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Abstract：
BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare and genetically heterogeneous disease with a broad spectrum of clinical features, including but not limited to rod-cone dystrophy, postaxial polydactyly, central obesity, intellectual disability, hypogonadism, and renal dysfunction. Twenty-one BBS (Bardet-Biedl syndrome) genes have been identified to date. There is minimal mutation information on BBS in Chinese populations and the exact pathogenic mechanism of the null mutation of BBS9 remains unknown.
METHODS: A patient from a Chinese consanguineous family presented with polydactyly, truncal obesity, intellectual disability, genital anomaly, and retinitis pigmentosa was analyzed in this study. Blood DNA and RNA were extracted from the blood of the proband and the parents. The proband was screened for mutations by whole-exome sequencing. The likely pathogenic mutation detected in the proband was further confirmed by the Sanger sequence in the family. Real-time RT-PCR was used to measure the expression of BBS9 in the proband and the control.
RESULTS: Targeted exome sequencing identified a novel homozygous null mutation (NM_198428.3: c.445C>T) in the 6th exon of the BBS9 gene in the proband and Sanger sequencing was used to validate the heterozygosity in the parents. The mutation was validated to induce the nonsense-mediated decay of BBS9 messenger RNAs by real-time RT-PCR.
CONCLUSIONS: The molecular findings helped to explain the clinical manifestations. The novel homozygous pathogenic variation expanded the mutational spectrum of the BBS9 gene in the Chinese population and will help to understand the pathogenic mechanism of BBS9 null mutation.
METHODS: A patient from a Chinese consanguineous family presented with polydactyly, truncal obesity, intellectual disability, genital anomaly, and retinitis pigmentosa was analyzed in this study. Blood DNA and RNA were extracted from the blood of the proband and the parents. The proband was screened for mutations by whole-exome sequencing. The likely pathogenic mutation detected in the proband was further confirmed by the Sanger sequence in the family. Real-time RT-PCR was used to measure the expression of BBS9 in the proband and the control.
RESULTS: Targeted exome sequencing identified a novel homozygous null mutation (NM_198428.3: c.445C>T) in the 6th exon of the BBS9 gene in the proband and Sanger sequencing was used to validate the heterozygosity in the parents. The mutation was validated to induce the nonsense-mediated decay of BBS9 messenger RNAs by real-time RT-PCR.
CONCLUSIONS: The molecular findings helped to explain the clinical manifestations. The novel homozygous pathogenic variation expanded the mutational spectrum of the BBS9 gene in the Chinese population and will help to understand the pathogenic mechanism of BBS9 null mutation.
摘要：
背景：Bardet-Biedl综合征（BBS）是一种罕见的遗传异质性疾病，具有广泛的临床特征，包括但不限于杆状锥体营养不良，后轴多指，中心性肥胖,智力残疾,性腺功能减退,肾功能不全.迄今为止，已鉴定出21个BBS（Bardet-Biedl综合征）基因。在中国人群中，关于BBS的突变信息很少，BBS9无效突变的确切致病机制仍然未知。
方法：来自中国近亲家庭的患者表现为多指，躯干肥胖，智力残疾,生殖器异常,和视网膜色素变性在这项研究中进行了分析。从先证者和父母的血液中提取血液DNA和RNA。通过全外显子组测序筛选先证子的突变。在先证者中检测到的可能的致病突变进一步由家族中的Sanger序列证实。使用实时RT-PCR检测先证者和对照中BBS9的表达。
结果：靶向外显子组测序在先证中BBS9基因的第6个外显子中发现了一个新的纯合无效突变（NM_198428.3:c.445C>T），并使用Sanger测序来验证亲本中的杂合性。通过实时RT-PCR验证该突变诱导BBS9信使RNA的无义介导的衰变。
结论：分子研究结果有助于解释临床表现。新的纯合致病变异扩大了BBS9基因在中国人群中的突变谱，将有助于理解BBS9无效突变的致病机制。
方法：来自中国近亲家庭的患者表现为多指，躯干肥胖，智力残疾,生殖器异常,和视网膜色素变性在这项研究中进行了分析。从先证者和父母的血液中提取血液DNA和RNA。通过全外显子组测序筛选先证子的突变。在先证者中检测到的可能的致病突变进一步由家族中的Sanger序列证实。使用实时RT-PCR检测先证者和对照中BBS9的表达。
结果：靶向外显子组测序在先证中BBS9基因的第6个外显子中发现了一个新的纯合无效突变（NM_198428.3:c.445C>T），并使用Sanger测序来验证亲本中的杂合性。通过实时RT-PCR验证该突变诱导BBS9信使RNA的无义介导的衰变。
结论：分子研究结果有助于解释临床表现。新的纯合致病变异扩大了BBS9基因在中国人群中的突变谱，将有助于理解BBS9无效突变的致病机制。
