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-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.

Keywords: ERCC2; hypomyelination; leukodystrophy; trichothiodystrophy.

FIGURE 1

Progressive hypomyelination over serial brain imaging spanning over 4.5 years. (A) Brain MRI (8 months) demonstrated unremarkable imaging findings on axial, coronal and sagittal T1‐weighted (A, C, E) and correspondent T2‐weighted sequences (B, D, F). (B) Brain MRI (at 22 months) revealed deep and bilateral subcortical frontal, parietal, and occipital hyperintense signals on T2‐ weighted images and to lesser extent deep periventricular white matter hypomyelination. The axial, coronal and sagittal T2‐ weighted spaces (G, I, K) and correspondent T1‐weighted images (H, J, L) were normal. (C) Brain MRI (4 years, 2 months) showed diffuse abnormal increased signals on T2‐weighted images in the supratentorial white matter and poor gray‐white—differentiation on T1‐weighted images compatible with hypomyelination. There appears to be further interval loss of normal myelination compared to the prior exams at ages 22 and 8 months old including regions of subcortical white matter abnormal signal currently, previously demonstrating a more normal signal. Overall cerebral volume appears normal T2‐weighted images (M, O, Q) and corresponding T1‐weighted images (N, P, R).

FIGURE 2

Publicly available single‐cell sequencing database, recruited to investigate the cell type gene expression of ERCC2 in human brain. ERCC2 is widely expressed in a range of neurons, fibroblast and mesenchymal lineage biology. The cell type expression of ERCC2 shows this gene is expressed in most or all regions of the brain suggest that this gene is important for central nerve system development. This statement supported by gene expression pattern of ERCC2 paralogous in other specious as this gene is highly conserved during the evolution.

FIGURE 3

ERCC2 remains conserved during evolution through different organisms. Single cell transcriptome sequencing in C.elegans shows that xpd‐1, ortholog of ERCC2, is widely expressed in Germline and neurons. In addition, Publicly available single‐cell sequencing of mouse shows that Ercc2, ortholog of ERCC2 in mouse, indicates that this gene is broadly expressed through the body, including neuronal cells in the brain.

FIGURE 4

The schematic representation of the ERCC2 gene and protein domains. The upper part shows the exon structure of the ERCC2, while the lower part illustrates the protein domains and their respective positions along the amino acid sequence. Specific domains such as the ATP‐binding type‐2 domain and the helical and beta‐bridge domain are highlighted along with the C‐terminal helicase domain of xeroderma pigmentosum. Variants are marked on both the gene and protein level diagrams: Frameshift and in‐frame variants are shown in red, and missense variants are displayed in purple. This schematic effectively maps variants to specific exons and protein domains, indicating how genetic alterations could potentially influence protein function.

FIGURE 5

Visualization of amino acid interactions in ERCC2 protein structures using PyMOL, based on the PDB5IVW model from the Protein Data Bank. Each section illustrates specific changes in amino acid residues documented in the literature: Interaction changes of p.R112H before and after variation (A), interaction of Ser23 before deletion (B), and p.R722W before and after variation (C). Additionally, we used the I‐TASSER protein prediction database to model the structural impacts of frameshift variants, including p.E731Rfs14 (E) and p.K603Sfs45 (D). Affected amino acids are highlighted in red within the sequence alignments, illustrating the connection between sequence alterations and structural deviations. This comprehensive representation elucidates the potential functional impacts of these genetic changes on protein architecture and functionality.