Constitutional mismatch repair deficiency (CMMRD) is an aggressive and highly penetrant cancer predisposition syndrome. Because of its variable clinical presentation and phenotypical overlap with neurofibromatosis, timely diagnosis remains challenging, especially in countries with limited resources. Since current tests are either difficult to implement or interpret or both we used a novel and relatively inexpensive functional genomic assay (LOGIC) which has been recently reported to have high sensitivity and specificity in diagnosing CMMRD. Here we report the clinical and molecular characteristics of nine patients diagnosed with cancer and suspected to have CMMRD and highlight the challenges with variant interpretation and immunohistochemical analysis that led to an uncertain interpretation of genetic findings in 6 of the 9 patients. Using LOGIC, we were able to confirm the diagnosis of CMMRD in 7 and likely exclude it in 2 patients, resolving ambiguous result interpretation. LOGIC also enabled predictive testing of asymptomatic siblings for early diagnosis and implementation of surveillance. This study highlights the varied manifestations and practical limitations of current diagnostic criteria for CMMRD, and the importance of international collaboration for implementing robust and low-cost functional assays for resolving diagnostic challenges.

结构性错配修复缺陷 (CMMRD) 是一种侵袭性和高度渗透的癌症易感综合征。由于其多变的临床表现和与神经纤维瘤病的表型重叠，及时诊断仍然具有挑战性，尤其是在资源有限的国家。由于目前的测试要么难以实施，要么难以解释，或者两者兼而有之，我们使用了一种新颖且相对便宜的功能基因组测定 (LOGIC)，该测定最近被报道在诊断 CMMRD 方面具有高灵敏度和特异性。在这里，我们报告了 9 名被诊断患有癌症并疑似患有 CMMRD 的患者的临床和分子特征，并强调了变异解释和免疫组织化学分析的挑战，这些挑战导致了 9 名患者中 6 名基因发现的不确定解释。使用逻辑，我们能够在 7 名患者中确认 CMMRD 的诊断，并可能在 2 名患者中排除它，解决了不明确的结果解释。LOGIC 还可以对无症状的兄弟姐妹进行预测性测试，以进行早期诊断和实施监测。本研究强调了当前 CMMRD 诊断标准的各种表现和实际局限性，以及国际合作对于实施稳健且低成本的功能检测以解决诊断挑战的重要性。