Intellectual disability update Jan 2018

Gene: MRE11

Red List (low evidence)

Clinical team review confirmed this gene should remain rated as Red on the ID panel. HB noted that although ID can be a feature there are usually other clues re DNA repair disorders. Gene added as Amber to Cockayne and Xeroderna Pigmentosum-like disorder and New gene for Primary Microcephaly - Microcephalic Dwarfism Spectrum panels.

Created: 8 Mar 2018, 3:29 p.m.

Flagged for clinical team to review - could potentially be Amber based on PMID: 21227757 (2011). However, only a single published study to date and since then (see clinvar) there are many more cases but with other associated conditions with : Microcephaly, normal intelligence and immunodeficiency (ID is normal) and is linked to Hereditary cancer-predisposing syndrome.

Created: 8 Mar 2018, 3:27 p.m.

Comment on publications: added publication to support association to Nijmegen breakage syndrome-like severe microcephaly

Created: 7 Mar 2018, 11:49 a.m.

Comment on list classification: two cases with ID for Nijmegen breakage syndrome-like severe microcephaly, both cases had speech and learning difficulties, however there are other reports with pathogenic variants in patients with conditions such as Hereditary cancer-predisposing syndrome and Microcephaly, normal intelligence and immunodeficiency.

Created: 7 Mar 2018, 11:46 a.m.

Comment on phenotypes: phenotype from PMID: 21227757

Created: 7 Mar 2018, 11:45 a.m.

Variants of this gene have been confirmed to cause Ataxia-telangiectasia-like disorder, an autosomal recessive movement disorder characterized clinically by progressive cerebellar degeneration resulting in ataxia and oculomotor apraxia (PMID: 10612394, 11371508, 22863007, 15269180).

However, Matsumoto Y et al., (2011) PMID: 21227757 found that two unrelated patients with MRE11A mutations and Nijmegen breakage syndrome-like severe microcephaly. Noting that MRE11 and NBN function together as components of a MRE11/RAD50/NBN protein complex, deficiency of either protein did not result in the same clinical features. Mutations in the NBN gene underlie Nijmegen breakage syndrome (NBS), a chromosomal instability syndrome characterized by microcephaly, bird-like faces, growth and mental retardation, and cellular radiosensitivity. Additionally, mutations in the MRE11A gene are known to lead to an ataxia-telangiectasia-like disorder (ATLD), a late-onset, slowly progressive variant of ataxia-telangiectasia without microcephaly. In their study Matsumoto Y et al., (2011) PMID: 21227757 describe two unrelated patients with NBS-like severe microcephaly (head circumference -10.2 SD and -12.8 SD) with mutations just in the MRE11A gene. Both patients were compound heterozygotes for a truncating or missense mutation and carried a translationally silent mutation. The truncating and missense mutations were assumed to be functionally debilitating. The translationally silent mutation common to both patients had an effect on splicing efficiency resulting in reduced but normal MRE11 protein.

Created: 7 Mar 2018, 11:41 a.m.

Nomenclature history profile of this gene (from correspondence with HGNC) : a change was made in the 1990s of the gene symbol MRE11 to MRE11A which left a withdrawn MRE11 gene symbol even though this was really just a rename. Then, recently, MRE11A was named back to MRE11after MRE11B turned out to be a pseudogene and was renamed to MRE11P1. HGNC will now delete the MRE11~withdrawn symbol so that this confusion will not occur again. There is now only one MRE11 record, with HGNC:7230.

Created: 7 Mar 2018, 11:14 a.m.

Phenotypes
21227757