Long continuous stretches of homozygosity (LCSH) are associated with risk of recessive disorders. Though LCSH can be detected by SNP microarrays, additional testing is necessary to clarify the clinical significance. This study is to assess the yield of additional exome sequencing (ES) after LCSH detection and inform the likelihood of eventual diagnosis. In 2226 patients referred to SNP microarrays, 35 patients met the criteria of indicative LCSH. These patients were recruited and went through additional ES. The diagnostic yield was analyzed, and the LCSH pattern was compared between eventually diagnosed cases and those undiagnosed. The results showed additional ES attained a diagnostic yield of 31.4% (11/35), but only one-third of the yield (11.4%, 4/35) was relevant to LCSH. In contrast, two-thirds of the diagnostic variants (20%, 7/35) were de novo or dominantly inherited, irrelevant to the original LCSH finding. No particular LCSH pattern, including the chromosomal coverage or LCSH size, was found to associate with the diagnostic outcome. We concluded that additional ES after LCSH detection could reveal diagnostic variants, but it is strongly recommended to consider all possible inheritance mode, as the diagnostic variants may be irrelevant to the original LCSH finding.

长期连续的纯合子序列 (LCSH) 与隐性疾病的风险相关。虽然 LCSH 可以通过 SNP 微阵列检测到，但需要额外的测试来阐明临床意义。本研究旨在评估 LCSH 检测后额外外显子组测序 (ES) 的产量，并告知最终诊断的可能性。在转诊到 SNP 微阵列的 2226 名患者中，35 名患者符合指示性 LCSH 的标准。这些患者被招募并接受了额外的 ES。分析了诊断率，并比较了最终确诊病例和未确诊病例之间的 LCSH 模式。结果显示额外的 ES 获得了 31.4% (11/35) 的诊断率，但只有三分之一的产率 (11.4%, 4/35) 与 LCSH 相关。相比之下，三分之二的诊断变异（20%，7/35) 是新发的或显性遗传的，与最初的 LCSH 发现无关。没有发现特定的 LCSH 模式（包括染色体覆盖率或 LCSH 大小）与诊断结果相关。我们得出结论，LCSH 检测后的额外 ES 可以揭示诊断变异，但强烈建议考虑所有可能的遗传模式，因为诊断变异可能与原始 LCSH 发现无关。