What is the prevalence of MRE11 (Meiotic Recombination 11) mutations?

Prevalence of MRE11 Mutations

MRE11 mutations are extremely rare, with the highest documented carrier frequency being 0.5% (1 in 200) for a specific founder mutation in the Saudi Arabian population, while mutations causing ataxia-telangiectasia-like disorder (ATLD) remain exceedingly uncommon worldwide. 1

Population-Specific Prevalence Data

Saudi Arabian Population

• A cohort study of 428 Saudi nationals identified a heterozygous carrier frequency of 0.5% for the G630C mutation in MRE11 1
• The mutant C allele frequency was 0.2% in this population 1
• This specific mutation was identified in 10 ATLD patients from three unrelated Saudi Arabian families, representing the largest documented ATLD patient group 1
• The carrier frequency may be higher in geographically isolated families with high rates of consanguinity 1

General Population Estimates

• MRE11 mutations causing ATLD are considered very rare variants of ataxia-telangiectasia globally 1, 2
• No population-wide prevalence data exists for other ethnic groups or geographic regions 1
• The rarity of reported cases suggests prevalence is substantially lower than other DNA repair disorders like ataxia-telangiectasia (caused by ATM mutations) 3

Clinical Context: MRE11-Related Disorders

Ataxia-Telangiectasia-Like Disorder (ATLD)

• ATLD patients with MRE11 mutations typically present with mild ataxia without cutaneous features or clinical immunodeficiency 3
• The disorder shows late-onset, slowly progressive cerebellar degeneration, distinguishing it from classic ataxia-telangiectasia 4
• Unlike Nijmegen breakage syndrome (NBS), classic ATLD does not feature microcephaly 5

Atypical Presentations

• Two unrelated patients with MRE11 mutations presented with NBS-like severe microcephaly (head circumference -10.2 SD and -12.8 SD), demonstrating phenotypic variability 5
• Some MRE11 mutations can cause early-onset pulmonary adenocarcinoma, as documented in two ATLD siblings who died at ages 9 and 16 2

Cancer-Associated Somatic Mutations

Sporadic Tumor Prevalence

• A mutation analysis of 159 unselected primary tumors identified three missense mutations at conserved positions in breast and lymphoid tumors 6
• One aberrant transcript without genomic mutation was found in a breast tumor 6
• These somatic alterations suggest an occasional role for MRE11 in tumor development, though the frequency remains low 6

Prostate Cancer Context

• MRE11A is included in comprehensive DNA repair gene panels for prostate cancer screening, though specific germline mutation rates are not separately reported 3
• The gene is part of the MRN DNA repair pathway (MRE11, RAD50, NBN), but when high-risk families were screened, no mutations were clearly associated with increased cancer risk or specific clinical phenotype 3

Important Clinical Caveats

Premarital, preimplementation, and prenatal screening for MRE11 G630C mutation should be considered in Saudi Arabian populations or families with known ATLD history to limit genetic disease risk. 1

• The frequency of MRE11 mutations is substantially lower than moderate-penetrance breast cancer genes like ATM (estimated 1% prevalence) or PALB2 (1-2% prevalence) 3
• MRE11 mutations demonstrate variable penetrance and phenotypic expression, ranging from mild ataxia to severe microcephaly and early cancer 2, 5, 4
• Hypomorphic mutations causing reduced but not absent protein function are more common than complete loss-of-function mutations 5, 4