Trichothiodystrophy due to ERCC2 Variants: Uncommon Contributor to Progressive Hypomyelinating Leukodystrophy
ABSTRACT Background Trichothiodystrophy (TTD) is caused by homozygous or compound heterozygous variants in genes associated with DNA repair. The ERCC2 gene encoded a protein, XPD, that is a subunit of the general transcription factor TFIIH and important in both DNA repair and transcription. Disease‐...
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Wiley
2025-02-01
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| Series: | Molecular Genetics & Genomic Medicine |
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| Online Access: | https://doi.org/10.1002/mgg3.70067 |
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| author | Ali Reza Tavasoli Arastoo Kaki Maedeh Ganji Seyyed Mohammad Kahani Foozhan Radmehr Pouria Mohammadi Morteza Heidari Mahmoud Reza Ashrafi Kara S. Lewis |
| author_facet | Ali Reza Tavasoli Arastoo Kaki Maedeh Ganji Seyyed Mohammad Kahani Foozhan Radmehr Pouria Mohammadi Morteza Heidari Mahmoud Reza Ashrafi Kara S. Lewis |
| author_sort | Ali Reza Tavasoli |
| collection | DOAJ |
| description | ABSTRACT Background Trichothiodystrophy (TTD) is caused by homozygous or compound heterozygous variants in genes associated with DNA repair. The ERCC2 gene encoded a protein, XPD, that is a subunit of the general transcription factor TFIIH and important in both DNA repair and transcription. Disease‐causing variants in ERCC2 can partially inactivate these activities, giving rise to symptoms seen in TTD, Cockayne syndrome (CS) and xeroderma pigmentosa (XP). Although generalized cerebral white matter abnormalities is reported in TTD, myelination disorders specifically linked to ERCC2 gene variants are exceptionally uncommon. Here, we introduce a thorough investigation of a patient exhibiting classic TTD symptoms alongside progressive cerebral hypomyelination with ERCC2 variants. Methods In a non‐consanguineous family, we conducted Autism/ID gene Panel on a 5‐year‐old affected child who presented with microcephaly, failure to thrive, developmental delay, and progressive hypomyelination on three serial brain imaging over 5‐years follow‐up. Our investigation aimed to elucidate the genetic underpinnings of the observed phenotype. We also conducted a comprehensive review of the genetic profiles of all documented ERCC2‐related patients exhibiting myelination disorders. Results Autism/ID gene Panel identified a compound heterozygous variant in ERCC2 gene causing TTD. Clinical and paraclinical findings enabled differentiation of TTD from Cockayne syndrome and XP. Segregation analysis revealed that, the variation in the paternal allele was a splice junction loss (c.2190 + 1delG), and the other alteration in the maternal allele was a pathogenic variant (c.1479 + 2dupT). It has been noted that these variants were reported in previous studies in homozygous or compound heterozygous form in patients with TTD, but none of them exhibited hypomyelinating leukodystrophy. Conclusion The identification of hypomyelination in TTD due to ERCC2 sheds a light on the molecular diagnosis and contributing to the limited literature on ERCC2 variants and associated hypomyelinating leukodystrophy in patients with TTD. |
| format | Article |
| id | doaj-art-619281d289254e1fa638b282a8cbc2d3 |
| institution | DOAJ |
| issn | 2324-9269 |
| language | English |
| publishDate | 2025-02-01 |
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| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj-art-619281d289254e1fa638b282a8cbc2d32025-08-20T03:11:14ZengWileyMolecular Genetics & Genomic Medicine2324-92692025-02-01132n/an/a10.1002/mgg3.70067Trichothiodystrophy due to ERCC2 Variants: Uncommon Contributor to Progressive Hypomyelinating LeukodystrophyAli Reza Tavasoli0Arastoo Kaki1Maedeh Ganji2Seyyed Mohammad Kahani3Foozhan Radmehr4Pouria Mohammadi5Morteza Heidari6Mahmoud Reza Ashrafi7Kara S. Lewis8Neurology Division Barrow Neurological Institute, Phoenix Children's Phoenix Arizona USADepartment of Medical Genetics, School of Medicine Hamadan University of Medical Sciences Hamadan IranDeNA Genetics Laboratory Tehran