基因组测序提供了一个无针对性的,数据驱动的基因诊断方法;然而,意义不确定的变异通常会阻碍诊断过程。在没有先前已知的致病性功能证据的情况下发现罕见的基因组变异,通常会导致变异被忽略为潜在的致病因素。特别是在具有未分化表型的个体中。因此,许多神经代谢疾病,包括GABA(γ-氨基丁酸)分解代谢途径中的那些,被诊断不足。琥珀酸半醛脱氢酶缺乏症(SSADHD,OMIM#271980)是GABA分解代谢途径中的神经代谢紊乱。该疾病是由于ALDH5A1的双等位基因致病变异,通常以中度至重度发育迟缓为特征,低张力,智力残疾,共济失调,癫痫发作,运动过度行为,侵略,精神疾病,和睡眠障碍。在这项研究中,我们利用一种综合方法来诊断SSADHD,通过检查分子,临床,和来自单个大型商业实验室的代谢组学数据。我们的分析导致鉴定出16例可能患有SSADHD的患者以及三种新的变体。我们还表明,患有这种疾病的患者具有清晰的代谢组学特征,连同分子和临床发现,可以允许更快速和有效的诊断。我们进一步调查了所有可用的致病/可能的致病变异,并使用这些信息来估计这种疾病的全球患病率。一起来看,我们的综合分析为SSADHD的诊断提供了全球方法,并为改善诊断和纳入新生儿筛查计划提供了途径.此外,早期诊断有助于转诊到遗传咨询,家庭支持,以及获得有针对性的治疗——一起服用,这些为患有GABA-TD或SSADHD的个体提供了最好的结果,以及其他罕见的情况。
Genomic sequencing offers an untargeted, data-driven approach to genetic diagnosis; however, variants of uncertain significance often hinder the diagnostic process. The discovery of rare genomic variants without previously known functional evidence of pathogenicity often results in variants being overlooked as potentially causative, particularly in individuals with undifferentiated phenotypes. Consequently, many neurometabolic conditions, including those in the GABA (gamma-aminobutyric acid) catabolism pathway, are underdiagnosed. Succinic semialdehyde dehydrogenase deficiency (SSADHD, OMIM #271980) is a neurometabolic disorder in the GABA catabolism pathway. The disorder is due to bi-allelic pathogenic variants in
ALDH5A1 and is usually characterized by moderate-to-severe developmental delays, hypotonia, intellectual disability, ataxia, seizures, hyperkinetic behavior, aggression, psychiatric disorders, and sleep disturbances. In this study, we utilized an integrated approach to diagnosis of SSADHD by examining molecular, clinical, and metabolomic data from a single large commercial laboratory. Our analysis led to the identification of 16 patients with likely SSADHD along with three novel variants. We also showed that patients with this disorder have a clear metabolomic signature that, along with molecular and clinical findings, may allow for more rapid and efficient diagnosis. We further surveyed all available pathogenic/likely pathogenic variants and used this information to estimate the global prevalence of this disease. Taken together, our comprehensive analysis allows for a global approach to the diagnosis of SSADHD and provides a pathway to improved diagnosis and potential incorporation into newborn screening programs. Furthermore, early diagnosis facilitates referral to genetic counseling, family support, and access to targeted treatments-taken together, these provide the best outcomes for individuals living with either GABA-TD or SSADHD, as well as other rare conditions.