Li Jinliang, Xie Han, Jiang Yuwu
Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China.
BMC Med Genet. 2018 Apr 2;19(1):51. doi: 10.1186/s12881-018-0562-4.
Sanfilippo type B syndrome (mucopolysac-charidosis type IIIB; MPS IIIB) is an autosomal recessive lysosomal storage disorder. It is caused by a critically reduced α-2-acetamido-2-deoxy-D-glucoside acetamidodeoxy glucohydrolase (α-N-acetylglucosaminidase or NAGLU) activity. Recently, an autosomal recessive disorder of skeletal dysplasia associated with CYP26B1 was reported in three families, in which the patients were all homozygous variations. However, the co-occurrence of two rare diseases in a person is very rare. Here, we reported one patient with two novel pathogenic missense variations in NAGLU and CYP26B1.
We found an infant with biallelic variation both in NAGLU-compound heterozygous c.1843C > T (p. R615C) and c.1224C > A (p. H408Q) as well as in CYP26B1-compound heterozygous c.529G > A (p. E177K) and c.525C > A (p. H175Q). All variations were novel but predicted pathogenicity according to American College of Medical Genetics and Genomics (ACMG) guidelines. The main phenotypes of the infant were quite different from those previously reported, and some were combinations of the two rare diseases, including epilepsy, early onset epileptic encephalopathy, hypermyotonia, skull deformity, dilatation of the lateral ventricles and premature closure of fontanel. His NAGLU enzyme activity was significantly decreased.
NAGLU and CYP26B1 mutations were related to MPS IIIB and skeletal dysplasia, respectively. Here, we first reported the pathogenic mutations of two genes concurrent in one patient, which not only expands the phenotype and genotype spectra of NAGLU and CYP26B1, but more importantly indicates the possibility of simultaneous occurrence of two rare diseases in one patient. This interesting finding should be attributed to the use of whole exome sequencing (WES), which indicates that we should be aware of the importance of WES in diagnosing rare diseases.
桑菲利波B型综合征（黏多糖贮积症IIIB型；MPS IIIB）是一种常染色体隐性溶酶体贮积症。它是由α-2-乙酰氨基-2-脱氧-D-葡萄糖苷乙酰氨基脱氧葡糖苷水解酶（α-N-乙酰葡糖胺酶或NAGLU）活性严重降低引起的。最近，在三个家庭中报道了一种与CYP26B1相关的常染色体隐性骨骼发育不良疾病，其中患者均为纯合变异。然而，一个人同时患两种罕见疾病的情况非常罕见。在此，我们报告了一名患者，其NAGLU和CYP26B1存在两种新的致病性错义变异。
我们发现一名婴儿，其NAGLU基因存在双等位基因变异，为复合杂合子c.1843C>T（p.R615C）和c.1224C>A（p.H408Q），同时CYP26B1基因也存在复合杂合子c.529G>A（p.E177K）和c.525C>A（p.H175Q）。所有变异均为新发现，但根据美国医学遗传学与基因组学学会（ACMG）指南预测具有致病性。该婴儿的主要表型与先前报道的有很大不同，有些是两种罕见疾病的组合，包括癫痫、早发性癫痫性脑病、高肌张力、颅骨畸形、侧脑室扩张和囟门过早闭合。其NAGLU酶活性显著降低。
NAGLU和CYP26B1突变分别与MPS IIIB和骨骼发育不良有关。在此，我们首次报告了一名患者同时存在两个基因的致病性突变，这不仅扩展了NAGLU和CYP26B1的表型和基因型谱，更重要的是表明了一名患者同时患两种罕见疾病的可能性。这一有趣的发现应归功于全外显子测序（WES）的应用，这表明我们应意识到WES在罕见病诊断中的重要性。
