Ben Ayed Ikhlas, Jallouli Olfa, Murakami Yoshiko, Souissi Amal, Mallouli Salma, Bouzid Amal, Kamoun Fatma, Elloumi Ines, Frikha Fakher, Tlili Abdelaziz, Weckhuysen Sarah, Kinoshita Taroh, Triki Chahnez Charfi, Masmoudi Saber
Laboratory of Molecular and Cellular Screening Processes (LPCMC), Center of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia.
Medical Genetics Department, University Hedi Chaker Hospital of Sfax, Sfax, Tunisia.
Front Neurol. 2023 Mar 9;14:1092887. doi: 10.3389/fneur.2023.1092887. eCollection 2023.
Pathogenic germline variants in the gene are associated with the "multiple congenital anomalies-hypotonia-seizures syndrome 3" (MCAHS3) phenotype. So far, fifty patients have been reported, most of whom suffer from intractable epilepsy. Recently, a comprehensive analysis of a cohort of 26 patients with variants has broadened the phenotypical spectrum and indicated that both p.Asn527Ser and p.Val528Met are associated with a milder epilepsy phenotype and less severe outcomes. Since all reported patients are of Caucasian/Polish origin and most harbor the same variant (p.Val528Met), the ability to draw definitive conclusions regarding the genotype-phenotype correlation remains limited. We report a new case with a homozygous variant p.Arg507Trp in the gene, detected on clinical exome sequencing. The North African patient in question displays a predominantly neurological phenotype with global developmental delay, hypotonia, brain abnormalities, and well-controlled epileptic seizures. Homozygous and heterozygous variants in codon 507 have been reported to cause deficiency without biochemical confirmation. In this study, FACS analysis of knockout HEK293 cells that had been transfected with wild-type or mutant cDNA constructs demonstrated that the p.Arg507Trp variant leads to mildly reduced activity. Our result confirm the pathogenicity of this variant and strengthen recently reported evidence on the genotype-phenotype correlation of the variant.
该基因的致病性种系变异与“多发性先天性异常-低张力-癫痫综合征3”（MCAHS3）表型相关。到目前为止，已报道了50例患者，其中大多数患有难治性癫痫。最近，对一组26例携带该变异的患者进行的综合分析拓宽了表型谱，并表明p.Asn527Ser和p.Val528Met均与较轻的癫痫表型和不太严重的预后相关。由于所有报道的患者均为白种人/波兰血统，且大多数携带相同的变异（p.Val528Met），因此就基因型-表型相关性得出明确结论的能力仍然有限。我们报告了1例通过临床外显子组测序检测到的该基因纯合变异p.Arg507Trp的新病例。该北非患者主要表现为神经学表型，伴有全面发育迟缓、低张力、脑部异常以及得到良好控制的癫痫发作。据报道，密码子507处的纯合和杂合变异可导致该蛋白缺乏，但未经生化确认。在本研究中，对转染了野生型或突变型cDNA构建体的基因敲除HEK293细胞进行的流式细胞术分析表明，p.Arg507Trp变异导致该蛋白活性轻度降低。我们的结果证实了该变异的致病性，并加强了最近报道的关于该基因变异的基因型-表型相关性的证据。
