Mendelian etiologies identified with whole exome sequencing in cerebral palsy.
Mendelian etiologies identified with whole exome sequencing in cerebral palsy.
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DOI：
10.1002/acn3.51506
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发表时间：
2022-03
影响因子：
5.3
通讯作者：
Srivastava S
中科院分区：
文献类型：
--
作者：
Chopra M;Gable DL;Love-Nichols J;Tsao A;Rockowitz S;Sliz P;Barkoudah E;Bastianelli L;Coulter D;Davidson E;DeGusmao C;Fogelman D;Huth K;Marshall P;Nimec D;Sanders JS;Shore BJ;Snyder B;Stone SSD;Ubeda A;Watkins C;Berde C;Bolton J;Brownstein C;Costigan M;Ebrahimi-Fakhari D;Lai A;O'Donnell-Luria A;Paciorkowski AR;Pinto A;Pugh J;Rodan L;Roe E;Swanson L;Zhang B;Kruer MC;Sahin M;Poduri A;Srivastava S
脑性瘫痪（CP）是最常见的儿童运动障碍，但其与单基因疾病的联系尚不清楚。为了探索CP的遗传景观，我们在一组CP患者中进行了全外显子组测序（WES）。我们对隐源性CP（符合CP标准;没有风险因素），非隐源性CP（符合CP标准;至少有一个风险因素）和CP伪装者（可以诊断为CP，但有消退/进行性症状）的前瞻性队列进行了全面的表型分析和WES。我们的特点运动表型，确定医疗合并症，并分类脑MRI。我们使用机构管道分析了WES数据。我们纳入了50名先证者（20名女性，30名男性）。24例隐源性CP，20例非隐源性CP，5例CP伪装分类，1例分类未知。低渗-共济失调亚型在分类组间的患病率存在差异（p = 0.01）。26%的受试者（13/50）在13个独特基因（ECHS 1、SATB 2、ZMYM 2、ADAT 3、COL 4A 1、THOC 2、SLC 16 A2、SPAST、POLR 2A、GNAO 1、PDHX、ACADM、ATL 1）中存在致病性/可能致病性变异，包括1名患有2种遗传疾病（ACADM、PDHX）的患者和2名患有SPAST相关疾病的患者。CP伪装者类别的诊断率最高（n = 3/5，60%），其次是隐源性CP类别（n = 7/24，29%）。15%的非隐源性CP患者（n = 3/20）在WES上患有孟德尔疾病。WES证明临床诊断为CP的个体中孟德尔疾病的显著患病率，包括具有已知CP风险因素的个体。
Cerebral palsy (CP) is the most common childhood motor disability, yet its link to single‐gene disorders is under‐characterized. To explore the genetic landscape of CP, we conducted whole exome sequencing (WES) in a cohort of patients with CP. We performed comprehensive phenotyping and WES on a prospective cohort of individuals with cryptogenic CP (who meet criteria for CP; have no risk factors), non‐cryptogenic CP (who meet criteria for CP; have at least one risk factor), and CP masqueraders (who could be diagnosed with CP, but have regression/progressive symptoms). We characterized motor phenotypes, ascertained medical comorbidities, and classified brain MRIs. We analyzed WES data using an institutional pipeline. We included 50 probands in this analysis (20 females, 30 males). Twenty‐four had cryptogenic CP, 20 had non‐cryptogenic CP, five had CP masquerader classification, and one had unknown classification. Hypotonic‐ataxic subtype showed a difference in prevalence across the classification groups (p = 0.01). Twenty‐six percent of participants (13/50) had a pathogenic/likely pathogenic variant in 13 unique genes (ECHS1, SATB2, ZMYM2, ADAT3, COL4A1, THOC2, SLC16A2, SPAST, POLR2A, GNAO1, PDHX, ACADM, ATL1), including one patient with two genetic disorders (ACADM, PDHX) and two patients with a SPAST‐related disorder. The CP masquerader category had the highest diagnostic yield (n = 3/5, 60%), followed by the cryptogenic CP category (n = 7/24, 29%). Fifteen percent of patients with non‐cryptogenic CP (n = 3/20) had a Mendelian disorder on WES. WES demonstrated a significant prevalence of Mendelian disorders in individuals clinically diagnosed with CP, including in individuals with known CP risk factors.
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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