Exome sequencing (ES) is an important diagnostic tool for individuals with neurodevelopmental disorders (NDD) and/or multiple congenital anomalies (MCA). However, the cost of ES limits the test's accessibility for many patients. We evaluated the yield of publicly funded clinical ES, performed at a tertiary center in Israel, over a 3-year period (2018–2020). Probands presented with (1) moderate-to-profound global developmental delay (GDD)/intellectual disability (ID); or (2) mild GDD/ID with epilepsy or congenital anomaly; and/or (3) MCA. Subjects with normal chromosomal microarray analysis who met inclusion criteria were included, totaling 280 consecutive cases. Trio ES (proband and parents) was the default option. In 252 cases (90.0%), indication of NDD was noted. Most probands were males (62.9%), and their mean age at ES submission was 9.3 years (range 1 month to 51 years). Molecular diagnosis was reached in 109 probands (38.9%), mainly due to de novo variants (91/109, 83.5%). Disease-causing variants were identified in 92 genes, 15 of which were implicated in more than a single case. Male sex, families with multiple-affected members and premature birth were significantly associated with lower ES yield (p < 0.05). Other factors, including MCA and coexistence of epilepsy, autism spectrum disorder, microcephaly or abnormal brain magnetic resonance imaging findings, were not associated with the yield. To conclude, our findings support the utility of clinical ES in a real-world setting, as part of a publicly funded genetic workup for individuals with GDD/ID and/or MCA.

外显子组测序 (ES) 是神经发育障碍 (NDD) 和/或多种先天性异常 (MCA) 患者的重要诊断工具。然而，ES 的成本限制了许多患者进行测试的可及性。我们评估了在 3 年期间（2018-2020 年）在以色列三级中心进行的公共资助临床 ES 的产量。先证者表现为 (1) 中度至重度全球发育迟缓 (GDD)/智力障碍 (ID)；(2) 轻度 GDD/ID 伴癫痫或先天性异常；和/或 (3) MCA。染色体微阵列分析正常且符合纳入标准的受试者被纳入，共计280例连续病例。Trio ES（先证者和父母）是默认选项。在 252 例 (90.0%) 中，注意到 NDD 的迹象。大多数先证者是男性（62.9%），他们提交 ES 时的平均年龄为 9 岁。3 年（范围从 1 个月到 51 岁）。109 名先证者（38.9%）获得分子诊断，主要是由于新发变异（91/109，83.5%）。在 92 个基因中发现了致病变异，其中 15 个与不止一个病例有关。男性、多发性家庭成员和早产与较低的 ES 产量显着相关。p  < 0.05)。其他因素，包括 MCA 和癫痫、自闭症谱系障碍、小头畸形或异常脑磁共振成像结果的共存，与产量无关。总而言之，我们的研究结果支持临床 ES 在现实环境中的效用，作为公共资助的基因检查的一部分，用于 GDD/ID 和/或 MCA。