DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration.,Genetics in Medicine

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DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration.
Genetics in Medicine ( IF 6.6 ) Pub Date : 2020-08-05 , DOI: 10.1038/s41436-020-0915-1
Anjali Vig _{1,

2} , James A Poulter ₃ , Daniele Ottaviani ₄ , Erika Tavares ₁ , Katerina Toropova ₅ , Anna Maria Tracewska _{6,

7} , Antonio Mollica ₁ , Jasmine Kang ₁ , Oshini Kehelwathugoda ₁ , Tara Paton _{1,

8} , Jason T Maynes ₉ , Gabrielle Wheway ₁₀ , Gavin Arno _{4,

11} , , Kamron N Khan ₃ , Martin McKibbin ₃ , Carmel Toomes ₃ , Manir Ali ₃ , Matteo Di Scipio ₁ , Shuning Li ₁ , Jamie Ellingford _{12,

13} , Graeme Black _{12,

14} , Andrew Webster _{4,

11} , Małgorzata Rydzanicz ₇ , Piotr Stawiński ₇ , Rafał Płoski ₇ , Ajoy Vincent _{1,

2,

15} , Michael E Cheetham ₄ , Chris F Inglehearn ₃ , Anthony Roberts ₅ , Elise Heon _{1,

2,

15}

Affiliation

Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
Institute of Medical Science, The University of Toronto, Toronto, Canada.
Department of Ophthalmology, St James' University Hospital, Leeds, UK.
UCL Institute of Ophthalmology, London, UK.
Department of Biological Sciences, Birbeck, University of London, London, UK.
DNA Analysis Unit, ŁUKASIEWICZ Research Network-PORT Polish Center for Technology Development, Wrocław, Poland.
Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.
The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Canada.
Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, Toronto, Canada.
Faculty of Medicine, University of Southampton, Southampton, UK.
Moorfields Eye Hospital, London, UK.
Division of Evolution and Genomic Sciences, Faculty of Biology, Medicines and health, The University of Manchester, Manchester, UK.
Manchester Academic Health Science Centre (MAHSC), University of Manchester, Manchester, UK.
Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, Canada.

Purpose

Determining the role of DYNC2H1 variants in nonsyndromic inherited retinal disease (IRD).

Methods

Genome and exome sequencing were performed for five unrelated cases of IRD with no identified variant. In vitro assays were developed to validate the variants identified (fibroblast assay, induced pluripotent stem cell [iPSC] derived retinal organoids, and a dynein motility assay).

Results

Four novel DYNC2H1 variants (V1, g.103327020_103327021dup; V2, g.103055779A>T; V3, g.103112272C>G; V4, g.103070104A>C) and one previously reported variant (V5, g.103339363T>G) were identified. In proband 1 (V1/V2), V1 was predicted to introduce a premature termination codon (PTC), whereas V2 disrupted the exon 41 splice donor site causing incomplete skipping of exon 41. V1 and V2 impaired dynein-2 motility in vitro and perturbed IFT88 distribution within cilia. V3, homozygous in probands 2–4, is predicted to cause a PTC in a retina-predominant transcript. Analysis of retinal organoids showed that this new transcript expression increased with organoid differentiation. V4, a novel missense variant, was in trans with V5, previously associated with Jeune asphyxiating thoracic dystrophy (JATD).

Conclusion

The DYNC2H1 variants discussed herein were either hypomorphic or affecting a retina-predominant transcript and caused nonsyndromic IRD. Dynein variants, specifically DYNC2H1 variants are reported as a cause of non syndromic IRD.

中文翻译：

DYNC2H1 亚形性或视网膜显性变异会导致非综合征性视网膜变性。

目的

确定DYNC2H1变异在非综合征性遗传性视网膜疾病 (IRD) 中的作用。

方法

对 5 例不相关的 IRD 病例进行了基因组和外显子组测序，未发现任何变异。开发了体外测定来验证所识别的变异（成纤维细胞测定、诱导多能干细胞 [iPSC] 衍生的视网膜类器官和动力蛋白运动测定）。

结果

四种新型DYNC2H1变体（V1，g.103327020_103327021dup；V2，g.103055779A>T；V3，g.103112272C>G；V4，g.103070104A>C）和一种先前报道的变体（V5，g.103339363T>G）确定。在先证者 1 (V1/V2) 中，V1 预计会引入过早终止密码子 (PTC)，而 V2 破坏了外显子 41 剪接供体位点，导致外显子 41 不完全跳跃。V1 和 V2 在体外损害了动力蛋白 2 运动性并受到干扰IFT88 在纤毛内分布。 V3 在先证者 2-4 中为纯合子，预计会在视网膜主要转录物中引起 PTC。视网膜类器官的分析表明，这种新转录本的表达随着类器官的分化而增加。 V4 是一种新的错义变体，与 V5呈反式，之前与青年窒息性胸廓营养不良 (JATD) 有关。