Next-generation sequencing reveals a new mutation in the LTBP2 gene associated with microspherophakia in a Spanish family

Abstract

BackgroundMicrospherophakia is a rare autosomal recessive eye disorder characterized by small spherical lens. It may present as an isolated finding or in association with other ocular and/or systemic disorders. This clinical and genetic heterogeneity requires the study of large genes (ADAMTSL4, FBN1, LTBP2, ADAMTSL-10 and ADAMTSL17). The purpose of the present study is to identify the genetic cause of this pathology in a consanguineous Spanish family.MethodsA clinical exome sequencing experiment was executed by the TruSight One® Sequencing Panel (TSO) from Illumina©. Sanger sequencing was used to validate the NGS results.ResultsOnly the insertion of an adenine in exon 36 of the LTBP2 gene (c.5439_5440insA) was associated with pathogenicity. This new mutation was validated by Sanger sequencing and segregation analysis was also performed. Haplotype analyses using the polymorphic markers D14S1025, D14S43 and D14S999 close to the LTBP2 gene indicated identity by descent in this family.ConclusionWe describe the first case of a microspherophakia phenotype associated with a novel homozygous mutation in the LTBP2 gene in a consanguineous Caucasian family by means of NGS technology.

Multi‐organ phenotypes in mice lacking latent TGFβ binding protein 2 (LTBP2)

“…Both of these newer strains have a demonstrated eye phenotype which affects the strength and longevity of zonular fibers, resulting in ectopia lentis. Human mutations in LTBP2 are associated with primary congenital glaucoma, [16][17][18][19] microspherophakia, 20,21 and a recessive form of Weill-Marchesani syndrome (type 3). 22,23 As an additional note, we speculate that previous reports of embryonic lethality may be a result of problems with the targeting construct or potential off target deletions, since the previously mentioned line produced by Inoue and our current Ltbp2 À/À line live to adulthood.…”

“…Mutations in LTBP2 have been reported in humans with primary congenital glaucoma, 16–19 microspherophakia, 20,21 and a recessive form of Weill‐Marchesani syndrome (type 3) 22,23 . Animal science studies have suggested that Ltbp2 could be a candidate gene for determining vertebrae and rib number in mammals, specifically quadrupeds 24,25 .…”

Zonule-Associated Gene Variants in Isolated Ectopia Lentis and Glaucoma

“… 46 It has been postulated that LTBP2 interacts with some members of the TGF-β family to regulate microfibril storage in the extracellular matrix 47 . Patients with mutations in LTBP2 may present with ocular manifestations including congenital macrocornea, microspherophakia, EL, lens-related secondary glaucoma, cataracts, high myopia, and some features of MFS in elder individuals 48–50 …”

“…47 Patients with mutations in LTBP2 may present with ocular manifestations including congenital macrocornea, microspherophakia, EL, lens-related secondary glaucoma, cataracts, high myopia, and some features of MFS in elder individuals. [48][49][50] Mutations in LTBP2 may not only increase the elasticity of the ciliary body and lead to changes in the structural support of the surrounding tissue but also affect the structure of the Schlemm canal and the trabecular meshwork and then affect aqueous humor drainage. 39 The total number and size distribution of zonule fibers in LTBP2 knock-out mice were essentially normal, but the viscoelastic behavior of the fibers was significantly altered with EL and secondary glaucoma occurred.…”

Compound heterozygous mutations in the LTBP2 gene associated with microspherophakia in a Chinese patient: a case report and literature review

“…Kumar et al [ 30 ] found that a homozygous duplication mutation (c.5446dupC) in exon 36 of LTBP2 could lead to isolated MSP. Alías et al [ 28 ] detected the insertion of an adenine (c.5439_5440insA) in exon 36 of LTBP2 in a Spanish family with MSP. Shahzadi et al [ 31 ] presented a genetic linkage between MSP and LTBP2 locus in a large consanguineous Pakistani family.…”