Aboud Syriani Dona, Wong Darice, Andani Sameer, De Gusmao Claudio M, Mao Yuanming, Sanyoura May, Glotzer Giacomo, Lockhart Paul J, Hassin-Baer Sharon, Khurana Vikram, Gomez Christopher M, Perlman Susan, Das Soma, Fogel Brent L
Department of Neurology (D.A.S., D.W., Y.M., S.P., B.L.F.), Program in Neurogenetics, David Geffen School of Medicine, University of California, Los Angeles; Department of Neurology (D.W., B.L.F.), Clinical Neurogenomics Research Center, David Geffen School of Medicine, University of California, Los Angeles; Department of Human Genetics (S.A., M.S., S.D.), University of Chicago, IL; Department of Neurology (C.M.D.G., V.K.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Neurology (G.G., C.M.G.), University of Chicago, IL; Bruce Lefroy Centre (P.J.L.), Murdoch Children's Research Institute; Department of Paediatrics (P.J.L.), University of Melbourne, Parkville, Australia; Sackler Faculty of Medicine (S.H.-B.), Tel-Aviv University, Tel-Aviv, Israel; and Department of Human Genetics (B.L.F.), David Geffen School of Medicine, University of California, Los Angeles.
Neurol Genet. 2020 May 20;6(3):e440. doi: 10.1212/NXG.0000000000000440. eCollection 2020 Jun.
We evaluated the prevalence of pathogenic repeat expansions in replication factor C subunit 1 () and disabled adaptor protein 1 in an undiagnosed ataxia cohort from North America.
A cohort of 596 predominantly adult-onset patients with undiagnosed familial or sporadic cerebellar ataxia was evaluated at a tertiary referral ataxia center and excluded for common genetic causes of cerebellar ataxia. Patients were then screened for the presence of pathogenic repeat expansions in (AAGGG) and (ATTTC) using fluorescent repeat-primed PCR (RP-PCR). Two additional undiagnosed ataxia cohorts from different centers, totaling 302 and 13 patients, respectively, were subsequently screened for , resulting in a combined 911 subjects tested.
In the initial cohort, 41 samples were identified with 1 expanded allele in the gene (6.9%), and 9 had 2 expanded alleles (1.5%). For the additional cohorts, we found 20 heterozygous samples (6.6%) and 17 biallelic samples (5.6%) in the larger cohort and 1 heterozygous sample (7.7%) and 3 biallelic samples (23%) in the second. In total, 29 patients were identified with biallelic repeat expansions in (3.2%). Of these 29 patients, 8 (28%) had a clinical diagnosis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), 14 had cerebellar ataxia with neuropathy (48%), 4 had pure cerebellar ataxia (14%), and 3 had spinocerebellar ataxia (10%). No patients were identified with expansions in the gene (spinocerebellar ataxia type 37).
In a large undiagnosed ataxia cohort from North America, biallelic pathogenic repeat expansion in was observed in 3.2%. Testing should be strongly considered in patients with ataxia, especially those with CANVAS or neuropathy.
我们评估了北美一个未确诊共济失调队列中复制因子C亚基1（）和失活衔接蛋白1中致病重复序列扩增的患病率。
在一家三级转诊共济失调中心对一组主要为成年发病的596例未确诊的家族性或散发性小脑共济失调患者进行了评估，并排除了小脑共济失调的常见遗传病因。然后使用荧光重复引物PCR（RP-PCR）对患者进行（AAGGG）和（ATTTC）中致病重复序列扩增的筛查。随后对另外两个来自不同中心的未确诊共济失调队列（分别为302例和13例患者）进行了筛查，总计911名受试者接受了检测。
在初始队列中，41个样本在基因中检测到1个扩增等位基因（6.9%），9个样本有2个扩增等位基因（1.5%）。对于另外两个队列，在较大的队列中我们发现了20个杂合样本（6.6%）和17个双等位基因样本（5.6%），在第二个队列中发现了1个杂合样本（7.7%）和3个双等位基因样本（23%）。总共29例患者被鉴定为基因双等位基因重复扩增（3.2%）。在这29例患者中，8例（28%）临床诊断为小脑共济失调、神经病和前庭反射消失综合征（CANVAS），14例患有小脑共济失调伴神经病（48%），4例患有单纯小脑共济失调（14%），3例患有脊髓小脑共济失调（10%）。未发现患者基因（脊髓小脑共济失调37型）有扩增。
在北美一个大型未确诊共济失调队列中，观察到基因双等位致病重复扩增的比例为3.2%。对于共济失调患者，尤其是患有CANVAS或神经病的患者，应强烈考虑进行检测。
