A Truncating Variant in the ERCC6 Gene With Three Different Phenotypes: Significant Effects of Modifier Genes.

Area of Science:

• Genetics
• Molecular Biology
• Rare Diseases

Background:

• Cockayne syndrome (CS) is a rare, autosomal-recessive disorder affecting multiple systems, including neurological and developmental aspects.
• CS is caused by variants in ERCC6 or ERCC8 genes, crucial for DNA repair.
• CS is classified into types I, II, III, and cerebrooculofacioskeletal syndrome (COFS), with debate on whether COFS is distinct or a severe CS form.

Purpose of the Study:

• To investigate the genetic basis of a patient presenting with intermediate symptoms between CS and COFS.
• To analyze the clinical significance of a specific ERCC6 gene variant.

Main Methods:

• Whole-exome sequencing (WES) was employed to identify potential causative variants.
• Sanger sequencing was used for co-segregation analysis to confirm the identified variant.

Main Results:

• A nonsense variant (NM_000124: c.3862C>T, p.R1288X) in the ERCC6 gene was identified via WES and confirmed by Sanger sequencing.
• The patient exhibited symptoms intermediate between typical CS and COFS.
• This specific variant has been previously associated with CS and COFS individually.

Conclusions:

• The findings broaden the known clinical spectrum for the ERCC6 variant (NM_000124: c.3862C>T, p.R1288X).
• This study supports the view of CS and COFS as a phenotypic spectrum, influenced by genetic and epigenetic factors.
• The severity of symptoms in CS/COFS may be modulated by genetic and epigenetic factors.