Exome sequencing reveals compound heterozygous mutations in ATP8B1 in a JAG1/NOTCH2 mutation-negative patient with clinically diagnosed Alagille syndrome.
Exome sequencing reveals compound heterozygous mutations in ATP8B1 in a JAG1/NOTCH2 mutation-negative patient with clinically diagnosed Alagille syndrome.
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外显子组测序揭示了一名临床诊断为 Alagille 综合征的 JAG1/NOTCH2 突变阴性患者的 ATP8B1 复合杂合突变。
DOI：
10.1002/ajmg.a.36946
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Spinner,NancyB
中科院分区：
文献类型：
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作者：
Grochowski,ChristopherM;Rajagopalan,Ramakrishnan;Falsey,AlexandraM;Loomes,KathleenM;Piccoli,DavidA;Krantz,IanD;Devoto,Marcella;Spinner,NancyB
Alagille综合征（ALGS）是一种常染色体显性遗传疾病，其特征为胆管缺乏，伴有5种主要临床表现，包括胆汁淤积、心脏异常（最常见的是外周肺动脉狭窄或法洛四联症）、骨骼畸形（最常见的是蝶形椎骨或其他轻度椎骨异常）、眼部异常（最常见的是后部胚胎毒素）和特征性面部特征。其他受影响的系统包括肾脏和脉管系统，异常发生的频率低于五个主要系统。在基因检测可用之前，ALGS在胆管缺乏加上五个主要发现中的至少三个的个体中被临床诊断。临床诊断一致的ALGS患者中可识别的基因突变频率很高，其中94%的患者发现了JAGGED 1（JAG 1）突变，2%的患者发现了NOTCH 2突变。我们报告了一位女性患者，在婴儿期出现ALGS的五个临床特征中的四个，包括胆管缺乏和由此产生的胆汁淤积，心脏杂音，后部胚胎毒素和面部特征，经我们团队经验丰富的临床成员检查后与ALGS一致。这些面部特征包括高宽的前额、深陷的眼睛和三角形的脸，构成了ALGS的特征面部特征。这些发现导致ALGS（综合征性胆管缺乏）的临床诊断。根据报告，超声心动图正常，据我们所知，未进行进一步的心脏检查。据报道，该患者没有蝴蝶椎骨，但脊柱X光片的结果无法供审查。她在7岁时在我们的机构进行了评估，当时她的主要主诉是发育不良和多种药物治疗无效的严重瘙痒。当时，她的体重为13.2 kg（<第3百分位数;第50百分位数为2.5年），身高为99.8 cm（<第3百分位数;第50百分位数为4年）。当时进行的实验室检查显示总胆红素（1.7 mg/dl;正常范围0.6-1.4 mg/dl）和胆固醇（227 mg/dl;正常范围109- 189 mg/dl）轻微升高。除了γ谷氨酰转移酶外，肝酶均正常
Alagille syndrome (ALGS) is an autosomal dominant disorder characterized by bile duct paucity in combination with five primary clinical findings, including cholestasis, cardiac abnormalities (most commonly peripheral pulmonary stenosis or tetralogy of Fallot), skeletal malformations (most commonly butterfly vertebrae or other mild vertebral anomalies), ocular abnormalities (most commonly posterior embryotoxon), and characteristic facial features. Other affected systems include the kidney and vasculature, with anomalies occurring at lower frequency than in the five primary systems. Prior to the availability of genetic testing, ALGS was diagnosed clinically in individuals with bile duct paucity plus at least three of the five primary findings. The frequency of identifiable genetic mutations in ALGS patients with a clinically consistent diagnosis is high, with JAGGED1 (JAG1) mutations identified in 94% and NOTCH2 mutations in 2% of patients. We report on a female patient who presented in infancy with four out of five clinical features of ALGS, including bile duct paucity and resultant cholestasis, a cardiac murmur, posterior embryotoxon and facial features consistent with ALGS after examination by experienced clinical members of our team. These facial features included a high broad forehead, deep-set eyes and a triangular face constituting the characteristic facial features of ALGS. These findings led to a clinical diagnosis of ALGS (syndromic bile duct paucity). Echocardiography was normal by report and to our knowledge, no further cardiac workup was carried out. The patient was not reported to have butterfly vertebrae, but results of spine radiographs were not available for review. She was evaluated at our institution at age 7, at which time her main complaints were failure to thrive and severe pruritus refractory to multiple medications. At that time, her weight was 13.2 kg (< 3rd centile; 50th centile for 2.5 years) and height was 99.8 cm (< 3rd centile; 50th centile for 4 years). Laboratory testing done at that time revealed slightly elevated total bilirubin (1.7 mg/dl; normal range 0.6–1.4 mg/dl) and cholesterol (227mg/dl; normal range 109–189mg/dl). Liver enzymes were normal except for a gamma glutamyl transferase