Harrison Alicia G, Magielski Jan H, McSalley Ian, Ganesan Shiva, Prentice Anna J, Cunningham Kristin G, Pierce Samuel R, Boland Michael J, Prosser Benjamin L, Helbig Ingo, McKee Jillian L
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Epilepsia. 2025 May 23. doi: 10.1111/epi.18469.
SYNGAP1-related disorders are common neurodevelopmental conditions characterized by autism spectrum disorder, developmental delay, intellectual disability, and a range of generalized seizure types. Disease-causing variants in SYNGAP1 typically occur de novo. This study aims to characterize inherited cases of SYNGAP1-related disorders.
Here we report three families including eight total individuals with inherited, protein-truncating variants in SYNGAP1, recruited through a natural history study. In two of the families, the proband inherited their pathogenic variant from a heterozygous parent. In the remaining family, the variant was inherited from a mosaic parent. This study additionally reports two families with inherited missense variants classified as variants of uncertain significance, which are not clearly diagnostic at this time.
Phenotypes in affected children and parents included both typical and attenuated SYNGAP1 presentations, including a single individual with a mosaic SYNGAP1 variant who was clinically unaffected. Among the individuals with protein-truncating variants, generalized epilepsy was observed in six individuals, autism spectrum disorder in two individuals, and developmental delay or intellectual disability in all individuals with germline variants.
We demonstrate that SYNGAP1-related disorder can occur in families and that clinical presentations of familial cases are not limited to milder phenotypes. We estimate that 3% of cases of SYNGAP1-related disorder are inherited. Recognition of familial SYNGAP1-related disorders delineates edge cases of a relatively common neurodevelopmental disorder and has implications for variant interpretation and clinical practice.
SYNGAP1相关疾病是常见的神经发育疾病，其特征为自闭症谱系障碍、发育迟缓、智力残疾以及一系列全身性癫痫类型。SYNGAP1中的致病变异通常为新发突变。本研究旨在对SYNGAP1相关疾病的遗传病例进行特征描述。
在此，我们报告了三个家族，共八名个体，他们通过一项自然病史研究招募而来，携带SYNGAP1中遗传性的蛋白质截短变异。在其中两个家族中，先证者从杂合子父母那里遗传了其致病变异。在其余一个家族中，该变异是从嵌合型父母那里遗传而来。本研究还报告了另外两个家族，其携带被分类为意义未明变异的遗传性错义变异，目前这些变异尚不能明确用于诊断。
受影响儿童和父母的表型包括典型和症状减轻的SYNGAP1表现，其中包括一名携带SYNGAP1嵌合变异但临床未受影响的个体。在携带蛋白质截短变异的个体中，六名个体出现全身性癫痫，两名个体患有自闭症谱系障碍，所有携带种系变异的个体均有发育迟缓或智力残疾。
我们证明SYNGAP1相关疾病可在家族中发生，且家族性病例的临床表现并不局限于较轻的表型。我们估计3%的SYNGAP1相关疾病病例是遗传性的。对家族性SYNGAP1相关疾病的认识界定了一种相对常见的神经发育疾病的边缘病例，并对变异解读和临床实践具有启示意义。
