■生化检测是对无法解释的发育迟缓患者进行遗传评估的一种常见的第一层方法。然而,结果可能不清楚,必须根据患者的生化结果和临床表现确定二级分析计划-在许多情况下,触发诊断冒险。
■一名美国男性患者,出现无法解释的发育迟缓,小头畸形,低张力,喂养困难在8月龄时被转介进行临床遗传评估。生化测试显示,尿液有机酸谱上戊二酸的浓度明显升高,无相关代谢物升高。进一步的测试包括GCDH测序,神经代谢基因小组,染色体微阵列,PraderWilli/Angelman测试,和溶酶体病酶组,所有这些都是非诊断性的。病人有持续的发育迟缓和低张力,肌张力障碍,感觉神经性听力损失,和磁共振成像的异常脑髓鞘形成。进行全外显子组测序(WES),发现戊二酸尿症III(GAIII)和BCAP31相关疾病的双重诊断,X-连锁智力障碍综合征,由一种新的致病变异引起的。
■GAIII历来被认为是良性的,报告病例很少。该患者的症状与GAI和GAII中常见的症状相似,然而生化异常与这些疾病不一致,提示额外的分子和生化测试。最终,WES证实了BCAP31相关综合征的诊断,一种罕见的神经系统疾病,这解释了病人出现的症状。WES还确定了GAIII的二级诊断。我们介绍了一个有两种罕见遗传病的病人,强调深度表型的重要性和WES在双基因诊断患者中的实用性。
UNASSIGNED: 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.
UNASSIGNED: 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 GCDH 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 BCAP31-related disorder, an X-linked intellectual disability syndrome, caused by a novel pathogenic variant.
UNASSIGNED: 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 BCAP31-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.