PDF(Pubmed)
Abstract：
UNASSIGNED: Multiple sclerosis (MS) shares clinical/radiological features with several monogenic diseases that can mimic MS.
UNASSIGNED: We aimed to determine if exome sequencing can identify monogenic diseases in patients diagnosed with MS according to the McDonald criteria thus uncovering them as being misdiagnosed.
UNASSIGNED: We performed whole exome sequencing in a cohort of 278 patients with MS, clinically or radiologically isolated syndrome without cerebrospinal fluid-specific oligoclonal bands (CSF-OCBs) (n = 228), a positive family history of MS (n = 44), or both (n = 6), thereby focusing on individuals potentially more likely to have underlying monogenic conditions mimicking MS. We prioritized 495 genes associated with monogenic diseases sharing features with MS.
UNASSIGNED: A disease-causing variant in NOTCH3 was identified in one patient without CSF-OCBs, no spinal lesions, with non-response to immunotherapy, and a family history of dementia, thereby converting the diagnosis to cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Moreover, 18 patients (6.5% of total) carried variants of unclear significance.
UNASSIGNED: Monogenic diseases being misdiagnosed as MS seem rare in patients diagnosed with MS according to the McDonald criteria, even in CSF-OCB negative cases. The detected pathogenic NOTCH3 variant emphasizes CADASIL as a rare differential diagnosis and highlights the relevance of genetic testing in selected MS cases with atypical presentations.
UNASSIGNED: We aimed to determine if exome sequencing can identify monogenic diseases in patients diagnosed with MS according to the McDonald criteria thus uncovering them as being misdiagnosed.
UNASSIGNED: We performed whole exome sequencing in a cohort of 278 patients with MS, clinically or radiologically isolated syndrome without cerebrospinal fluid-specific oligoclonal bands (CSF-OCBs) (n = 228), a positive family history of MS (n = 44), or both (n = 6), thereby focusing on individuals potentially more likely to have underlying monogenic conditions mimicking MS. We prioritized 495 genes associated with monogenic diseases sharing features with MS.
UNASSIGNED: A disease-causing variant in NOTCH3 was identified in one patient without CSF-OCBs, no spinal lesions, with non-response to immunotherapy, and a family history of dementia, thereby converting the diagnosis to cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Moreover, 18 patients (6.5% of total) carried variants of unclear significance.
UNASSIGNED: Monogenic diseases being misdiagnosed as MS seem rare in patients diagnosed with MS according to the McDonald criteria, even in CSF-OCB negative cases. The detected pathogenic NOTCH3 variant emphasizes CADASIL as a rare differential diagnosis and highlights the relevance of genetic testing in selected MS cases with atypical presentations.
摘要：
多发性硬化症（MS）与几种可以模仿MS的单基因疾病具有共同的临床/放射学特征。
■我们旨在确定外显子组测序是否可以根据McDonald标准识别诊断为MS的患者的单基因疾病，从而发现它们被误诊。
■我们对278例MS患者进行了全外显子组测序，临床或放射学孤立综合征，无脑脊液特异性寡克隆带（CSF-OCB）（n=228），MS家族史阳性（n=44），或两者(n=6)，从而专注于可能更有可能具有模仿MS的潜在单基因疾病的个体。我们优先考虑了与MS共享特征的单基因疾病相关的495个基因。
■在一名没有CSF-OCB的患者中发现了NOTCH3的致病变异，没有脊髓损伤,对免疫疗法没有反应，有痴呆症家族史,从而将诊断转化为伴有皮质下梗塞和白质脑病的常染色体显性遗传性脑动脉病（CADASIL）。此外，18例患者（占总数的6.5%）携带了意义不明的变异。
■单基因疾病被误诊为MS，在根据麦当劳标准诊断为MS的患者中似乎很少见，即使在CSF-OCB阴性病例中。检测到的致病性NOTCH3变体强调CADASIL是一种罕见的鉴别诊断，并强调了在具有非典型表现的某些MS病例中进行基因检测的相关性。
■我们旨在确定外显子组测序是否可以根据McDonald标准识别诊断为MS的患者的单基因疾病，从而发现它们被误诊。
■我们对278例MS患者进行了全外显子组测序，临床或放射学孤立综合征，无脑脊液特异性寡克隆带（CSF-OCB）（n=228），MS家族史阳性（n=44），或两者(n=6)，从而专注于可能更有可能具有模仿MS的潜在单基因疾病的个体。我们优先考虑了与MS共享特征的单基因疾病相关的495个基因。
■在一名没有CSF-OCB的患者中发现了NOTCH3的致病变异，没有脊髓损伤,对免疫疗法没有反应，有痴呆症家族史,从而将诊断转化为伴有皮质下梗塞和白质脑病的常染色体显性遗传性脑动脉病（CADASIL）。此外，18例患者（占总数的6.5%）携带了意义不明的变异。
■单基因疾病被误诊为MS，在根据麦当劳标准诊断为MS的患者中似乎很少见，即使在CSF-OCB阴性病例中。检测到的致病性NOTCH3变体强调CADASIL是一种罕见的鉴别诊断，并强调了在具有非典型表现的某些MS病例中进行基因检测的相关性。
