Whole exome sequence analysis of Peters anomaly

• Published in: Human genetics 2014-12, Vol.133 (12), p.1497-1511
• Main Authors: Weh, Eric, Reis, Linda M., Happ, Hannah C., Levin, Alex V., Wheeler, Patricia G., David, Karen L., Carney, Erin, Angle, Brad, Hauser, Natalie, Semina, Elena V.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Anion Transport Proteins - genetics; Anterior Eye Segment - abnormalities; Antiporters - genetics; Biomedical and Life Sciences; Biomedicine; Child; Congenital diseases; Corneal Opacity - diagnosis; Corneal Opacity - genetics; DNA Mutational Analysis; Exome; Eye Abnormalities - diagnosis; Eye Abnormalities - genetics; Eye Proteins - genetics; Family medical history; Filamins - genetics; Gene Function; Genetic Association Studies; Genetic Predisposition to Disease; Genetics; Glaucoma; Homeodomain Proteins - genetics; Hospitals; Human Genetics; Humans; Infant; Lyases - genetics; Male; Metabolic Diseases; Molecular Medicine; Molecular Sequence Data; Mutation; Mutation, Missense; Nerve Tissue Proteins - genetics; Neurosciences; Original Investigation; Paired Box Transcription Factors - genetics; PAX6 Transcription Factor; Pediatrics; Pedigree; Prenatal Diagnosis; Repressor Proteins - genetics; Sequence Analysis, RNA; Transcription Factor AP-2 - genetics
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-014-1481-x

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 first 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.