Mutation spectrum of Kallmann syndrome: identification of five novel mutations across ANOS1 and FGFR1.
Mutation spectrum of Kallmann syndrome: identification of five novel mutations across ANOS1 and FGFR1.
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卡尔曼综合征的突变谱：识别 ANOS1 和 FGFR1 的五种新突变。
DOI：
10.1186/s12958-023-01074-w
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发表时间：
2023-03-01
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影响因子：
--
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Kallmann综合征（KS）是一种常见的特发性低促性腺激素性性腺功能减退症。迄今为止，包括ANOS 1和FGFR 1在内的30多个基因已在KS的不同遗传模型中被发现，但基因型与表型之间没有确定的相关性，并发现了新的突变。进行定制面板测序或全外显子组测序以检测致病性突变。进行桑格测序以验证单核苷酸变体。进行拷贝数变异测序（CNV-seq）以确定CNV。通过计算机模拟预测所鉴定的变体的致病性。通过mRNA转录分析和小基因报告基因分析来检测突变对剪接的影响。用几种常用的软件对ANOS 1基因c.709 T > A和c.711 G > T进行了致病性评估，用转录剪接法验证了c.1063-2 A > T。c.1063-2 A > T突变激活了原剪接受体位点下游的一个隐蔽剪接受体位点，导致外显子8 5′端24碱基对的异常剪接，产生一个新的转录本，其中c.1063-1086缺失。根据ACMG指南，FRFR 1基因c.1835delA被评估为致病性。del（8）（p12p11.22）chr 8：g.36140000_38460000del的CNV根据ACMG和ClinGen技术标准判定为致病性。在此，我们确定了三个新的ANOS 1突变和两个新的FGFR 1变异在中国KS家庭。计算机预测和功能实验评估了ANOS 1突变的发病机制。FRFR 1 c.1835delA突变和del（8）（p12p11.22）chr 8：g.36140000_38460000del被评估为致病性变异。因此，我们的研究扩大了与KS相关的突变谱，并为将来携带相同突变的患者提供诊断证据。在线版本包含补充材料，可通过10.1186/s12958-023-01074-w获得。
Kallmann syndrome (KS) is a common type of idiopathic hypogonadotropic hypogonadism. To date, more than 30 genes including ANOS1 and FGFR1 have been identified in different genetic models of KS without affirmatory genotype–phenotype correlation, and novel mutations have been found. A total of 35 unrelated patients with clinical features of disorder of sex development were recruited. Custom-panel sequencing or whole-exome sequencing was performed to detect the pathogenic mutations. Sanger sequencing was performed to verify single-nucleotide variants. Copy number variation-sequencing (CNV-seq) was performed to determine CNVs. The pathogenicity of the identified variant was predicted in silico. mRNA transcript analysis and minigene reporter assay were performed to test the effect of the mutation on splicing. ANOS1 gene c.709 T > A and c.711 G > T were evaluated as pathogenic by several commonly used software, and c.1063-2 A > T was verified by transcriptional splicing assay. The c.1063-2 A > T mutation activated a cryptic splice acceptor site downstream of the original splice acceptor site and resulted in an aberrant splicing of the 24-basepair at the 5′ end of exon 8, yielding a new transcript with c.1063–1086 deletion. FRFR1 gene c.1835delA was assessed as pathogenic according to the ACMG guideline. The CNV of del(8)(p12p11.22)chr8:g.36140000_38460000del was judged as pathogenic according to the ACMG & ClinGen technical standards. Herein, we identified three novel ANOS1 mutations and two novel FGFR1 variations in Chinese KS families. In silico prediction and functional experiment evaluated the pathogenesis of ANOS1 mutations. FRFR1 c.1835delA mutation and del(8)(p12p11.22)chr8:g.36140000_38460000del were assessed as pathogenic variations. Therefore, our study expands the spectrum of mutations associated with KS and provides diagnostic evidence for patients who carry the same mutation in the future. The online version contains supplementary material available at 10.1186/s12958-023-01074-w.
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影响因子：
3.4
作者：
Hwang JL;Park SY;Ye H;Sanyoura M;Pastore AN;Carmody D;Del Gaudio D;Wilson JF;Hanis CL;Liu X;Atzmon G;Glaser B;Philipson LH;Greeley SAW;T2D-Genes Consortium
通讯作者：
T2D-Genes Consortium
DOI：
10.1038/nrendo.2009.177
发表时间：
2009-10
期刊：
Nature reviews. Endocrinology
影响因子：
--
作者：
通讯作者：
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影响因子：
2.6
作者：
Saadah OI;Banaganapalli B;Kamal NM;Sahly AN;Alsufyani HA;Mohammed A;Ahmad A;Nasser KK;Al-Aama JY;Shaik NA;Elango R
通讯作者：
Elango R
影响因子：
3.5
作者：
Jiang, Xiaohui;Li, Dingming;Shen, Ying
通讯作者：
Shen, Ying
影响因子：
30.8
作者：
Dodé, C;Levilliers, J;Hardelin, JP
通讯作者：
Hardelin, JP