Deep-intronic variants in CNGB3 cause achromatopsia by pseudoexon activation.
Deep-intronic variants in CNGB3 cause achromatopsia by pseudoexon activation.
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CNGB3中的深入型变体通过伪exon激活引起Achromomatia。
DOI：
10.1002/humu.23920
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发表时间：
2020-01
期刊：
影响因子：
3.9
通讯作者：
Kohl S
中科院分区：
文献类型：
--
作者：
Weisschuh N;Sturm M;Baumann B;Audo I;Ayuso C;Bocquet B;Branham K;Brooks BP;Catalá-Mora J;Giorda R;Heckenlively JR;Hufnagel RB;Jacobson SG;Kellner U;Kitsiou-Tzeli S;Matet A;Martorell Sampol L;Meunier I;Rudolph G;Sharon D;Stingl K;Streubel B;Varsányi B;Wissinger B;Kohl S
我们的1100名无关色盲(ACHM)患者的综合队列包括相当数量的病例(~5%)，主要的ACHM基因CNGB3只有一个致病变异。我们对其中33名患者的整个CNGB3基因座进行了测序，以找到最终解释患者表型的第二个变异。在28名受试者中，经过基于频率的筛选步骤并排除带有致病等位基因的顺式基因的变异后，在28名受试者中鉴定出47个内含子CNGB3变异。在第二步中，在电子计算机中，预测工具被用来过滤掉那些几乎没有有害几率的变异。这就留下了三个使用异源剪接分析的变异体。在14个受试者中发现的变异体C.1663-1205G>；A和在两个受试者中发现的变异体c.1663-2137C>；T确实被证明通过导致假外显子插入转录本而产生剪接缺陷。随后对进一步未解决的CNGB3受试者进行的筛查发现了另外四例携带c.1663-1205G>；A变异的病例，使其成为我们队列中第八常见的CNGB3变异。可在10例患者中验证复合杂合性。我们的研究表明，在显然只有一个致病变异的患者中，全基因测序可以成为识别第二个致病等位基因的有效方法。
Our comprehensive cohort of 1100 unrelated achromatopsia (ACHM) patients comprises a considerable number of cases (~5%) harboring only a single pathogenic variant in the major ACHM gene CNGB3. We sequenced the entire CNGB3 locus in 33 of these patients to find a second variant which eventually explained the patients’ phenotype. Forty-seven intronic CNGB3 variants were identified in 28 subjects after a filtering step based on frequency and the exclusion of variants found in cis with pathogenic alleles. In a second step, in silico prediction tools were used to filter out those variants with little odds of being deleterious. This left three variants that were analyzed using heterologous splicing assays. Variant c.1663-1205G>A, found in 14 subjects, and variant c.1663-2137C>T, found in two subjects, were indeed shown to exert a splicing defect by causing pseudoexon insertion into the transcript. Subsequent screening of further unsolved CNGB3 subjects identified four additional cases harboring the c.1663-1205G>A variant which makes it the eighth most frequent CNGB3 variant in our cohort. Compound heterozygosity could be validated in ten cases. Our study demonstrates that whole gene sequencing can be a powerful approach to identify the second pathogenic allele in patients apparently harboring only one disease-causing variant.
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影响因子：
2.5
作者：
Schindelin J;Rueden CT;Hiner MC;Eliceiri KW
通讯作者：
Eliceiri KW
DOI：
10.1016/j.omtn.2018.07.010
发表时间：
2018-09-07
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
Dulla K;Aguila M;Lane A;Jovanovic K;Parfitt DA;Schulkens I;Chan HL;Schmidt I;Beumer W;Vorthoren L;Collin RWJ;Garanto A;Duijkers L;Brugulat-Panes A;Semo M;Vugler AA;Biasutto P;Adamson P;Cheetham ME
通讯作者：
Cheetham ME
影响因子：
12.3
作者：
McLaren W;Gil L;Hunt SE;Riat HS;Ritchie GR;Thormann A;Flicek P;Cunningham F
通讯作者：
Cunningham F
影响因子：
3.5
作者：
Braun TA;Mullins RF;Wagner AH;Andorf JL;Johnston RM;Bakall BB;Deluca AP;Fishman GA;Lam BL;Weleber RG;Cideciyan AV;Jacobson SG;Sheffield VC;Tucker BA;Stone EM
通讯作者：
Stone EM
影响因子：
14.9
作者：
Desmet FO;Hamroun D;Lalande M;Collod-Béroud G;Claustres M;Béroud C
通讯作者：
Béroud C