Department of Ophthalmology, The First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Rd, Nanjing, 210029, China.
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
J Transl Med. 2021 Dec 6;19(1):495. doi: 10.1186/s12967-021-03155-z.
Comitant strabismus (CS) is a heterogeneous disorder that is a major contributing factor to unilateral childhood-onset visual impairment. Studies have confirmed that genetic factors play an important role in the development of CS. The aim of this study was to identify the genetic cause of non-syndromic familial CS.
Fourteen unrelated CS families were recruited for the study. Twelve affected and 2 unaffected individuals from a large four-generation family (CS08) were selected to perform whole genome-wide linkage analysis. Parallel whole-exome sequencing (WES) was conducted in the same family (9 patients and 1 unaffected member) and 31 additional CS cases from 13 other unrelated families. Sanger sequencing was used to determine whether any of the remaining variants co-segregated with the disease phenotype in the corresponding family.
Based on linkage analysis, CS in family CS08 mapped to a novel region of 34.17 centimorgan (cM) on chromosome 2q22.3-2q32.1 between markers D2S151 and D2S364, with a maximum log odds (LOD) score of 3.54 (theta = 0) at D2S142. Parallel WES identified a heterozygous variant, LRP2 c.335 A > G (p.Q112R), located in such a linkage interval that completely co-segregated with the disease in the family. Furthermore, another novel heterozygous variant (c.7274A > G, p.D2425G) in LRP2 that co-segregated was detected in 2 additional affected individuals from another unrelated family by WES. Both variants are predicted to be damaging by PolyPhen-2, SIFT and MutationTaster, and were absent in 100 ethnically matched normal controls.
LRP2 is a novel candidate genetic cause of non-syndromic familial CS.
共同性斜视（CS）是一种异质性疾病，是导致儿童单侧发病的主要原因之一。研究证实遗传因素在 CS 的发病中起重要作用。本研究旨在探讨非综合征性家族性 CS 的遗传病因。
招募了 14 个无关的 CS 家系进行研究。选择一个包含 4 代的大型 CS08 家系（包括 12 个 CS 患者和 2 个非患者）进行全基因组连锁分析，对 9 个患者和 1 个非患者进行全外显子测序（WES），对 13 个其他无关 CS 家系中的 31 例患者进行 WES。对其余候选变异进行 Sanger 测序，以确定它们是否与相应家系的疾病表型共分离。
连锁分析显示 CS08 家系的 CS 定位于 2q22.3-2q32.1 染色体上的 34.17cM 的新区域，在 D2S151 和 D2S364 之间，最大对数优势（LOD）评分 3.54（theta=0），位于 D2S142。平行 WES 发现一个杂合变异，LRP2 c.335A>G（p.Q112R），位于连锁区域内，与家系中的疾病完全共分离。此外，通过 WES 在另一个无关家系的另外 2 个受影响个体中还发现了另一个新的杂合变异（c.7274A>G，p.D2425G），该变异也与疾病共分离。这两个变异都被 PolyPhen-2、SIFT 和 MutationTaster 预测为有害，并且在 100 名匹配的正常对照中不存在。
LRP2 是一种新的非综合征性家族性 CS 的候选遗传病因。
