Tavasoli Ali Reza, Kaki Arastoo, Ganji Maedeh, Kahani Seyyed Mohammad, Radmehr Foozhan, Mohammadi Pouria, Heidari Morteza, Ashrafi Mahmoud Reza, Lewis Kara S
Neurology Division, Barrow Neurological Institute, Phoenix Children's, Phoenix, Arizona, USA.
Myelin Disorders Clinic, Children's Medical Center, Pediatric Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran.
Mol Genet Genomic Med. 2025 Feb;13(2):e70067. doi: 10.1002/mgg3.70067.
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.
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.
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.
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.
毛发硫营养不良（TTD）由与DNA修复相关基因的纯合或复合杂合变异引起。ERCC2基因编码一种蛋白质XPD，它是通用转录因子TFIIH的一个亚基，在DNA修复和转录中都很重要。ERCC2中的致病变异可部分使这些活性失活，导致TTD、科凯恩综合征（CS）和着色性干皮病（XP）中出现的症状。虽然TTD中报道有广泛性脑白质异常，但与ERCC2基因变异特异性相关的髓鞘形成障碍极为罕见。在此，我们对一名表现出典型TTD症状以及伴有ERCC2变异的进行性脑髓鞘形成不足的患者进行了全面调查。
在一个非近亲家庭中，我们对一名5岁患病儿童进行了自闭症/智力发育障碍基因检测，该儿童出现小头畸形、生长发育迟缓、发育延迟，并在5年随访期间的三次连续脑部成像中显示出进行性髓鞘形成不足。我们的调查旨在阐明所观察到的表型的遗传基础。我们还对所有记录在案的表现出髓鞘形成障碍的ERCC2相关患者的基因谱进行了全面回顾。
自闭症/智力发育障碍基因检测在ERCC2基因中发现了一个导致TTD的复合杂合变异。临床和辅助检查结果使TTD与科凯恩综合征和着色性干皮病得以区分。家系分析显示，父本等位基因的变异是一个剪接位点缺失（c.2190 + 1delG），母本等位基因的另一个改变是一个致病变异（c.1479 + 2dupT）。值得注意的是，这些变异在先前的研究中曾在TTD患者中以纯合或复合杂合形式被报道，但均未表现出髓鞘形成不足性脑白质营养不良。
ERCC2导致TTD患者出现髓鞘形成不足的这一发现为分子诊断提供了线索，并丰富了关于TTD患者中ERCC2变异及相关髓鞘形成不足性脑白质营养不良的有限文献。
