Two novel variations in LRP2 cause Donnai-Barrow syndrome in a Chinese family with severe early-onset high myopia

Abstract

Donnai-Barrow syndrome (DBS) is a rare autosomal recessive disorder caused by mutation in the low density lipoprotein receptor-related protein 2 gene (LRP2). Defects in this protein may lead to clinical multiple organ malformations by affecting the development of organs such as the nervous system, eyes, ears, and kidneys. Although some variations on LRP2 have been found to be associated with DBS, early diagnosis and prevention of patients with atypical DBS remains a challenge for many physicians because of their clinical heterogeneity. The objective of this study is to explore the association between the clinical presentation and the genotype of a DBS patient who was initially diagnosed with early-onset high myopia (eoHM) from a healthy Chinese family. To this end, we tested the patient of this family via whole exome sequencing and further verified the results among other family members by Sanger sequencing. Comprehensive ophthalmic tests as well as other systemic examinations were also performed on participants with various genotypes. Genetic assessment revealed that two novel variations in LRP2, a de novo missense variation (c.9032G>A; p.Arg3011Lys) and a novel splicing variation (c.2909-2A>T) inherited from the father, were both carried by the proband in this family, and they are strongly associated with the typical clinical features of DBS patients. Therefore, in this paper we are the first to report two novel compound heterozygous variations in LPR2 causing DBS. Our study extends the genotypic spectrums for LPR2-DBS and better assists physicians in predicting, diagnosing, and conducting gene therapy for DBS.

Keywords: Donnai-Barrow syndrome; clinical features; compound heterozygous variation; early-onset high myopia; genetic assessment.

FIGURE 1

External photographs of DBS patient with early-onset high myopia. Patient is characterized by (A) Carrying hearing-aid as well as cochlear implant. (B) Ocular hypertelorism, exophthalmos, broad and high forehead, receding hairline, depressed nasal bridge, short nose with broad tip, and esotropia. (C, D) Hypermobility of the hand joints.

FIGURE 2

Validation of the variation. (A) Pedigree information. Filled black symbol represents the affected member. Two variations are M1: c.9032G>A (p.Arg3011Lys) and M2: c.2909-2A>T, Wt indicates Wild type. Proband is indicated by arrow. (B) Complementary sequence chromatograms of identified sites for all family members. (C) Orthologous protein sequence alignment of LRP2 from human (H. sapiens), chimpanzees (P. troglodytes), rhesus macaque (M.mulatta), mouse (M. musculus), rats (R. norvegicus), Goldfish (C.auratus), Chicken (G. gallus), Rock dove (C.livia), and cows (B. taurus). Conserved residues are shaded. (D) Structural analysis of the wild type and mutant LRP2 protein. Hydrogen bonds between residue 3011 and Tyr3029 were eliminated due to the substitution from arginine to lysine. Overall structure of human LRP2 and effect of the M1: c.9032G>A (p.Arg3011Lys) (top), Squares within solid red lines are cropped for magnification (bottom). The yellow dashed line indicates hydrogen bonds.

FIGURE 3

Clinical photograph of DBS patient with early-onset high myopia patient and unaffected members. (A) Anterior segment photography of the individuals I:2, II:1, and II:2, showing persistent pupillary membrane (red arrow) in II:2 but normal anterior segment in I:1 and II:1. (B) Fundus photography shows severe high myopic retinopathy in II:2 but no change in I:1 and II:1. (C) Ocular color duplex ultrasonography of the individuals I:2, II:1, and II:2, showing bilateral posterior staphylomata and vitreous opacities in both eyes of II:2 while no change in I:1 and II:1. (D) Visual field of II:2 shows small central scotoma and multiple paracentral scotoma in both eyes, but only very small paracentral scotoma were detected in both eyes of I:2 and II:1. (E) Optical coherence tomography of the individuals I:2, II:1, and II:2, showing fovea macula disappeared in II:2 but normal fovea macula in I:1 and II:1. (F) Uterine color ultrasound of the individuals I:2, II:1, and II:2, showing dicornal uterus (red coil) in II:2, but the uteruses (yellow coil) of I:1 and II:1 are normal, and the uterus of II:1 is larger than that of I:2 and II:1.