Department of Medical Genomics, Centre for Genomic Medicine, MBC: 75, P.O. Box 3354, King Faisal Specialist Hospital, and Research Centre, Riyadh 11211, Saudi Arabia.
College of Medicine, P.O. Box 50927, AlFaisal University, Riyadh 11533, Saudi Arabia.
Genes (Basel). 2022 Nov 30;13(12):2252. doi: 10.3390/genes13122252.
Heterozygous pathogenic variants in are linked to an autosomal dominant form of epileptic encephalopathy. Recently, homozygous loss-of-function variants in were reported to cause an autosomal recessive form of developmental and epileptic encephalopathy in unrelated patients. Here, we investigated a singleton from a first-degree cousin marriage who presented with facial dysmorphism, global developmental delay, seizure disorder, and nystagmus. To identify the involvement of any likely genetic cause, diagnostic clinical exome sequencing was performed. Comprehensive filtering revealed a single plausible candidate variant in . Sanger sequencing of the trio, the patient, and her parents, confirmed the full segregation of the variant. The variant is a deletion leading to a premature stop codon and is predicted to cause a protein truncation. Structural modeling implicated a complete loss of function of the Dynamin 1 (DNM1). Such mutation is predicted to impair the nucleotide binding, dimer formation, and GTPase activity of DNM1. Our study expands the phenotypic spectrum of pathogenic homozygous loss-of-function variants in .
在 中存在杂合致病性变异与常染色体显性形式的癫痫性脑病相关。最近，在无关联的患者中报道了 中的纯合功能丧失变异导致常染色体隐性形式的发育性和癫痫性脑病。在这里，我们研究了一位来自一级表亲婚姻的单身患者，其表现为面部畸形、全面发育迟缓、癫痫发作和眼球震颤。为了确定任何可能的遗传原因的参与，进行了诊断性临床外显子组测序。全面筛选显示 中存在单一合理的候选变异。对三人组、患者及其父母进行 Sanger 测序，证实了该变异的完全分离。该变异是一个导致提前终止密码子的缺失，预计会导致蛋白质截断。结构建模表明 Dynamin 1（DNM1）完全失去功能。这种突变预计会损害 DNM1 的核苷酸结合、二聚体形成和 GTPase 活性。我们的研究扩展了 中致病性纯合功能丧失变异的表型谱。
