背景:癫痫,一种具有挑战性的神经系统疾病,常伴有严重影响诊断和治疗的合并症。在巴基斯坦人口中,在财务限制和地理挑战阻碍获得先进的诊断方法的地方,了解癫痫的遗传基础及其相关疾病变得至关重要。
方法:这项研究调查了四个不同的巴基斯坦家庭,每个人都有癫痫和一系列合并症,使用全外显子组测序(WES)和Sanger测序的组合。癫痫患者服用了多种抗癫痫药物(ASM),然而他们的癫痫发作持续存在,表明ASM抵抗性癫痫的挑战性。
结果:鉴定的遗传变异导致了一系列不同的临床表型。在出现癫痫的家庭1中,发育迟缓(DD),睡眠障碍,和攻击性行为,纯合剪接位点变异体,c.1339-6C>T,在COL18A1基因中检测到。家庭2出现癫痫,智力残疾(ID),DD,和焦虑表型,纯合错义变体,c.344T>A(p。Val115Glu),在UFSP2基因中被鉴定。在显示癫痫的家庭3中,共济失调,ID,DD,和言语障碍,一种新的纯合移码变体,c.1926_1941del(p。Tyr643MetfsX2),在ZFYVE26基因中发现。最后,4个家庭患有癫痫,ID,DD,耳聋,流口水,言语障碍,低张力,微弱的哭声。纯合错义变体,c.1208C>A(p。Ala403Glu),在ATP13A2基因中进行了鉴定。
结论:这项研究强调了巴基斯坦家庭中ASM抵抗癫痫和合并症的遗传异质性,强调基因型-表型相关性的重要性以及在复杂临床病例中扩大基因检测的必要性。
BACKGROUND: Epilepsy, a challenging neurological condition, is often present with comorbidities that significantly impact diagnosis and management. In the Pakistani population, where financial limitations and geographical challenges hinder access to advanced diagnostic methods, understanding the genetic underpinnings of epilepsy and its associated conditions becomes crucial.
METHODS: This study investigated four distinct Pakistani families, each presenting with epilepsy and a spectrum of comorbidities, using a combination of whole exome sequencing (WES) and Sanger sequencing. The epileptic patients were prescribed multiple antiseizure medications (ASMs), yet their seizures persist, indicating the challenging nature of ASM-resistant epilepsy.
RESULTS: Identified genetic variants contributed to a diverse range of clinical phenotypes. In the family 1, which presented with epilepsy, developmental delay (DD), sleep disturbance, and aggressive behavior, a homozygous splice site variant, c.1339-6 C > T, in the COL18A1 gene was detected. The family 2 exhibited epilepsy, intellectual disability (ID), DD, and anxiety phenotypes, a homozygous missense variant, c.344T > A (p. Val115Glu), in the UFSP2 gene was identified. In family 3, which displayed epilepsy, ataxia, ID, DD, and speech impediment, a novel homozygous frameshift variant, c.1926_1941del (p. Tyr643MetfsX2), in the ZFYVE26 gene was found. Lastly, family 4 was presented with epilepsy, ID, DD, deafness, drooling, speech impediment, hypotonia, and a weak cry. A homozygous missense variant, c.1208 C > A (p. Ala403Glu), in the ATP13A2 gene was identified.
CONCLUSIONS: This study highlights the genetic heterogeneity in ASM-resistant epilepsy and comorbidities among Pakistani families, emphasizing the importance of genotype-phenotype correlation and the necessity for expanded genetic testing in complex clinical cases.