Abstract
BackgroundComitant 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.MethodsFourteen 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.ResultsBased 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.ConclusionLRP2 is a novel candidate genetic cause of non-syndromic familial CS.
Highlights
Strabismus is clinically defined as a condition in any misalignment of the eyes in coordination, which is a major ocular abnormality in children and often accompanied byWang et al Journal of Translational Medicine (2021) 19:495 absence of amblyopia, subsequently affecting daily physiological and psychosocial performance unless successfully treated [4, 5].Comitant strabismus (CS) is highly heterogeneous and influenced by genetic and environmental factors, though the pathogenesis remains unclear [6, 7]
366 microsatellite markers and 3 single nucleotide polymorphisms (SNPs) spanning the entire human genome with an interval of approximately 10 cM (Weber set 6.0) were amplified by polymerase chain reaction (PCR) using primers labelled with Fam (Additional file 1)
The proband (III:19) was a 22-year-old female with intermittent exotropia, which occurred at approximately 5 years of age
Summary
Strabismus is clinically defined as a condition in any misalignment of the eyes in coordination, which is a major ocular abnormality in children and often accompanied byWang et al Journal of Translational Medicine (2021) 19:495 absence of amblyopia, subsequently affecting daily physiological and psychosocial performance unless successfully treated [4, 5].CS is highly heterogeneous and influenced by genetic and environmental factors, though the pathogenesis remains unclear [6, 7]. Based on the inheritance pattern, numerous studies have been performed to investigate the genetic causation of CS using different methods. Two other susceptibility loci, 4q28.3 and 7q31.2, were recently identified in the Japanese population in association with the candidate genes MGST2 and WNT2 [15, 16]. Variants of AHI1 and PAX3 have been detected by whole-exome sequencing (WES) in Chinese families, contributing to strabismus [17, 18]. Anyway, these studies indicate that CS may manifest as a rare and monogenic subtype. Comitant strabismus (CS) is a heterogeneous disorder that is a major contributing factor to unilateral childhood-onset visual impairment. The aim of this study was to identify the genetic cause of non-syndromic familial CS
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