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Sairah Yousaf, Rehan Sadiq Shaikh, Rehana Iqbal, Saima Riazuddin, Zubair Ahmed; Variable penetrance of Fraser syndrome-associated FREM2 allele and candidate genetic modifier. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4527.
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© ARVO (1962-2015); The Authors (2016-present)
Fraser syndrome is a rare genetically heterogeneous recessive multisystem malformation disorder characterized by cryptopthalmos, cutaneous syndactyly, and urogenital anomalies. Here, we performed detailed clinical & molecular characterization of a large consanguineous family to improve our understanding of Fraser genetic network.
With IRB approval, a large family (PKFS001) with 6 affecteds was enrolled. Physical and detailed clinical histories were obtained. Whole exome sequencing (WES) was performed to identify underlying genetic deficit. Immunohistochemistry followed by confocal imaging was performed for WT and truncated protein localization. Molecular modeling using Phyre2 & HOPE prediction programs was performed.
The clinical spectrum of family PKFS001 includes unilateral cryptopthalmos, cutaneous syndactyly, and unilateral renal hypoplasia. Through WES, we identified a novel missense mutation in FREM2 gene, encoding Fras1-Related Extracellular Matrix Protein 2. The identified p.(Arg2167Trp) variant is in the Calx-beta 4 domain of FREM2, which binds and regulates Ca2+ with high affinity and is required for normal cell adhesion functions. Molecular modeling suggested that due to the differences in size, charge and hydrophobic properties, the mutated residue (tryptophan) is predicted to disrupt protein topology, which could result in protein misfolding. Intriguingly, three apparently healthy (non-penetrant) individuals of PKFS001 family are also homozygous for p.(Arg2167Trp) allele, potentially indicating reduced penetrance. Genetic modifiers are one of several elements that can influence the phenotypic expression of a genetic disorder. To determine the genetic cause of reduced penetrance, we performed WES studies on the three non-penetrant and two additional affected individuals. Intriguingly, bioinformatic analysis of WES data revealed a candidate heterozygous variant in an unrelated gene on human chromosome 11q, which may act as a dominant modifier of FREM2. Currently, studies are underway to determine the mechanism of suppression of FREM2 allele.
Our studies provide first evidence of a potential genetic dominant modifier that could cause reduced penetrance of FREM2 allele. Validating and deciphering the molecular mechanism of modification has potential clinical relevance to target a disease with no known treatments.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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