XPA

Gene Facts

• HGNC Symbol: XPA (HGNC:12814)
• HGNC Name: XPA, DNA damage recognition and repair factor
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: XPAC, XP1
• %HI: 25.19
• pLI: 0
• LOEUF: 1.07
• Cytoband: 9q22.33
• Genomic Coordinates:

  GRCh37/hg19:	chr9:100437191-100459622
  GRCh38/hg38:	chr9:97654398-97697340

• MANE Select Transcript: NM_000380.4 ENST00000375128.5
• Function: Involved in DNA excision repair. Initiates repair by binding to damaged sites with various affinities, depending on the photoproduct and the transcriptional state of the region. Required for UV-induced CHEK1 phosphorylation and the recruitment of CEP164 to cyclobutane pyrimidine dimmers (CPD), sites of DNA damage after UV irradiation. {ECO:0000269|PubMed:19197159}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-7601
• ClinGen Curation ID: CCID:008119
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Gene Associated with Autosomal Recessive Phenotype (30)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 02/14/2024

Haploinsufficiency (HI) Score Details

• HI Score: 30
• HI Evidence Strength: Gene Associated with Autosomal Recessive Phenotype

HI Disease

• xeroderma pigmentosum group A

• HI Evidence Comments: Jahn et al (2022; PMID: 35988656 Annals of Oncology) reports on a large multi-site hereditary cancer study in which 157 patients were enrolled. The authors detect heterozygous carriers in 5% of patients. Among this cohort, XPA heterozygous variants that ranged from missense, splice site, and frameshift are reported spanning pathogenic, likely pathogenic, and uncertain significance classifications . A total of 17 patients (supp table S5) are reported who have non specific findings (of note, none related to Xeroderma pigmentosum, group A), and all were carriers of the autosomal recessive variants in XPA. These carriers reported GI, head/neck, and bone tumors. Another study by Fassihi et al 2016 (PNAS) analyzed RNA using RT-PCR followed by Sanger sequencing. All mutations were confirmed using Sanger sequencing of genomic DNA from blood. Eighteen Xeroderma pigmentosum patients from 14 families (Table 1) had homozygous variants, indicated as causative. These patients demonstrated pigmentary changes and skin cancers without abnormally severe sunburn reactions, however homozygous variants were detected in this study , underscoring AR phenotype. Ghfouri-Fard et al (Gene 2016) reports on a small case report/letter to the editor in which a novel homozygous frameshift variant , c.349_353 del in XPA is reported . The results were validated by Sanger and targeted sequencing on the parents showed the anticipated segregation pattern. The variant is located in exon 3 of XPA which codes for the zinc finger domain. This variant truncates the carboxyl terminal site of the corresponding protein at an early part of its zinc-finger domain and is expected to affect the protein function. Zhou et al 2016 (PMID: 27607234 J of Dermatology) reports on a case series of 19 patients from 17 unrelated families. This work was performed by targeted DNA sequencing. A heterozygous nonsense variant, R211*,was detected. This variant was carried by the parents of the XP-A patient. Overall bi-allelic alterations in XP are required to manifest the AR phenotype; mechanistically XPA is believed to play a key role in the damaged DNA response (PMID: 27247238). Of note, a spectrum of cancer types are noted on HGMD (accessed Feb 2024) other than XPA.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity