Sangermano Riccardo, Deitch Iris, Peter Virginie G, Ba-Abbad Rola, Place Emily M, Zampaglione Erin, Wagner Naomi E, Fulton Anne B, Coutinho-Santos Luisa, Rosin Boris, Dunet Vincent, AlTalbishi Ala'a, Banin Eyal, Sousa Ana Berta, Neves Mariana, Larson Anna, Quinodoz Mathieu, Michaelides Michel, Ben-Yosef Tamar, Pierce Eric A, Rivolta Carlo, Webster Andrew R, Arno Gavin, Sharon Dror, Huckfeldt Rachel M, Bujakowska Kinga M
Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Retina Service, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
NPJ Genom Med. 2021 Jun 29;6(1):53. doi: 10.1038/s41525-021-00214-8.
Pathogenic variants in INPP5E cause Joubert syndrome (JBTS), a ciliopathy with retinal involvement. However, despite sporadic cases in large cohort sequencing studies, a clear association with non-syndromic inherited retinal degenerations (IRDs) has not been made. We validate this association by reporting 16 non-syndromic IRD patients from ten families with bi-allelic mutations in INPP5E. Additional two patients showed early onset IRD with limited JBTS features. Detailed phenotypic description for all probands is presented. We report 14 rare INPP5E variants, 12 of which have not been reported in previous studies. We present tertiary protein modeling and analyze all INPP5E variants for deleteriousness and phenotypic correlation. We observe that the combined impact of INPP5E variants in JBTS and non-syndromic IRD patients does not reveal a clear genotype-phenotype correlation, suggesting the involvement of genetic modifiers. Our study cements the wide phenotypic spectrum of INPP5E disease, adding proof that sequence defects in this gene can lead to early-onset non-syndromic IRD.
INPP5E基因的致病性变异可导致Joubert综合征（JBTS），这是一种伴有视网膜病变的纤毛病。然而，尽管在大型队列测序研究中有散发病例，但尚未明确其与非综合征性遗传性视网膜变性（IRD）的关联。我们通过报告来自十个家庭的16例非综合征性IRD患者，这些患者的INPP5E基因存在双等位基因突变，从而验证了这种关联。另外两名患者表现为早发性IRD，具有有限的JBTS特征。本文给出了所有先证者的详细表型描述。我们报告了14种罕见的INPP5E变异，其中12种在先前的研究中未曾报道。我们进行了三级蛋白质建模，并分析了所有INPP5E变异的有害性和表型相关性。我们观察到，INPP5E变异对JBTS和非综合征性IRD患者的综合影响并未显示出明确的基因型-表型相关性，这表明存在遗传修饰因子的参与。我们的研究巩固了INPP5E疾病广泛的表型谱，进一步证明该基因的序列缺陷可导致早发性非综合征性IRD。
