichi Moriwaki Norisato Mitsutake Tomoo Ogi Tomoo Ogi Tomoo Ogi Aicardi–Goutières syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis test Frontiers in Pediatrics Aicardi-Goutières syndrome (AGS) SAMHD1 unscheduled DNA synthesis (UDS) cockayne syndrome (CS) transcription coupled repair (TCR) |
| title | Aicardi–Goutières syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis test |
| title_full | Aicardi–Goutières syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis test |
| title_fullStr | Aicardi–Goutières syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis test |
| title_full_unstemmed | Aicardi–Goutières syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis test |
| title_short | Aicardi–Goutières syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis test |
| title_sort | aicardi goutieres syndrome with samhd1 deficiency can be diagnosed by unscheduled dna synthesis test |
| topic | Aicardi-Goutières syndrome (AGS) SAMHD1 unscheduled DNA synthesis (UDS) cockayne syndrome (CS) transcription coupled repair (TCR) |
| url | https://www.frontiersin.org/articles/10.3389/fped.2022.1048002/full |
| work_keys_str_mv | AT chikakosenju aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest AT chikakosenju aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest AT chikakosenju aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest AT chikakosenju aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest AT chikakosenju aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest AT yukanakazawa aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest AT yukanakazawa aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest AT yukanakazawa aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest AT mayukoshimada aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest AT mayukoshimada aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest AT mayukoshimada aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest AT daiiwata aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest AT daiiwata aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest AT michikomatsuse aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest AT katsumitanaka aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest AT yasushimiyazaki aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest AT shinichimoriwaki aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest AT norisatomitsutake aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest AT tomooogi aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest AT tomooogi aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest AT tomooogi aicardigoutieressyndromewithsamhd1deficiencycanbediagnosedbyunscheduleddnasynthesistest |