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Clin Genet. 2015 Nov;88(5):468-73. doi: 10.1111/cge.12543. Epub 2015 Jan 6.

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

Author information

1
Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
2
Program in Human Genetics, University of California San Francisco, San Francisco, CA, USA.
3
Personalis, Inc., Menlo Park, CA, USA.
4
Division of Medical Genetics, Einstein Medical Center, Philadelphia, PA, USA.
5
Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan.
6
Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
7
Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
8
Division of Medical Genetics, Children's Hospitals & Clinics, Minneapolis, MN, USA.
9
Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
10
Department of Ophthalmology, University of California San Francisco, San Francisco, CA, USA.

Abstract

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 Exome(TM) (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.

KEYWORDS:

COL4A1; FBLN1; PNPT1; anophthalmia/microphthalmia; exome sequencing

PMID:
25457163
PMCID:
PMC4452457
DOI:
10.1111/cge.12543
[Indexed for MEDLINE]
Free PMC Article

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