White matter disorders and cerebral calcification - narrow panel

Gene: ERCC4

I don't know

The rating of this gene has been updated to Amber following NHS Genomic Medicine Service approval.

Created: 30 Jan 2023, 4:26 p.m. | Last Modified: 30 Jan 2023, 4:26 p.m.

Panel Version: 2.9

I don't know

Comment on list classification: Leaving as green for now, but with a recommendation for an amber rating following GMS review. One case where white matter lesions are reported as part of a broader phenotype and 2 cases with milder phenotypes related to white matter.

Created: 11 May 2021, 1:59 p.m. | Last Modified: 11 May 2021, 1:59 p.m.

Panel Version: 1.83

Associated with Xeroderma pigmentosum, type F/Cockayne syndrome #278760, Fanconi anemia, complementation group Q #615272 and XFE progeroid syndrome #610965 in OMIM.

ERCC4 is also known as XPF

Focussed on the reports of patients with Xeroderma pigmentosum, type F/Cockayne syndrome and XFE progeroid syndrome rather than the cancer phenotype of Fanconi anemia. Some evidence of white matter changes but not a prominent feature.

PMID: 23623389 - Kashiyama et al 2013 - report 2 unrelated individuals with Cockayne syndrome and variants identified in ERCC4. For patient CS1USAU there were no obvious brain abnormalities apart from some delayed myelination on brain MRI at the age of 3 years, although basal ganglia T1 shortening was observed at the age of 7 years. For patient XPCS1CD MRI of the brain showed increased signal in the peritrigonal white-matter bilaterally.

PMID: 29105242 - Mori et al 2018 - carried out sequencing for 42 unsolved cases submitted to the International Registry of Werner Syndrome and found two patients with variants in ERCC4. One patient, CALIF1010 was presented at age 35 for evaluation of microcephaly, enophthalmos and a prematurely aged appearance. A brain MRI confirmed enophthalmos, brain abnormalities, including white matter lesions. She was found to be compound heterozygous for variants in ERCC4 (parental DNA unvailable). No brain abnormalities were reported in the other patient.

Created: 11 May 2021, 1:57 p.m. | Last Modified: 11 May 2021, 1:57 p.m.

Panel Version: 1.82

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Xeroderma pigmentosum, type F/Cockayne syndrome, OMIM:278760; XFE progeroid syndrome, OMIM:610965

Publications

• 23623389
• 29105242

Red List (low evidence)

Cannot find specific reports of white matter abnormalities/leukodystrophy associated with variants in this gene.

Created: 15 Sep 2020, 10:21 a.m. | Last Modified: 15 Sep 2020, 10:21 a.m.

Panel Version: 1.14

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Xeroderma pigmentosum, group F, MIM# 278760