Identification of a Novel ZNF469 Mutation in a Pakistani Family With Brittle Cornea Syndrome

Abstract

Purpose: Brittle cornea syndrome (BCS) is a rare recessive disorder affecting connective tissues, most prominently in the eye. Pathogenic mutations causing BCS have been identified in PRDM5 and ZNF469 genes. This study investigates the genetic cause of BCS in a large, consanguineous Pakistani family with 4 affected and 3 unaffected individuals. Methods: The coding region and exon–intron splice junctions of PRDM5 and ZNF469 genes were amplified by polymerase chain reaction, and bidirectional Sanger sequencing was performed to find the pathogenic change responsible for causing the disease in the family. Results: A novel homozygous duplication c.9831dupC (p.Arg3278GlnfsX197) in the ZNF469 gene was identified, which was found to be co-segregating with the disease in the family. Conclusions: This is the first report of a ZNF469 homozygous mutation causing a BCS phenotype in a consanguineous Pakistani family. Our data extend the mutation spectrum of ZNF469 variants implicated in BCS.

More than meets the eye: Expanding and reviewing the clinical and mutational spectrum of brittle cornea syndrome

“…Blue sclerae were present in the sister of a reported proband, who had a heterozygous ZNF469 nonsense variant (Khan et al, 2010). In another family with a ZNF469 frameshift variant, one carrier member had joint hypermobility and two carriers displayed myopia (Micheal et al, 2019). Multiple heterozygous members of the family in whom a deletion of exon 9–14 in PRDM5 was identified had joint hypermobility and blue sclerae, and one carrier also displayed keratoconus and myopia (Burkitt Wright et al, 2011).…”

“…Little is known about the function of ZNF469, but based on a limited homology (~30%) to the helical domains of certain collagen chains strongly expressed in the cornea (α1[I], α2[I], α1[IV] collagen), it was suggested that ZNF469 could act as a (transcriptional) regulator in the synthesis or assembly of collagen fibrils (Abu et al, 2008). To date, 20 homozygous or compound heterozygous pathogenic variants have been identified in ZNF469 (Abu et al, 2008; Al‐Owain et al, 2012; Christensen et al, 2010; Khan et al, 2010; Khan et al, 2012; Menzel‐Severing et al, 2019; Micheal et al, 2019; Ramappa et al, 2014; Rohrbach et al, 2013; Rolvien et al, 2020; Skalicka et al, 2019). Some of these were found in patients previously diagnosed with EDS VIB (Al‐Hussain et al, 2004; Rohrbach et al, 2013).…”

More than meets the eye: expanding and reviewing the clinical and mutational spectrum of brittle cornea syndrome

“…Skin and craniofacial abnormalities are mild, if present. In some, but not all, family members carrying heterozygous pathogenic variants in PRDM5 and ZNF469 , a mildly reduced central corneal thickness can be observed, in addition to blue sclerae, keratoconus or joint hypermobility (Burkitt Wright et al, 2011;Khan et al, 2010;Lechner et al, 2014;Micheal et al, 2019;Rohrbach et al, 2013;Stein et al, 1968).…”

“…Blue sclerae were present in the sister of a reported proband, who had a heterozygous ZNF469 nonsense variant (Khan et al, 2010). In another family with a ZNF469 frameshift variant, one carrier member had joint hypermobility and two carriers displayed myopia (Micheal et al, 2019). Multiple heterozygous members of the family in whom a deletion of exon 9-14 in PRDM5 was identified had joint hypermobility and blue sclerae, and one carrier also displayed keratoconus and myopia (Burkitt Wright et al, 2011).…”

“…Little is known about the function of ZNF469, but based on a limited homology (˜30%) to the helical domains of certain collagen chains strongly expressed in cornea (α1(I), α2(I), α1(IV) collagen), it was suggested that ZNF469 could act as a (transcriptional) regulator in the synthesis or assembly of collagen fibrils (Abu et al, 2008). To date 20 homozygous or compound heterozygous pathogenic variants have been identified in ZNF469 (Abu et al, 2008;Al-Owain, Al-Dosari, Sunker, Shuaib, & Alkuraya, 2012;Christensen et al, 2010;Khan, Aldahmesh, & Alkuraya, 2012;Khan, Aldahmesh, Mohamed, & Alkuraya, 2010;Menzel-Severing, Meiller, Kraus, Trollmann, & Atalay, 2019;Micheal et al, 2019;Ramappa, Wilson, Rogers, & Trivedi, 2014;Rohrbach et al, 2013;Rolvien, Kornak, Linke, Amling, & Oheim, 2020;Skalicka et al, 2019). Some of these were found in patients previously diagnosed with EDS VIB (Al-Hussain, Zeisberger, Huber, Giunta, & Steinmann, 2004;Rohrbach et al, 2013).…”