White matter disorders and cerebral calcification - narrow panel

Gene: ERCC1

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 rating as green for now, but with recommendation for amber or red rating at the next GMS review. There does not appear to be evidence that this is a white matter disorder.

Created: 29 Apr 2021, 2:26 p.m. | Last Modified: 29 Apr 2021, 2:26 p.m.

Panel Version: 1.55

4 patients reported with biallelic variants in ERCC1. In two cases there were developmental symptoms from birth. In the third neurodegenerative symptoms became apparent at age 15. And in the 4th family liver dysfunction was reported from a young age. No specific mention of white matter abnormalities.

PMID: 17273966 - Jaspers et al 2007 - report a child (165TOR) with cerebro-oculo-facio-skeletal syndrome showing relatively mild impairment of Nucleotide excision repair (NER) but very severe developmental symptoms and death in early infancy. Compound heterozygous variants in ERCC1 were found (one nonsense and and one missense) each inherited from one parent. NMR showed simplified gyral pattern and cerebellar hypoplasia. NO specific white matter abnormalites are reported.

PMID: 23623389 - Kashiyama et al 2013 - through targeted sequencing of ERCC1 and ERCC4 they report 1 patient with a homozygous missense variant. The child (CS20LO) was diagnosed with Cockayne syndrome type II. Brain MRI at birth indicated a possible polymicrogyria; a NMR scan at 4 months of age showed large bilateral subdurals but no major visible malformations; at 9 months an abnormal electroencephalogram was recorded.

Imoto K, Boyle J, Oh K, Khan S, Ueda T, Nadem C, Slor H, Orgal S, Gadoth N, Busch D, Jaspers NG, Tamura D, JJ DiGiovanna, Kraemer KH. Patients with defects in the interacting nucleotide excision repair proteins ERCC1 or XPF show xeroderma pigmentosum with late onset severe neurological degeneration. J Invest Dermatol. 2007;127 Supp. 92 - conference abstract - can't access. Review by Gregg et al 2011 (PMID: 21612988) report that this abstract describes a patient with compound het variants in ERCC1 (nonsense mutation and a splicing mutation). The patient showed progressive neurodegeneration from age 15 resulting in dementia and cortical atrophy.

PMID: 33315086 - Apelt et al 2020 - describe 2 siblings with bi-allelic ERCC1 mutations (a missense and a deletion of exon 4) and a unique phenotype of short stature, photosensitivity, progressive cholestatic liver disease, and renal tubulopathy. Mild intellectual disability is reported. Brain magnetic resonance imaging (MRI) at 10 and 12 years for the respective siblings showed mild cerebral atrophy with moderate cerebellar atrophy, and mild brainstem atrophy in one sibling.

Created: 29 Apr 2021, 2:10 p.m. | Last Modified: 29 Apr 2021, 4:44 p.m.

Panel Version: 1.56

Comment on phenotypes: Only associated with Cerebrooculofacioskeletal syndrome 4 in OMIM and Gene2Phenotype so removing Xeroderma pigmentosum as a phenotype.

Created: 29 Apr 2021, 11:29 a.m. | Last Modified: 29 Apr 2021, 11:29 a.m.

Panel Version: 1.53

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 17273966
• 23623389
• 21612988
• 33315086

Red List (low evidence)

Cannot find specific reports of leukodystrophy/white matter abnormalities.

Created: 15 Sep 2020, 10:16 a.m. | Last Modified: 15 Sep 2020, 10:16 a.m.

Panel Version: 1.14

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cerebrooculofacioskeletal syndrome 4 610758