Barcia Giulia, Chemaly Nicole, Gobin-Limballe Stéphanie, Losito Emma, Aubart Mélodie, Sarda Eugénie, Assouline Zahra, Plante-Bordeneuve Pauline, Hully Marie, Barrois Remi, Barnerias Christine, Sareidaki Doxa, Zeitoun Delphine Coste, Eisermann Monika, Fourrage Cécile, Hanein Sylvain, Rio Marlène, Boddaert Nathalie, Desguerre Isabelle, Kaminska Anna, Steffann Julie, Nabbout Rima
Service de Médecine Génomique, Necker Enfants-Malades Hospital, APHP, Université de Paris, Paris, France.
INSERM U1163, Imagine Institute for Rare Diseases, Université de Paris, Paris, France.
Epilepsia Open. 2025 May 10. doi: 10.1002/epi4.70057.
Genetic testing is now included in the diagnostic assessment of childhood onset epilepsies. We evaluated the yield of a targeted next generation sequencing (TNGS) panel dedicated to pediatric epilepsies.
We tested by TNGS panel 1000 consecutive patients presenting with childhood onset epilepsies and including mainly patients with early onset epilepsies (under 2 years, 61%).
Causal variants were identified in 31% of patients, spanning 78 different genes. Patients with benign familial neonatal/infantile epilepsy (BFN/IS) exhibited the highest rate of positive findings (82%). Developmental and epileptic encephalopathies (DEEs) had a global diagnostic yield of 37%, with epilepsy of infancy with migrating focal seizures (EIMFSI) and Dravet syndrome (DS) presenting the highest yield in this group (78%) and early infantile DEE (EIDEE) laying next with a yield of 43%. The lowest rates of genetic diagnosis were observed in infantile epileptic spasms syndrome (IESS, 17%), epilepsy with myoclonic-atonic seizures (EMAtS, 19%), and DEE-SWAS (14%). Patients with GEFS+ had a yield of 16%. Among patients with developmental encephalopathies and refractory seizures with onset after 2 years, TNGS yielded a 33% diagnostic rate. Atypical absences yielded 16%, focal epilepsy yielded 18%, and generalized epilepsies with refractory seizures yielded 13%. These groups exhibited a high genetic heterogeneity.
TNGS is an effective first-step genetic screening in patients with high diagnostic yields (BFN/IS, EIMFS, DS, EIDEE) and for epilepsy syndromes associated with one or a few major genes (BFN/IS, EIMFS, DS, GEFS+, DEE-SWAS). Whole exome or genome sequencing (WES/WGS) should be considered as a second step in these groups with a probably relevant Mendelian inheritance. WES/WGS could be proposed as first-tier analysis in patients with IESS, EMAtS, generalized or focal epilepsies refractory to ASMs, and developmental encephalopathies with seizure onset after 2 years. However, the lower diagnostic yield obtained in these groups may suggest a complex inheritance.
This study emphasizes the importance of accurately identifying different types of epilepsy and epilepsy syndromes to improve genetic testing strategies. We suggest that a targeted gene panel can be a good first step for some genetic conditions, such as benign familial neonatal/infantile epilepsy, Dravet syndrome, and epilepsy of infancy with migrating focal seizures.
基因检测现已纳入儿童期癫痫的诊断评估中。我们评估了一个专门针对小儿癫痫的靶向二代测序（TNGS）panel的检测效能。
我们通过TNGS panel对1000例连续的儿童期癫痫患者进行检测，这些患者主要为早发性癫痫患者（2岁以下，占61%）。
在31%的患者中鉴定出致病变异，涉及78个不同基因。良性家族性新生儿/婴儿癫痫（BFN/IS）患者的阳性检出率最高（82%）。发育性和癫痫性脑病（DEE）的总体诊断率为37%，其中婴儿游走性局灶性癫痫发作（EIMFSI）和Dravet综合征（DS）在该组中的诊断率最高（78%），早发性婴儿DEE（EIDEE）次之，诊断率为43%。婴儿痉挛症综合征（IESS，17%）、肌阵挛-失张力性癫痫发作（EMAtS，19%）和DEE-SWAS（14%）的基因诊断率最低。GEFS+患者的诊断率为16%。在2岁后起病的发育性脑病和难治性癫痫患者中，TNGS的诊断率为33%。非典型失神发作的诊断率为16%，局灶性癫痫的诊断率为18%，难治性全身性癫痫的诊断率为13%。这些组表现出高度的基因异质性。
TNGS是对诊断率高的患者（BFN/IS、EIMFS、DS、EIDEE）以及与一个或几个主要基因相关的癫痫综合征（BFN/IS、EIMFS、DS、GEFS+、DEE-SWAS）进行有效基因筛查的第一步。对于这些可能具有相关孟德尔遗传的组，应考虑将全外显子组或基因组测序（WES/WGS）作为第二步检测。对于IESS、EMAtS、对抗癫痫药物难治的全身性或局灶性癫痫以及2岁后起病的伴有癫痫发作的发育性脑病患者，可将WES/WGS作为一线分析方法。然而，在这些组中获得的较低诊断率可能提示存在复杂遗传。
本研究强调了准确识别不同类型癫痫和癫痫综合征对于改进基因检测策略的重要性。我们建议，对于某些遗传疾病，如良性家族性新生儿/婴儿癫痫、Dravet综合征和婴儿游走性局灶性癫痫，靶向基因panel可能是一个很好的第一步检测方法。
