PURPOSE: To investigate the diverse ocular manifestations and identify the causative mutation in a large family with autosomal dominant anterior segment dysgenesis accompanied in some individuals by cerebral vascular disease. DESIGN: Retrospective observational case series and laboratory investigation. METHODS: Forty-five family members from 4 generations underwent ophthalmic examination. Molecular genetic investigation included analysis with single nucleotide polymorphism (SNP) markers and DNA sequencing. Whole exome sequencing was performed in 1 individual. RESULTS: A broad range of ocular manifestations was observed. Typical cases presented with corneal clouding, anterior synechiae, and iris hypoplasia. Posterior embryotoxon, corectopia, and early cataract development were also seen. One obligate carrier and several other family members had minor ocular anomalies, thus confounding the scoring of affected and unaffected individuals. Cerebral hemorrhages had occurred in 4 individuals, in 3 at birth or during the first year of life. Seven patients with corneal clouding were considered "definitely affected" for linkage studies. Haplotype mapping revealed that they shared a 14 cM region in the terminal part of chromosome 13q that included the locus for COL4A1. The affected family members were heterozygous for a novel COL4A1 sequence variant c.4881C>G (p.Asn1627Lys) predicted to be damaging and not found among 185 local blood donors. Exome sequencing showed that this variant was the only one in the candidate region not found in dbSNP. CONCLUSION: Among the family members shown to carry the novel COL4A1 mutation, heterogenous presentations of anterior segment dysgenesis was seen. Testing family members for this mutation also made a definite diagnosis possible in patients with a clinical presentation difficult to classify. In families where anterior segment dysgenesis occurs together with cerebral hemorrhages, genetic analysis of COL4A1 should be considered.
PURPOSE: To investigate the diverse ocular manifestations and identify the causative mutation in a large family with autosomal dominant anterior segment dysgenesis accompanied in some individuals by cerebral vascular disease. DESIGN: Retrospective observational case series and laboratory investigation. METHODS: Forty-five family members from 4 generations underwent ophthalmic examination. Molecular genetic investigation included analysis with single nucleotide polymorphism (SNP) markers and DNA sequencing. Whole exome sequencing was performed in 1 individual. RESULTS: A broad range of ocular manifestations was observed. Typical cases presented with corneal clouding, anterior synechiae, and iris hypoplasia. Posterior embryotoxon, corectopia, and early cataract development were also seen. One obligate carrier and several other family members had minor ocular anomalies, thus confounding the scoring of affected and unaffected individuals. Cerebral hemorrhages had occurred in 4 individuals, in 3 at birth or during the first year of life. Seven patients with corneal clouding were considered "definitely affected" for linkage studies. Haplotype mapping revealed that they shared a 14 cM region in the terminal part of chromosome 13q that included the locus for COL4A1. The affected family members were heterozygous for a novel COL4A1 sequence variant c.4881C>G (p.Asn1627Lys) predicted to be damaging and not found among 185 local blood donors. Exome sequencing showed that this variant was the only one in the candidate region not found in dbSNP. CONCLUSION: Among the family members shown to carry the novel COL4A1 mutation, heterogenous presentations of anterior segment dysgenesis was seen. Testing family members for this mutation also made a definite diagnosis possible in patients with a clinical presentation difficult to classify. In families where anterior segment dysgenesis occurs together with cerebral hemorrhages, genetic analysis of COL4A1 should be considered.
Authors: Mao Mao; Richard S Smith; Marcel V Alavi; Jeffrey K Marchant; Mihai Cosma; Richard T Libby; Simon W M John; Douglas B Gould Journal: Invest Ophthalmol Vis Sci Date: 2015-10 Impact factor: 4.799
Authors: Marie H Solheim; Allen C Clermont; Jonathon N Winnay; Erlend Hallstensen; Anders Molven; Pål R Njølstad; Eyvind Rødahl; C Ronald Kahn Journal: Invest Ophthalmol Vis Sci Date: 2017-06-01 Impact factor: 4.799
Authors: Sara Zagaglia; Christina Selch; Jelena Radic Nisevic; Davide Mei; Zuzanna Michalak; Laura Hernandez-Hernandez; S Krithika; Katharina Vezyroglou; Sophia M Varadkar; Alexander Pepler; Saskia Biskup; Miguel Leão; Jutta Gärtner; Andreas Merkenschlager; Michaela Jaksch; Rikke S Møller; Elena Gardella; Britta Schlott Kristiansen; Lars Kjærsgaard Hansen; Maria Stella Vari; Katherine L Helbig; Sonal Desai; Constance L Smith-Hicks; Naomi Hino-Fukuyo; Tiina Talvik; Rael Laugesaar; Pilvi Ilves; Katrin Õunap; Ingrid Körber; Till Hartlieb; Manfred Kudernatsch; Peter Winkler; Mareike Schimmel; Anette Hasse; Markus Knuf; Jan Heinemeyer; Christine Makowski; Sondhya Ghedia; Gopinath M Subramanian; Pasquale Striano; Rhys H Thomas; Caroline Micallef; Maria Thom; David J Werring; Gerhard Josef Kluger; J Helen Cross; Renzo Guerrini; Simona Balestrini; Sanjay M Sisodiya Journal: Neurology Date: 2018-11-09 Impact factor: 9.910
Authors: Xiaohe Yan; Sibylle Sabrautzki; Marion Horsch; Helmut Fuchs; Valerie Gailus-Durner; Johannes Beckers; Martin Hrabě de Angelis; Jochen Graw Journal: Hum Mol Genet Date: 2014-06-03 Impact factor: 6.150