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Abstract：
BACKGROUND: Nephronophthisis (NPHP) is a genetically heterogeneous disease that can lead to end-stage renal disease (ESRD) in children. The TTC21B variant is associated with NPHP12 and mainly characterized by cystic kidney disease, skeletal malformation, liver fibrosis, and retinopathy. Affected patients range from children to adults. Some patients experience ESRD in infancy or early childhood, but clinical reports on neonatal patients are rare. We report a case of NPHP12 in a premature infant and analyze its genetic etiology.
METHODS: Trio-whole exome sequencing analysis was performed on the patient and her parents; bioinformatics software was used to predict and analyze the hazards of the variants. Sanger sequencing was performed to verify variants. We calculated the free energy between mutant IFT139 and the IFT121-IFT122-IFT43 complex structure using molecular dynamics (MD). Finally, the clinical and genetic characteristics of patients with hotspot variant Cys518Arg were reviewed.
RESULTS: Genetic analysis revealed compound-heterozyous TTC21B variants in the patient, c.497delA (p.Lys166fs*36) and c.1552T>C (p.Cys518Arg). Her father and mother had heterozygous c.497delA (p.Lys166fs*36) and heterozygous c.1552T>C (p.Cys518Arg), respectively. Cys518Arg represents a hotspot variant, and the MD calculation results show that this can reduce the structural stability of the IFT121-IFT122-IFT139-IFT43 complex structure. A literature review showed that Cys518Arg might lead to the early occurrence of ESRD.
CONCLUSIONS: Compound-heterozygous TTC21B variants underlie the phenotype in this patient. Thus, Cys518Arg may be a hotspot variant in the Chinese population. Genetic testing should be recommended for NPHP in neonates and early infants.
METHODS: Trio-whole exome sequencing analysis was performed on the patient and her parents; bioinformatics software was used to predict and analyze the hazards of the variants. Sanger sequencing was performed to verify variants. We calculated the free energy between mutant IFT139 and the IFT121-IFT122-IFT43 complex structure using molecular dynamics (MD). Finally, the clinical and genetic characteristics of patients with hotspot variant Cys518Arg were reviewed.
RESULTS: Genetic analysis revealed compound-heterozyous TTC21B variants in the patient, c.497delA (p.Lys166fs*36) and c.1552T>C (p.Cys518Arg). Her father and mother had heterozygous c.497delA (p.Lys166fs*36) and heterozygous c.1552T>C (p.Cys518Arg), respectively. Cys518Arg represents a hotspot variant, and the MD calculation results show that this can reduce the structural stability of the IFT121-IFT122-IFT139-IFT43 complex structure. A literature review showed that Cys518Arg might lead to the early occurrence of ESRD.
CONCLUSIONS: Compound-heterozygous TTC21B variants underlie the phenotype in this patient. Thus, Cys518Arg may be a hotspot variant in the Chinese population. Genetic testing should be recommended for NPHP in neonates and early infants.
摘要：
背景：Nephronophisis（NPHP）是一种遗传异质性疾病，可导致儿童终末期肾病（ESRD）。TTC21B变体与NPHP12相关，主要表现为囊性肾病，骨骼畸形,肝纤维化,和视网膜病变。受影响的患者范围从儿童到成人。一些患者在婴儿期或儿童早期经历ESRD，但是新生儿患者的临床报告很少见。我们报告了一例早产儿NPHP12病例，并分析了其遗传病因。
方法：对患者及其父母进行三全外显子组测序分析；使用生物信息学软件预测和分析变异的危害。进行Sanger测序以验证变体。我们使用分子动力学（MD）计算了突变体IFT139和IFT121-IFT122-IFT43复合物结构之间的自由能。最后,对热点变异型Cys518Arg患者的临床和遗传学特征进行综述。
结果：遗传分析显示患者的复合杂合TTC21B变体，c.497delA（p.Lys166fs*36）和c.1552T>C（p。Cys518Arg）。她的父亲和母亲有杂合c.497delA（p。Lys166fs*36）和杂合c.1552T>C（p。Cys518Arg），分别。Cys518Arg代表热点变体，MD计算结果表明,这会降低IFT121-IFT122-IFT139-IFT43复合结构的结构稳定性。文献综述显示Cys518Arg可能导致ESRD的早期发生。
结论：复合杂合TTC21B变体是该患者表型的基础。因此，Cys518Arg可能是中国人群中的热点变体。应建议对新生儿和早期婴儿进行NPHP基因检测。
方法：对患者及其父母进行三全外显子组测序分析；使用生物信息学软件预测和分析变异的危害。进行Sanger测序以验证变体。我们使用分子动力学（MD）计算了突变体IFT139和IFT121-IFT122-IFT43复合物结构之间的自由能。最后,对热点变异型Cys518Arg患者的临床和遗传学特征进行综述。
结果：遗传分析显示患者的复合杂合TTC21B变体，c.497delA（p.Lys166fs*36）和c.1552T>C（p。Cys518Arg）。她的父亲和母亲有杂合c.497delA（p。Lys166fs*36）和杂合c.1552T>C（p。Cys518Arg），分别。Cys518Arg代表热点变体，MD计算结果表明,这会降低IFT121-IFT122-IFT139-IFT43复合结构的结构稳定性。文献综述显示Cys518Arg可能导致ESRD的早期发生。
结论：复合杂合TTC21B变体是该患者表型的基础。因此，Cys518Arg可能是中国人群中的热点变体。应建议对新生儿和早期婴儿进行NPHP基因检测。
