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.

Keywords: COL4A1; FBLN1; PNPT1; anophthalmia/microphthalmia; exome sequencing.

Fig. 1. A female with congenital cataracts and cardiomyopathy with p.(Gln773Arg) in COL4A1

(a) Photograph of gross pathology of heart muscle from a female with p.(Gln773Arg) in COL4A1, showing hypertrophy of the left and right ventricles consistent with cardiomyopathy. (b) Photograph of histology of heart muscle stained with trichrome to show fibrosis (indicated by blue staining), indicating long-standing cardiomyopathy. (c) Chromatogram showing c.2317G>A, predicting p.(Gly773Arg) in COL4A1. The mutation is present in the patient and not inherited from either parent.

Fig. 2. A Male with Developmental Delays, Seizures, Sensorineural Hearing Loss and a Unilateral Chorioretinal Defect with Two Inherited PNPT1 mutations

Fig. 2A. Frontal photograph of the patient at twenty two months of age. (b,c) Photographs of left retina, showing chorioretinal defect. Fig. 2D. Photograph of right retina showing normal morphology. Fig. 2E. Chromatogram showing splice mutation c.401-1G>A in PNPT1. The mutation is inherited from the patient’s unaffected mother.d Fig. 2F. Chromatogram showing c.1519G>T, predicting p.(Ala507Ser) in PNPT1. The mutation was inherited from the patient’s unaffected father.