IranDepartment of Medical Genetics Tarbiat Modares University Tehran IranDepartment of Molecular Medicine National Institute of Genetic Engineering and Biotechnology Tehran IranMyelin Disorders Clinic, Children's Medical Center, Pediatric Center of Excellence Tehran University of Medical Sciences Tehran IranMyelin Disorders Clinic, Children's Medical Center, Pediatric Center of Excellence Tehran University of Medical Sciences Tehran IranMyelin Disorders Clinic, Children's Medical Center, Pediatric Center of Excellence Tehran University of Medical Sciences Tehran IranNeurology Division Barrow Neurological Institute, Phoenix Children's Phoenix Arizona USAABSTRACT Background Trichothiodystrophy (TTD) is caused by homozygous or compound heterozygous variants in genes associated with DNA repair. The ERCC2 gene encoded a protein, XPD, that is a subunit of the general transcription factor TFIIH and important in both DNA repair and transcription. Disease‐causing variants in ERCC2 can partially inactivate these activities, giving rise to symptoms seen in TTD, Cockayne syndrome (CS) and xeroderma pigmentosa (XP). Although generalized cerebral white matter abnormalities is reported in TTD, myelination disorders specifically linked to ERCC2 gene variants are exceptionally uncommon. Here, we introduce a thorough investigation of a patient exhibiting classic TTD symptoms alongside progressive cerebral hypomyelination with ERCC2 variants. Methods In a non‐consanguineous family, we conducted Autism/ID gene Panel on a 5‐year‐old affected child who presented with microcephaly, failure to thrive, developmental delay, and progressive hypomyelination on three serial brain imaging over 5‐years follow‐up. Our investigation aimed to elucidate the genetic underpinnings of the observed phenotype. We also conducted a comprehensive review of the genetic profiles of all documented ERCC2‐related patients exhibiting myelination disorders. Results Autism/ID gene Panel identified a compound heterozygous variant in ERCC2 gene causing TTD. Clinical and paraclinical findings enabled differentiation of TTD from Cockayne syndrome and XP. Segregation analysis revealed that, the variation in the paternal allele was a splice junction loss (c.2190 + 1delG), and the other alteration in the maternal allele was a pathogenic variant (c.1479 + 2dupT). It has been noted that these variants were reported in previous studies in homozygous or compound heterozygous form in patients with TTD, but none of them exhibited hypomyelinating leukodystrophy. Conclusion The identification of hypomyelination in TTD due to ERCC2 sheds a light on the molecular diagnosis and contributing to the limited literature on ERCC2 variants and associated hypomyelinating leukodystrophy in patients with TTD.https://doi.org/10.1002/mgg3.70067ERCC2hypomyelinationleukodystrophytrichothiodystrophy |
| spellingShingle | Ali Reza Tavasoli Arastoo Kaki Maedeh Ganji Seyyed Mohammad Kahani Foozhan Radmehr Pouria Mohammadi Morteza Heidari Mahmoud Reza Ashrafi Kara S. Lewis Trichothiodystrophy due to ERCC2 Variants: Uncommon Contributor to Progressive Hypomyelinating Leukodystrophy Molecular Genetics & Genomic Medicine ERCC2 hypomyelination leukodystrophy trichothiodystrophy |
| title | Trichothiodystrophy due to ERCC2 Variants: Uncommon Contributor to Progressive Hypomyelinating Leukodystrophy |
| title_full | Trichothiodystrophy due to ERCC2 Variants: Uncommon Contributor to Progressive Hypomyelinating Leukodystrophy |
| title_fullStr | Trichothiodystrophy due to ERCC2 Variants: Uncommon Contributor to Progressive Hypomyelinating Leukodystrophy |
| title_full_unstemmed | Trichothiodystrophy due to ERCC2 Variants: Uncommon Contributor to Progressive Hypomyelinating Leukodystrophy |
| title_short | Trichothiodystrophy due to ERCC2 Variants: Uncommon Contributor to Progressive Hypomyelinating Leukodystrophy |
| title_sort | trichothiodystrophy due to ercc2 variants uncommon contributor to progressive hypomyelinating leukodystrophy |
| topic | ERCC2 hypomyelination leukodystrophy trichothiodystrophy |
| url | https://doi.org/10.1002/mgg3.70067 |
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