Submission Details

The relationship between LTBP2 and LTBP2-related ocular dysgenesis, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of February 16, 2023. LTBP2 belongs to the family of latent transforming growth factor (TGF)-beta binding proteins (LTBP), which are extracellular matrix proteins with multi-domain structure. This protein is expressed in elastic tissues and associates with fibrillin-1 containing microfibrils. Pathogenic variants in this gene are known to cause multiple disorders including Primary congenital glaucoma (MIM# 613086), Weill-Marchesani syndrome 3 (MIM# 614819), and Microspherophakia and/or megalocornea, with ectopia lentils and with or without secondary glaucoma (MIM# 251750). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) AND inheritance pattern AND phenotypic variability in the above mentioned disease entities. Therefore, all of the disease entities have been lumped into one disease entity, LTBP2-related ocular dysgenesis.

LTBP2 was first reported in relation to autosomal recessive LTBP2-related ocular dysgenesis in 2009 (Ali et al, 2009, PMID: 19361779; Narooie-Nejad, 2009, PMID: 19656777). More than 50 nonsense, frameshift, and missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data.

Summary of Case Level Data (12 points): Variants in this gene have been reported in at least 6 probands in 3 publications (PMID: 19361779, 20617341, 33958902). Variants in this gene segregated with disease in 13 additional family members. The mechanism for disease is biallelic loss of function.

Summary of experimental data (6 points): This gene-disease association is supported by in vitro functional assays and animal models. LTBP2 is expressed in tissues relevant to disease within the eye including trabecular meshwork, ciliary processes, lens capsule, Descemet membrane (PMID: 19361779 , 19656777). The LTBP2 protein has a function in promoting the assembly of mature microfibrils in ciliary zonules (PMID: 24908666). LTBP2 variants expressed in HEK293T cells are shown to be trapped intracellularly due to secretion defects and/or lack fibrillin-1-binding activity (PMID: 24908666). Homozygous knock out of LTBP2 in animal models recapitulates the human phenotype. An initial report of LTBP2 knock-out in mice showed complete embryonic lethality (PMID: 10848613). A conditional knock-out mouse model, however, survived to adulthood with no systemic abnormalities, but showed ectopia lentils due to defects in the formation of microfibrils (PMID: 24908666). A spontaneous form of primary congenital glaucoma inherited in the autosomal recessive manner in domestic cats was shown to result from a frameshift variant in the feline LTBP2 gene (PMID: 24908666).

In summary, LTBP2 is definitively associated with autosomal recessive LTBP2-related ocular dysgenesis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.