A single center experience with publicly funded clinical exome sequencing for neurodevelopmental disorders or multiple congenital anomalies.
A single center experience with publicly funded clinical exome sequencing for neurodevelopmental disorders or multiple congenital anomalies.
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DOI：
10.1038/s41598-021-98646-w
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发表时间：
2021-09-27
影响因子：
4.6
通讯作者：
Greenbaum L
中科院分区：
文献类型：
--
作者：
Pode-Shakked B;Barel O;Singer A;Regev M;Poran H;Eliyahu A;Finezilber Y;Segev M;Berkenstadt M;Yonath H;Reznik-Wolf H;Gazit Y;Chorin O;Heimer G;Gabis LV;Tzadok M;Nissenkorn A;Bar-Yosef O;Zohar-Dayan E;Ben-Zeev B;Mor N;Kol N;Nayshool O;Shimshoviz N;Bar-Joseph I;Marek-Yagel D;Javasky E;Einy R;Gal M;Grinshpun-Cohen J;Shohat M;Dominissini D;Raas-Rothschild A;Rechavi G;Pras E;Greenbaum L
外显子组测序（ES）是神经发育障碍（NDD）和/或多发性先天性异常（MCA）个体的重要诊断工具。然而，ES的成本限制了许多患者对测试的可及性。我们评估了公共资助的临床ES的产量，在以色列的一个三级中心进行，为期3年（2018-2020）。先证者表现为（1）中度至重度全面发育迟缓（GDD）/智力残疾（ID）;或（2）轻度GDD/ID伴癫痫或先天性异常;和/或（3）MCA。纳入符合纳入标准的染色体微阵列分析正常的受试者，共计280例连续病例。三ES（先证者和父母）是默认选项。在252例病例（90.0%）中，注意到NDD指征。大多数先证者为男性（62.9%），他们提交ES时的平均年龄为9.3岁（范围为1个月至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个与多个病例有关。男性、多发病家庭和早产与ES产量的降低显著相关（p < 0.05）。其他因素，包括大脑中动脉与癫痫、自闭症谱系障碍、小头畸形或异常脑磁共振成像结果共存，与产率无关。总之，我们的研究结果支持临床ES在现实世界中的实用性，作为GDD/ID和/或MCA个体的公共资助遗传检查的一部分。
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.
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