Huggins Erin, Jackson David G, Young Sarah P, Kishnani Priya S
Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
Duke University Health System Biochemical Genetics Laboratory, Durham, NC, USA.
Mol Genet Metab Rep. 2024 Jul 9;40:101117. doi: 10.1016/j.ymgmr.2024.101117. eCollection 2024 Sep.
Biochemical testing is a common first-tier approach in the setting of genetic evaluation of patients with unexplained developmental delay. However, results can be unclear, and a plan for second-tier analysis must be determined based on the patient's biochemical results and clinical presentation - in many cases, triggering a diagnostic odyssey.
A male patient from the United States presenting with unexplained developmental delay, microcephaly, hypotonia, and feeding difficulties was referred for clinical genetic evaluation at age 8 months. Biochemical testing revealed an isolated marked elevation of glutaric acid on urine organic acid profile, without elevations of related metabolites. Further testing included sequencing, a neurometabolic gene panel, chromosomal microarray, Prader Willi/Angelman testing, and lysosomal disease enzyme panel, all of which were non-diagnostic. The patient had persistent developmental delay and hypotonia, dystonia, sensorineural hearing loss, and abnormal brain myelination on magnetic resonance imaging. Whole exome sequencing (WES) was performed and revealed a dual diagnosis of glutaric aciduria III (GA III) and related disorder, an X-linked intellectual disability syndrome, caused by a novel pathogenic variant.
GA III has historically been considered clinically benign, with few reported cases. This patient's presenting symptoms were similar to those commonly seen in GA I and GA II, however the biochemical abnormalities were not consistent with these disorders, prompting additional molecular and biochemical testing. Ultimately, WES confirmed a diagnosis of -related syndrome, a rare neurological disorder, which explained the patient's presenting symptoms. WES also identified a secondary diagnosis of GA III. We present a patient with two rare genetic conditions, highlighting the importance of deep phenotyping and the utility of WES in the setting of a patient with dual genetic diagnoses.
在对不明原因发育迟缓患者进行基因评估时，生化检测是一种常见的一线方法。然而，结果可能不明确，必须根据患者的生化结果和临床表现确定二线分析计划——在许多情况下，这会引发一段诊断历程。
一名来自美国的男性患者，出现不明原因的发育迟缓、小头畸形、肌张力减退和喂养困难，8个月大时被转诊进行临床基因评估。生化检测显示尿有机酸谱中戊二酸单独显著升高，相关代谢物未升高。进一步检测包括测序、神经代谢基因 panel、染色体微阵列、普拉德-威利/安吉尔曼检测和溶酶体疾病酶 panel，所有这些检测均未得出诊断结果。该患者持续存在发育迟缓和肌张力减退、肌张力障碍、感音神经性听力损失，磁共振成像显示脑髓鞘形成异常。进行了全外显子组测序（WES），结果显示为戊二酸尿症III型（GA III）和相关疾病的双重诊断，这是一种由新型致病变异引起的X连锁智力障碍综合征。
GA III在历史上一直被认为临床症状较轻，报道的病例很少。该患者的表现症状与GA I和GA II中常见的症状相似，然而生化异常与这些疾病不一致，促使进行额外的分子和生化检测。最终，WES确诊为一种相关综合征，这是一种罕见的神经疾病，解释了患者的表现症状。WES还确定了GA III的次要诊断。我们介绍了一名患有两种罕见遗传病的患者，强调了深度表型分析的重要性以及WES在双重基因诊断患者中的实用性。
