Transcript Long-Read Sequencing Unveils the Molecular Complexity of a Novel ROGDI Splicing Variant in a Tunisian Family With Kohlschütter-Tönz Syndrome.

IF 2.9 3区 医学 Q2 GENETICS & HEREDITY
Miriam Essid, Sana Karoui, Mouna Zribi, Thouraya Ben Younes, Louis Januel, Estelle Lafont, Audrey Labalme, Meriem Ben Hafsa, Go Hun Seo, Safa Khatrouch, Hela Boudabous, Amel Ben Chehida, Damien Sanlaville, Houweyda Jilani, Lamia Benjemaa, Ichraf Kraoua, Gaetan Lesca, Nicolas Chatron
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引用次数: 0

Abstract

Kohlschütter-Tönz Syndrome (KTS) is an ultra-rare autosomal recessive disorder, characterized by a clinical triad: infantile-onset epilepsy, global developmental delay, and amelogenesis imperfecta. KTS is caused by pathogenic variants in ROGDI, encoding a leucine zipper protein of unknown function. Our study characterizes a novel homozygous ROGDI variant (NM_024589.3:c.646-2A>G) identified in a Tunisian family case with KTS, renal tubular acidosis, and hyperammonemia. This variant disrupts a canonical acceptor splice site (ASS) in intron 8. Reverse-transcriptase polymerase chain reaction and targeted long-read cDNA sequencing, identified only abnormal transcripts secondary to the ROGDI ASS variant in the proband. Complex splicing events were detected including exon 9 skipping, cryptic ASS activation leading to 13-bp deletion in exon 9, and retention of intron 8 or both intron 8 and 9. These alterations were all predicted to result in nonsense mediated decay and ROGDI loss of function. By integrating complementary techniques, our study unveiled fundamental mechanisms underlying complex splice alterations, providing insights that may guide future therapeutic strategies in KTS.

转录本长读测序揭示了突尼斯Kohlschütter-Tönz综合征家族中新的ROGDI剪接变异的分子复杂性。
Kohlschütter-Tönz综合征(KTS)是一种超罕见的常染色体隐性遗传病,以临床三联征为特征:婴儿期癫痫、整体发育迟缓和淀粉样变性不全。KTS是由编码一种功能未知的亮氨酸拉链蛋白的ROGDI致病性变异引起的。我们的研究鉴定了一种新的纯合子ROGDI变异(NM_024589.3:c.646-2A>G),发现于突尼斯的KTS、肾小管酸中毒和高氨血症家庭病例。这种变异破坏了8号内含子中的典型受体剪接位点(ASS)。逆转录酶聚合酶链反应和靶向长读cDNA测序,仅鉴定出先证者中继发于ROGDI ASS变异的异常转录物。检测到复杂的剪接事件,包括外显子9跳变,导致外显子9缺失13 bp的隐式ASS激活,以及8号内含子或8号和9号内含子都保留。这些改变都被预测会导致无义介导的衰退和ROGDI功能丧失。通过整合互补技术,我们的研究揭示了复杂剪接改变的基本机制,为指导KTS的未来治疗策略提供了见解。
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来源期刊
Clinical Genetics
Clinical Genetics 医学-遗传学
CiteScore
6.50
自引率
0.00%
发文量
175
审稿时长
3-8 weeks
期刊介绍: Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice. Topics of particular interest are: • Linking genetic variations to disease • Genome rearrangements and disease • Epigenetics and disease • The translation of genotype to phenotype • Genetics of complex disease • Management/intervention of genetic diseases • Novel therapies for genetic diseases • Developmental biology, as it relates to clinical genetics • Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease
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