Celia Zazo Seco1, Julie Plaisancié1,2, Tatiana Lupasco1, Caroline Michot3, Jacmine Pechmeja4, Julian Delanne5, Edouard Cottereau6, Carmen Ayuso7, Marta Corton7, Patrick Calvas1,2, Nicola Ragge8,9, Nicolas Chassaing1,2. 1. a UDEAR , Université de Toulouse, UMRS 1056 INSERM-Université Paul Sabatier , Toulouse , France. 2. b Service de Génétique Médicale , Hôpital Purpan, CHU , Toulouse , France. 3. c INSERM UMR1163 Unit, Department of Genetics , Institut Imagine, Paris Descartes University-Sorbonne Paris Cité, Necker Enfants-Malades Hospital , Paris , France. 4. d Service d'ophtalmologie , Hôpital Purpan, CHU , Toulouse , France. 5. e Centre de Génétique et Centre de référence «Anomalies du Développement et Syndromes Malformatifs» , Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon , Dijon , France. 6. f CHU de Tours , Service de Génétique , Tours , France. 7. g Genetics Service , IIS - Fundación Jiménez Díaz University Hospital, CIBERER, (IIS-FJD, UAM) , Madrid , Spain. 8. h Department of Biological and Medical Sciences, Faculty of Health and Life Sciences , Oxford Brookes University , Oxford , UK. 9. i West Midlands Regional Clinical Genetics Service and Birmingham Health Partners , Birmingham Women and Children's Hospital NHS Foundation Trust , Birmingham , UK.
Abstract
BACKGROUND: Congenital cataract displays large phenotypic (syndromic and isolated cataracts) and genetic heterogeneity. Mutations in several transcription factors involved in eye development, like PITX3, have been associated with congenital cataracts and anterior segment mesenchymal disorders. MATERIALS AND METHODS: Targeted sequencing of 187 genes involved in ocular development was performed in 96 patients with mainly anophthalmia and microphthalmia. Additionally, Sanger sequencing analysis of PITX3 was performed on a second cohort of 32 index cases with congenital cataract and Peters anomaly and/or sclereocornea. RESULTS: We described five families with four different PITX3 mutations, two of which were novel. In Family 1, the heterozygous recurrent c.640_656dup (p.Gly220Profs*95) mutation cosegregated with eye anomalies ranging from congenital cataract to Peters anomaly. In Family 2, the novel c.669del [p.(Leu225Trpfs*84)] mutation cosegregated with dominantly inherited eye anomalies ranging from posterior embryotoxon to congenital cataract in heterozygous carriers and congenital sclereocornea and cataract in a patient homozygous for this mutation. In Family 3, we identified the recurrent heterozygous c.640_656dup (p.Gly220Profs*95) mutation segregating with congenital cataract. In Family 4, the de novo c.582del [p.(Ile194Metfs*115)] mutation was identified in a patient with congenital cataract, microphthalmia, developmental delay and autism. In Family 5, the c.38G>A (p.Ser13Asn) mutation segregated dominantly in a family with Peters anomaly, which is a novel phenotype associated with the c.38G>A variant compared with the previously reported isolated congenital cataract. CONCLUSIONS: Our study unveils different phenotypes associated with known and novel mutations in PITX3, which will improve the genetic counselling of patients and their families.
BACKGROUND:Congenital cataract displays large phenotypic (syndromic and isolated cataracts) and genetic heterogeneity. Mutations in several transcription factors involved in eye development, like PITX3, have been associated with congenital cataracts and anterior segment mesenchymal disorders. MATERIALS AND METHODS: Targeted sequencing of 187 genes involved in ocular development was performed in 96 patients with mainly anophthalmia and microphthalmia. Additionally, Sanger sequencing analysis of PITX3 was performed on a second cohort of 32 index cases with congenital cataract and Peters anomaly and/or sclereocornea. RESULTS: We described five families with four different PITX3 mutations, two of which were novel. In Family 1, the heterozygous recurrent c.640_656dup (p.Gly220Profs*95) mutation cosegregated with eye anomalies ranging from congenital cataract to Peters anomaly. In Family 2, the novel c.669del [p.(Leu225Trpfs*84)] mutation cosegregated with dominantly inherited eye anomalies ranging from posterior embryotoxon to congenital cataract in heterozygous carriers and congenital sclereocornea and cataract in a patient homozygous for this mutation. In Family 3, we identified the recurrent heterozygous c.640_656dup (p.Gly220Profs*95) mutation segregating with congenital cataract. In Family 4, the de novo c.582del [p.(Ile194Metfs*115)] mutation was identified in a patient with congenital cataract, microphthalmia, developmental delay and autism. In Family 5, the c.38G>A (p.Ser13Asn) mutation segregated dominantly in a family with Peters anomaly, which is a novel phenotype associated with the c.38G>A variant compared with the previously reported isolated congenital cataract. CONCLUSIONS: Our study unveils different phenotypes associated with known and novel mutations in PITX3, which will improve the genetic counselling of patients and their families.
Authors: Celia Zazo-Seco; Julie Plaisancié; Pierre Bitoun; Marta Corton; Ana Arteche; Carmen Ayuso; Adele Schneider; Dimitra Zafeiropoulou; Christian Gilissen; Olivier Roche; Felix Frémont; Patrick Calvas; Anne Slavotinek; Nicola Ragge; Nicolas Chassaing Journal: J Hum Genet Date: 2020-02-03 Impact factor: 3.172
Authors: Vanita Berry; Alex Ionides; Nikolas Pontikos; Anthony T Moore; Roy A Quinlan; Michel Michaelides Journal: Eye (Lond) Date: 2021-08-03 Impact factor: 4.456