Variants in HNRNPH1 are associated with high myopia in humans and ocular coloboma in zebrafish. Issue 5 (29th August 2022)

• Record Type: Journal Article
• Authors: Ouyang, Jiamin; Li, Shiqiang; Sun, Wenmin; Xiao, Xueshan; Wang, Yingwei; Jiang, Yi; Zhang, Qingjiong
• Is Part Of: Clinical genetics. Volume 102:Issue 5(2022)
• Page Start: 424
• Page End: 433
• Publication Date: 2022-08-29
• Subjects: early‐onset high myopia -- HNRNPH1 -- loss‐of‐function variants -- ocular coloboma -- zebrafish; Medical genetics -- Periodicals; 616.0420
• DOI: 10.1111/cge.14213
• Languages: English
• ISSNs: 0009-9163

Abstract

Abstract: High myopia is one of the most common causes for blindness due to its associated complications. Genetic factor has been considered as the major cause for early‐onset high myopia (eoHM), but exact genetic defects for most eoHM are yet to be identified. Through multi‐step bioinformatics analysis of our in‐house whole exome sequencing dataset from 6397 individuals, variants from 928 probands with eoHM were further compared with those from in‐house controls as well as gnomAD database. The results showed that loss‐of‐function (LoF) variants in a novel gene HNRNPH1 were identified in two of 928 probands with eoHM but in none of 5469 probands with other eye conditions ( p = 0.02). LoF variants in HNRNPH1 were extremely rare and intolerant, while two LoF variants in 928 eoHM were statistically higher than their frequency in gnomAD ( p = 5.98 × 10 −4 ). These two LoF variants, c.2dup/p.(M1?) and c.121dup/p.(Q41Pfs*20), were absent from existing database. Variants in HNRNPH1 have not been associated with any inherited eye disease before. Expression of HNRNPH1 was enriched in ganglion cell layer and inner nuclear layer in humans. Knockdown of hnrnph1 in zebrafish resulted in ocular coloboma. All these suggest that HNRNPH1 is potential contribution to eoHM when mutated. Abstract : Loss‐of‐function variants in HNRNPH1 are associated with early‐onset high myopia based on comparative analysis of in‐house data and data from gnomAD database. The HNRNPH1 is highly expressed in GCL and INL of human retina. Failure of optic fissure closure is present in hnrnph1 ‐knockdown zebrafish. These lines of evidence suggest its contribution to eoHM when mutated.