Whole exome sequence analysis of Peters anomaly

Abstract

Peters anomaly is a rare form of anterior segment ocular dysgenesis, which can also be associated with additional systemic defects. At this time, the majority of cases of Peters anomaly lack a genetic diagnosis. We performed whole exome sequencing of 27 patients with syndromic or isolated Peters anomaly to search for pathogenic mutations in currently known ocular genes. Among the eight previously recognized Peters anomaly genes, we identified a de novo missense mutation in PAX6, c.155G>A, p.(Cys52Tyr), in one patient. Analysis of 691 additional genes currently associated with a different ocular phenotype identified a heterozygous splicing mutation c.1025+2T>A in TFAP2A, a de novo heterozygous nonsense mutation c.715C>T, p.(Gln239*) in HCCS, a hemizygous mutation c.385G>A, p.(Glu129Lys) in NDP, a hemizygous mutation c.3446C>T, p.(Pro1149Leu) in FLNA, and compound heterozygous mutations c.1422T>A, p.(Tyr474*) and c.2544G>A, p.(Met848Ile) in SLC4A11; all mutations, except for the FLNA and SLC4A11 c.2544G>A alleles, are novel. This is the frst study to use whole exome sequencing to discern the genetic etiology of a large cohort of patients with syndromic or isolated Peters anomaly. We report five new genes associated with this condition and suggest screening of TFAP2A and FLNA in patients with Peters anomaly and relevant syndromic features and HCCS, NDP and SLC4A11 in patients with isolated Peters anomaly.

Deficiency of the RNA binding protein caprin2 causes lens defects and features of peters anomaly

“…Mutations or functional compromise in several genes have been linked to Peters anomaly in humans and mice. These are B3GLCT (B3GALTL), Cdh1 and Cdh2 (E-and N-Cadherin), Cdo, Cited2, COL4A1, CYP1B1, Fgfr, FLNA, FOXC1, FOXE3, HCCS, Msx2, c-Myc, NDP, PAX6, PITX2, PITX3, Pxdn, RIEG1, Shroom3, SLC4A11, Sox11, Spry1, Spry2, TFAP2A (AP2a), Zeb2 (Sip1) (Okajima et al, 1999;Ozeki et al, 2001;Chen et al, 2008;Wurm et al, 2008;Pontoriero et al, 2008Pontoriero et al, , 2009Zhang et al, 2009;Bhandari et al, 2011;Kuracha et al, 2011;Reis and Semina, 2011;Zhao et al, 2012;Cavalheiro et al, 2014;Lang et al, 2014;Weh et al, 2014;Yan et al, 2014). It is interesting to note that Caprin2 protein is expressed in cells located at the anterior rim region of the lens pit at E10.5.…”

Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network

“…Causative mutations are identified in ∼40% of individuals with Axenfeld-Rieger anomaly, mainly in two genes, PITX2 and FOXC1 (Pasutto et al 2015). Despite the fact that thirteen genes have been associated with Peters anomaly, the genetic basis of this ocular anomaly remains unknown in the majority of cases (Weh et al 2014).…”

Novel variants in CDH2 are associated with a new syndrome including Peters anomaly

“…identified, including 8q21 deletions and pathogenic variants in TFAP2A, FLNA, PAX6, PITX2, CYP1B1, FOXC1, and WDR37, however, the majority of cases of syndromic PA remains unexplained. [4][5][6][7] Here we report identification of novel variants in CDH2 in four patients with PA.…”

“…The best‐known cause of syndromic PA is classic Peters plus syndrome, characterized by PA, short stature, brachydactyly, dysmorphic facial features, and variable cardiac, genitourinary, and craniofacial defects, and caused by pathogenic variants in B3GLCT . Other occasional genetic causes have been identified, including 8q21 deletions and pathogenic variants in TFAP2A , FLNA , PAX6 , PITX2 , CYP1B1 , FOXC1 , and WDR37 , however, the majority of cases of syndromic PA remains unexplained . Here we report identification of novel variants in CDH2 in four patients with PA.…”