ABCA4-associated disease as a model for missing heritability in autosomal recessive disorders: novel noncoding splice, cis-regulatory, structural, and recurrent hypomorphic variants.,Genetics in Medicine

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ABCA4-associated disease as a model for missing heritability in autosomal recessive disorders: novel noncoding splice, cis-regulatory, structural, and recurrent hypomorphic variants.
Genetics in Medicine ( IF 6.6 ) Pub Date : 2019-01-23 , DOI: 10.1038/s41436-018-0420-y
Miriam Bauwens ₁ , Alejandro Garanto _{2,

3} , Riccardo Sangermano _{2,

4} , Sarah Naessens ₁ , Nicole Weisschuh ₅ , Julie De Zaeytijd ₆ , Mubeen Khan _{2,

3} , Françoise Sadler ₅ , Irina Balikova ₆ , Caroline Van Cauwenbergh _{1,

6} , Toon Rosseel ₁ , Jim Bauwens ₇ , Kim De Leeneer ₁ , Sarah De Jaegere ₁ , Thalia Van Laethem ₁ , Meindert De Vries ₈ , Keren Carss _{9,

10} , Gavin Arno ₁₁ , Ana Fakin _{11,

12} , Andrew R Webster _{11,

12} , Thomy J L de Ravel de l'Argentière ₁₃ , Yves Sznajer ₁₄ , Marnik Vuylsteke ₁₅ , Susanne Kohl ₅ , Bernd Wissinger ₅ , Timothy Cherry _{16,

17} , Rob W J Collin _{2,

3} , Frans P M Cremers _{2,

3} , Bart P Leroy _{1,

6,

18} , Elfride De Baere ₁

Affiliation

Center for Medical Genetics Ghent, Ghent University and Ghent University Hospital, Ghent, Belgium.
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Molecular Genetics Laboratory, Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.
Department of Ophthalmology, Ghent University and Ghent University Hospital, Ghent, Belgium.
Department of Computer Science, Free University of Brussels, Brussels, Belgium.
Department of Ophthalmology, Hôpital des Enfants Reine Fabiola, Brussels, Belgium.
Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge, UK.
UK NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
UCL Institute of Ophthalmology, London, UK.
Moorfields Eye Hospital NHS Foundation Trust, London, UK.
Center for Human Genetics, KU Leuven and UZ Leuven, Leuven, Belgium.
Centre de Génétique Humaine, Cliniques Universitaires St. Luc, Université Catholique de Louvain, Brussels, Belgium.
GNOMIXX ltd, Statistics for Genomics, Melle, Belgium.
Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA.
Division of Ophthalmology and Center for Cellular & Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

PURPOSE ABCA4-associated disease, a recessive retinal dystrophy, is hallmarked by a large proportion of patients with only one pathogenic ABCA4 variant, suggestive for missing heritability. METHODS By locus-specific analysis of ABCA4, combined with extensive functional studies, we aimed to unravel the missing alleles in a cohort of 67 patients (p), with one (p = 64) or no (p = 3) identified coding pathogenic variants of ABCA4. RESULTS We identified eight pathogenic (deep-)intronic ABCA4 splice variants, of which five are novel and six structural variants, four of which are novel, including two duplications. Together, these variants account for the missing alleles in 40.3% of patients. Furthermore, two novel variants with a putative cis-regulatory effect were identified. The common hypomorphic variant c.5603A>T p.(Asn1868Ile) was found as a candidate second allele in 43.3% of patients. Overall, we have elucidated the missing heritability in 83.6% of our cohort. In addition, we successfully rescued three deep-intronic variants using antisense oligonucleotide (AON)-mediated treatment in HEK 293-T cells and in patient-derived fibroblast cells. CONCLUSION Noncoding pathogenic variants, novel structural variants, and a common hypomorphic allele of the ABCA4 gene explain the majority of unsolved cases with ABCA4-associated disease, rendering this retinopathy a model for missing heritability in autosomal recessive disorders.

中文翻译：

ABCA4 相关疾病作为常染色体隐性遗传病遗传力缺失的模型：新型非编码剪接、顺式调控、结构和复发性亚型变异。

目的 ABCA4 相关疾病是一种隐性视网膜营养不良，其特征是大部分患者只有一种致病性 ABCA4 变异，提示遗传力缺失。方法通过对 ABCA4 的位点特异性分析，结合广泛的功能研究，我们旨在解开一组 67 名患者 (p) 中缺失的等位基因，其中一个 (p = 64) 或没有 (p = 3) 识别出编码致病变异ABCA4。结果我们确定了 8 个致病性（深）内含子 ABCA4 剪接变体，其中 5 个是新的，6 个结构变体，其中 4 个是新的，包括两个重复。这些变异共同导致 40.3% 的患者缺失等位基因。此外，还鉴定了两种具有推定的顺式调节作用的新变体。常见的异形变体 c.5603A>T p。(Asn1868Ile) 在 43.3% 的患者中被发现是候选的第二等位基因。总体而言，我们已经阐明了 83.6% 的队列中缺失的遗传力。此外，我们在 HEK 293-T 细胞和患者来源的成纤维细胞中使用反义寡核苷酸 (AON) 介导的治疗成功挽救了三种深内含子变体。结论 ABCA4 基因的非编码致病变异、新的结构变异和常见的亚型等位基因解释了大多数未解决的 ABCA4 相关疾病病例，使这种视网膜病变成为常染色体隐性遗传病中遗传力缺失的模型。我们在 HEK 293-T 细胞和患者来源的成纤维细胞中使用反义寡核苷酸 (AON) 介导的治疗成功地挽救了三个深内含子变体。结论 ABCA4 基因的非编码致病变异、新的结构变异和常见的亚型等位基因解释了大多数未解决的 ABCA4 相关疾病病例，使这种视网膜病变成为常染色体隐性遗传病中遗传力缺失的模型。我们在 HEK 293-T 细胞和患者来源的成纤维细胞中使用反义寡核苷酸 (AON) 介导的治疗成功地挽救了三个深内含子变体。结论 ABCA4 基因的非编码致病变异、新的结构变异和常见的亚型等位基因解释了大多数未解决的 ABCA4 相关疾病病例，使这种视网膜病变成为常染色体隐性遗传病中遗传力缺失的模型。

更新日期：2019-01-26

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