Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects

Anophthalmia/microphthalmia (A/M) is a genetically heterogeneous birth defect for which the etiology is unknown in more than 50% of patients. We used exome sequencing with the ACE ExomeTM (Personalis, Inc; 18 cases) and UCSF Genomics Core (21 cases) to sequence 28 patients with A/M and four patients...

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Published in:	Clinical genetics Vol. 88; no. 5; pp. 468 - 473
Main Authors:	Slavotinek, A.M., Garcia, S.T., Chandratillake, G., Bardakjian, T., Ullah, E., Wu, D., Umeda, K., Lao, R., Tang, P.L.-F., Wan, E., Madireddy, L., Lyalina, S., Mendelsohn, B.A., Dugan, S., Tirch, J., Tischler, R., Harris, J., Clark, M.J., Chervitz, S., Patwardhan, A., West, J.M., Ursell, P., de Alba Campomanes, A., Schneider, A., Kwok, P.-y., Baranzini, S., Chen, R.O.
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Publishing Ltd 01-11-2015
Subjects:	anophthalmia/microphthalmia Anophthalmos - genetics Anophthalmos - metabolism Birth defects Cardiomyopathy COL4A1 Collagen Type IV - genetics DNA Mutational Analysis Exome exome sequencing Exoribonucleases - genetics Eye Abnormalities - genetics Eye diseases FBLN1 Female Genetic disorders Humans Infant Male Membrane Proteins - genetics Microphthalmos - genetics Microphthalmos - metabolism Mutation Otx Transcription Factors - genetics PNPT1 Receptors, Retinoic Acid - genetics anophthalmia/microphthalmia exome sequencing FBLN1 PNPT1 COL4A1
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Summary:	Anophthalmia/microphthalmia (A/M) is a genetically heterogeneous birth defect for which the etiology is unknown in more than 50% of patients. We used exome sequencing with the ACE ExomeTM (Personalis, Inc; 18 cases) and UCSF Genomics Core (21 cases) to sequence 28 patients with A/M and four patients with varied developmental eye defects. In the 28 patients with A/M, we identified de novo mutations in three patients (OTX2, p.(Gln91His), RARB, p.Arg387Cys and GDF6, p.Ala249Glu) and inherited mutations in STRA6 in two patients. In patients with developmental eye defects, a female with cataracts and cardiomyopathy had a de novo COL4A1 mutation, p.(Gly773Arg), expanding the phenotype associated with COL4A1 to include cardiomyopathy. A male with a chorioretinal defect, microcephaly, seizures and sensorineural deafness had two PNPT1 mutations, p.(Ala507Ser) and c.401‐1G>A, and we describe eye defects associated with this gene for the first time. Exome sequencing was efficient for identifying mutations in pathogenic genes for which there is no clinical testing available and for identifying cases that expand phenotypic spectra, such as the PNPT1 and COL4A1‐associated disorders described here.
Bibliography:	Academic Senate, University of California, San Francisco National Eye Institute - No. R21EY022779-01 istex:6244E4ACC3F6CED8ED36EEC4D3E26D83A55ED86D Clinical Application of Exome Sequencing to Developmental Eye Disorders Higher Education Commission of Pakistan National Institutes of Health Chromatograms showing mutations in pathogenic genes in developmental eye disorders. (a) Chromatogram showing c.273G>C, predicting p.Gln91His in OTX2 in a patient with bilateral anophthalmia. The mutation is not present in the mother or father and thus is de novo. (b) Chromatogram showing c.1159C>T, predicting p.Arg387Cys in RARB in a patient with severe microphthalmia and coloboma. The mutation is not present in the mother or father and thus is de novo. (c). Chromatogram showing c.746C>A, predicting p.Ala249Glu in GDF6 in a patient with bilateral anophthalmia. The mutation is not present in the mother or father and thus is de novo. (d). Chromatogram showing c.128C>A, predicting p.Ala43Asn in ABCB6 in a patient with unilateral microphthalmia, cataract and persistent hyperplasia of the primary vitreous. The mutation was inherited from the unaffected mother.Chromatograms showing mutations and sequence variants of unknown significance in developmental eye disorders. (a) Chromatogram showing c.128C>A, predicting p.Ala43Asn in ABCB6 in a patient with unilateral microphthalmia, cataract and persistent hyperplasia of the primary vitreous. The mutation was inherited from the unaffected mother. (b) Chromatogram showing c.820C>T, predicting p.(Arg274Cys) in VSX2 in a patient with unilateral anterior segment dysgenesis. The mutation was inherited from the unaffected father. (c). Chromatogram showing c.385G>A, predicting p.(Glu129Lys) in SIX6 in a patient with bilateral coloboma. The mutation was inherited from the unaffected father. (d). Chromatogram showing c.1607C>T, predicting p.(Thr566Ile) in FBLN1 in a patient with bilateral anophthalmia. The mutation was homozygous and inherited from both parents.Clinical Details in 20 Patients with Eye Defects without Detected Pathogenic Mutations on Exome Sequencing ark:/67375/WNG-DN3KD2JJ-C ArticleID:CGE12543 Some authors, as indicated, are employed by and receive a salary and/or are shareholders in Personalis, Inc. Personalis' commercial services include an augmented clinical exome sequencing test: The ACE Clinical Exome™ Test. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0009-9163 1399-0004
DOI:	10.1111/cge.12543