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Abstract：
BACKGROUND: Syndromic ciliopathies are a group of congenital disorders characterized by broad clinical and genetic overlap, including obesity, visual problems, skeletal anomalies, mental retardation, and renal diseases. The hallmark of the pathophysiology among these disorders is defective ciliary functions or formation. Many different genes have been implicated in the pathogenesis of these diseases, but some patients still remain unclear about their genotypes.
METHODS: The aim of this study was to identify the genetic causes in patients with syndromic ciliopathy. Patients suspected of or meeting clinical diagnostic criteria for any type of syndromic ciliopathy were recruited at a single diagnostic medical center in Southern Taiwan. Whole exome sequencing (WES) was employed to identify their genotypes and elucidate the mutation spectrum in Taiwanese patients with syndromic ciliopathy. Clinical information was collected at the time of patient enrollment.
RESULTS: A total of 14 cases were molecularly diagnosed with syndromic ciliopathy. Among these cases, 10 had Bardet-Biedl syndrome (BBS), comprising eight BBS2 patients and two BBS7 patients. Additionally, two cases were diagnosed with Alström syndrome, one with Oral-facial-digital syndrome type 14, and another with Joubert syndrome type 10. A total of 4 novel variants were identified. A recurrent splice site mutation, BBS2: c.534 + 1G > T, was present in all eight BBS2 patients, suggesting a founder effect. One BBS2 patient with homozygous c.534 + 1G > T mutations carried a third ciliopathic allele, TTC21B: c.264_267dupTAGA, a nonsense mutation resulting in a premature stop codon and protein truncation.
CONCLUSIONS: Whole exome sequencing (WES) assists in identifying molecular pathogenic variants in ciliopathic patients, as well as the genetic hotspot mutations in specific populations. It should be considered as the first-line genetic testing for heterogeneous disorders characterized by the involvement of multiple genes and diverse clinical manifestations.
METHODS: The aim of this study was to identify the genetic causes in patients with syndromic ciliopathy. Patients suspected of or meeting clinical diagnostic criteria for any type of syndromic ciliopathy were recruited at a single diagnostic medical center in Southern Taiwan. Whole exome sequencing (WES) was employed to identify their genotypes and elucidate the mutation spectrum in Taiwanese patients with syndromic ciliopathy. Clinical information was collected at the time of patient enrollment.
RESULTS: A total of 14 cases were molecularly diagnosed with syndromic ciliopathy. Among these cases, 10 had Bardet-Biedl syndrome (BBS), comprising eight BBS2 patients and two BBS7 patients. Additionally, two cases were diagnosed with Alström syndrome, one with Oral-facial-digital syndrome type 14, and another with Joubert syndrome type 10. A total of 4 novel variants were identified. A recurrent splice site mutation, BBS2: c.534 + 1G > T, was present in all eight BBS2 patients, suggesting a founder effect. One BBS2 patient with homozygous c.534 + 1G > T mutations carried a third ciliopathic allele, TTC21B: c.264_267dupTAGA, a nonsense mutation resulting in a premature stop codon and protein truncation.
CONCLUSIONS: Whole exome sequencing (WES) assists in identifying molecular pathogenic variants in ciliopathic patients, as well as the genetic hotspot mutations in specific populations. It should be considered as the first-line genetic testing for heterogeneous disorders characterized by the involvement of multiple genes and diverse clinical manifestations.
摘要：
背景：综合征性纤毛病是一组以广泛的临床和遗传重叠为特征的先天性疾病，包括肥胖,视觉问题,骨骼异常,智力迟钝,和肾脏疾病。这些疾病中病理生理学的标志是纤毛功能或形成缺陷。许多不同的基因与这些疾病的发病机理有关，但一些患者仍不清楚他们的基因型。
方法：本研究的目的是确定综合征性纤毛病患者的遗传原因。在台湾南部的一个单一诊断医疗中心招募了怀疑或符合任何类型的综合征性纤毛病临床诊断标准的患者。全外显子组测序（WES）用于鉴定其基因型并阐明台湾综合征性纤毛病患者的突变谱。在患者登记时收集临床信息。
结果：共有14例分子诊断为综合征型纤毛病。在这些案例中,10人患有Bardet-Biedl综合征（BBS），包括8例BBS2患者和2例BBS7患者。此外,两例被诊断为Alström综合征,一个患有14型口腔-面部-数字综合征，另一个患有10型Joubert综合征。总共鉴定了4种新的变体。一个反复发生的剪接位点突变,BBS2：c.534+1G>T，存在于所有8名BBS2患者中，暗示了创始人的影响。一名具有纯合子c.534+1G>T突变的BBS2患者携带第三个纤毛等位基因，TTC21B：c.264_267dupTAGA，无义突变导致过早终止密码子和蛋白质截短。
结论：全外显子组测序（WES）有助于识别纤毛病患者的分子致病变异，以及特定人群的遗传热点突变。应将其视为以多种基因和多种临床表现为特征的异质性疾病的一线基因检测。
方法：本研究的目的是确定综合征性纤毛病患者的遗传原因。在台湾南部的一个单一诊断医疗中心招募了怀疑或符合任何类型的综合征性纤毛病临床诊断标准的患者。全外显子组测序（WES）用于鉴定其基因型并阐明台湾综合征性纤毛病患者的突变谱。在患者登记时收集临床信息。
结果：共有14例分子诊断为综合征型纤毛病。在这些案例中,10人患有Bardet-Biedl综合征（BBS），包括8例BBS2患者和2例BBS7患者。此外,两例被诊断为Alström综合征,一个患有14型口腔-面部-数字综合征，另一个患有10型Joubert综合征。总共鉴定了4种新的变体。一个反复发生的剪接位点突变,BBS2：c.534+1G>T，存在于所有8名BBS2患者中，暗示了创始人的影响。一名具有纯合子c.534+1G>T突变的BBS2患者携带第三个纤毛等位基因，TTC21B：c.264_267dupTAGA，无义突变导致过早终止密码子和蛋白质截短。
结论：全外显子组测序（WES）有助于识别纤毛病患者的分子致病变异，以及特定人群的遗传热点突变。应将其视为以多种基因和多种临床表现为特征的异质性疾病的一线基因检测。
