Komar Madeline, Sidhu Jashanpreet, Joseph Jiju, Kumar Ashna, Callen David J A, Mesterman Ronit, Ramachandrannair Rajesh, Jones Kevin C, Meaney Brandon F, Singh Sonali, McRae Lyndsey, Chau Vann, Sharma Suvasini, Donner Elizabeth J, Aaron Rekha, Danda Sumita, Thomas Maya, Saini Lokesh, Costain Gregory, Yoganathan Sangeetha, Jain Puneet, Whitney Robyn
Division of Neurology, Department of Paediatrics, McMaster University, Hamilton, Ontario, Canada.
Division of Neurology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Ontario, Canada.
Neurol Genet. 2025 May 20;11(3):e200267. doi: 10.1212/NXG.0000000000200267. eCollection 2025 Jun.
Pathogenic variants in the gene cause self-limited infantile epilepsy (SeLIE). Recently, atypical epilepsy phenotypes have been described. We explore the phenotypic spectrum of -related epilepsy through international collaboration.
All children with epilepsy and either a pathogenic variant or 16p11.2 microdeletion encompassing the gene were included in this retrospective study. Details related to the epilepsy, comorbidities, genetic results, EEG/neuroimaging findings, and treatments are summarized.
Forty children were identified, and 24 were male (n = 24/40, 60%). The median age at seizure onset was 5 months (IQR 4, 6) (range 2-150 months). Bilateral tonic-clonic (BTC) (n = 22/40, 55%) and focal motor seizures with impaired awareness evolving to BTC seizures (n = 9/40, 23%) were most common. Thirty-six children (n = 36/40, 90%) had pathogenic variants; 3 were homozygous, and 33 were heterozygous. Four children (n = 4/40, 10%) had 16p11.2 microdeletion. SeLIE was most common, diagnosed in 32 children with heterozygous variants (n = 32/33, 97%), 3 children with homozygous variants (n = 3/3, 100%), and 3 children with 16p11.2 microdeletion (n = 3/4, 75%). Atypical phenotypes were observed in 3 children with heterozygous variants; 1 child evolved from SeLIE to infantile epileptic spasms, another developed spike-wave activation in sleep, and 1 developed focal epilepsy in adolescence. Medically refractory genetic generalized epilepsy and intellectual disability were diagnosed in 1 child with a whole-gene deletion and 16p11.2 microdeletion. All children with homozygous variants had SeLIE with movement disorders. Thirty-seven children (n = 37/40, 93%) were treated with antiseizure medications, and sodium channel blockers were effective in most (20/27 responded, 74%). The median age at seizure freedom was 9 months (IQR 3, 10) (range 3-168 months).
Pathogenic variants are commonly associated with SeLIE. However, additional epilepsy phenotypes may be observed with heterozygous variants. In individuals with heterozygous variants, corresponding chromosomal microarray may be helpful to assess for concomitant 16p11.2 microdeletion, given the phenotypic overlap between the 2 conditions. Collection of additional cases is needed, however, to better understand the spectrum of epilepsy phenotypes associated with 16p11.2 microdeletion encompassing the gene and homozygous and compound heterozygous variants. Currently, precise genotype-phenotype relationships are lacking.
该基因的致病变异可导致自限性婴儿癫痫（SeLIE）。最近，已有非典型癫痫表型的相关描述。我们通过国际合作探究与该基因相关癫痫的表型谱。
本回顾性研究纳入了所有患有癫痫且携带致病变异或包含该基因的16p11.2微缺失的儿童。总结了与癫痫、合并症、基因检测结果、脑电图/神经影像学检查结果及治疗相关的详细信息。
共确定40名儿童，其中24名男性（n = 24/40，60%）。癫痫发作的中位年龄为5个月（四分位间距4，6）（范围2 - 150个月）。双侧强直阵挛发作（BTC）（n = 22/40，55%）和意识障碍性局灶性运动发作进展为BTC发作（n = 9/40，23%）最为常见。36名儿童（n = 36/40，90%）携带致病变异；3例为纯合子，33例为杂合子。4名儿童（n = 4/40，10%）存在16p11.2微缺失。SeLIE最为常见，32名携带杂合变异的儿童（n = 32/33，97%）、3名携带纯合变异的儿童（n = 3/3，100%）以及3名存在16p11.2微缺失的儿童（n = 3/4，75%）被诊断为此病。3名携带杂合变异的儿童出现了非典型表型；1名儿童从SeLIE进展为婴儿痉挛症，另一名在睡眠中出现棘波激活，还有1名在青少年期发展为局灶性癫痫。1名全基因缺失且伴有16p11.2微缺失的儿童被诊断为药物难治性遗传性全面性癫痫和智力残疾。所有携带纯合变异的儿童均患有伴有运动障碍的SeLIE。37名儿童（n = 37/40，93%）接受了抗癫痫药物治疗，大多数（20/27有反应，74%）对钠通道阻滞剂有效。癫痫发作缓解的中位年龄为9个月（四分位间距3，10）（范围3 - 168个月）。
致病变异通常与SeLIE相关。然而，杂合变异可能会出现其他癫痫表型。对于携带杂合变异的个体，鉴于这两种情况之间的表型重叠，相应的染色体微阵列可能有助于评估是否伴有16p11.2微缺失。然而，需要收集更多病例以更好地了解与包含该基因的16p11.2微缺失以及纯合和复合杂合变异相关的癫痫表型谱。目前，尚缺乏精确的基因型 - 表型关系。
