title: Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects.
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.
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.|Program in Human Genetics, University of California San Francisco, San Francisco, CA, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Slavotinek
authors.affiliation: Personalis, Inc., Menlo Park, CA, USA.
authors.forename: S T
authors.initials: ST
authors.lastname: Garcia
authors.affiliation: Personalis, Inc., Menlo Park, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Chandratillake
authors.affiliation: Division of Medical Genetics, Einstein Medical Center, Philadelphia, PA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Bardakjian
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.|Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: E
authors.initials: E
authors.lastname: Ullah
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Umeda
authors.affiliation: Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Lao
authors.affiliation: Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
authors.forename: P L-F
authors.initials: PL
authors.lastname: Tang
authors.affiliation: Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Wan
authors.affiliation: Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Madireddy
authors.affiliation: Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lyalina
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Mendelsohn
authors.affiliation: Division of Medical Genetics, Children's Hospitals & Clinics, Minneapolis, MN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Dugan
authors.affiliation: Personalis, Inc., Menlo Park, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Tirch
authors.affiliation: Personalis, Inc., Menlo Park, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Tischler
authors.affiliation: Personalis, Inc., Menlo Park, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Harris
authors.affiliation: Personalis, Inc., Menlo Park, CA, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Clark
authors.affiliation: Personalis, Inc., Menlo Park, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chervitz
authors.affiliation: Personalis, Inc., Menlo Park, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Patwardhan
authors.affiliation: Personalis, Inc., Menlo Park, CA, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: West
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Ursell
authors.affiliation: Department of Ophthalmology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: de Alba Campomanes
authors.affiliation: Division of Medical Genetics, Einstein Medical Center, Philadelphia, PA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Schneider
authors.affiliation: Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
authors.forename: P-Y
authors.initials: PY
authors.lastname: Kwok
authors.affiliation: Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Baranzini
authors.affiliation: Personalis, Inc., Menlo Park, CA, USA.
authors.forename: R O
authors.initials: RO
authors.lastname: Chen
mesh_terms: D000853:Anophthalmos / Q000235:genetics* / Q000378:metabolism; D024141:Collagen Type IV / Q000235:genetics; D004252:DNA Mutational Analysis; D059472:Exome; D005095:Exoribonucleases / Q000235:genetics; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008850:Microphthalmos / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D051857:Otx Transcription Factors / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics; D024101:Mitochondrial Proteins
chemical_list: D024141:Collagen Type IV; D005095:Exoribonucleases; D008565:Membrane Proteins; D051857:Otx Transcription Factors; D018168:Receptors, Retinoic Acid; C547475:COL4A1 protein, human; C497659:OTX2 protein, human; C519685:STRA6 protein, human; C082925:retinoic acid receptor beta; C476417:PNPT1 protein, human; D024101:Mitochondrial Proteins
keywords: COL4A1; FBLN1; PNPT1; anophthalmia/microphthalmia; exome sequencing