Xeroderma Pigmentosum-Trichothiodystrophy overlap patient with novel XPD/ERCC2 mutation.

Area of Science:

• Genetics and Molecular Biology
• DNA Repair Mechanisms
• Rare Genetic Disorders

Background:

• Xeroderma Pigmentosum (XP), Trichothiodystrophy (TTD), and Cockayne Syndrome (CS) are rare, recessive disorders linked to Nucleotide Excision Repair (NER) pathway defects.
• Mutations in the XPD/ERCC2 gene are implicated in these diseases, often presenting overlapping clinical features.
• Predicting clinical outcomes from XPD/ERCC2 mutations remains challenging due to complex genotype-phenotype relationships.

Purpose of the Study:

• To investigate a patient exhibiting characteristics of both XP and TTD/CS, representing a potential overlap syndrome.
• To identify the underlying genetic cause of the patient's complex phenotype through genetic sequencing.
• To explore the interplay between novel and known XPD/ERCC2 mutations and their contribution to the observed clinical manifestations.

Main Methods:

• Clinical examination and assessment of patient's symptoms, including photosensitivity, ichthyosis, brittle hair, developmental impairment, fertility issues, short stature, basal cell carcinoma, and kidney failure.
• Fibroblast culture to assess cellular UV sensitivity, Nucleotide Excision Repair (NER) activity, and Transcription Factor II H (TFIIH) activity.
• Genetic sequencing of the XPD/ERCC2 gene to identify specific mutations.

Main Results:

• The patient presented with a PIBIDS phenotype (Photosensitivity, Ichthyosis, Brittle hair, Impaired physical and mental development, Decreased fertility, Short stature) suggestive of TTD, alongside XP/CS features like basal cell carcinoma and adult-onset kidney failure.
• Fibroblast analysis showed only a mild increase in UV sensitivity (x2) with expected decreases in NER and TFIIH activity.
• Genetic sequencing revealed the patient is a compound heterozygote with a novel N-terminal XPD/ERCC2 mutation (Y18H) and a known C-terminal TTD mutation (A725P).

Conclusions:

• This case represents a rare overlap between XP and TTD/CS, caused by compound heterozygosity for distinct XPD/ERCC2 mutations.
• The novel Y18H mutation, in conjunction with the A725P mutation, contributes to a complex phenotype with features not typically associated with individual mutations.
• Further research is needed to fully elucidate the functional consequences of the novel Y18H mutation and its interaction with other XPD/ERCC2 variants in DNA repair and transcription.