Fig 1.
Segregation analyses in 10 of 11 families with rare genomic variants.
DNA samples from 19 parents were available for segregation analysis and revealed that eight SNVs in eight individuals were inherited. The SNV in Case 11 was de novo. The CNV identified in Case 18 had only one parental sample available and the inheritance could not be established. A diagnosis of optic nerve hypoplasia is indicated in black, suspected optic atrophy is indicated in grey, and no ophthalmological disorder, excluding refractive errors, is indicated in white.
Fig 2.
Fundus photographs from Case 18 with bilateral optic nerve hypoplasia.
Case 18 was born full term and developmental delay was noticed at one year of age. She was diagnosed with moderate intellectual disability and has autistic traits. She had strabismus and bilateral optic nerve hypoplasia was diagnosed at three years of age. The BCVA was 0.12 right and left eye at six years of age.
Table 1.
Clinical phenotypes and identified candidate variants in 11 optic nerve hypoplasia cases.
Fig 3.
Rare variants in COL4A1 and COL4A2.
Rare variants in COL4A1 and COL4A2 were identified in 4/29 (14%) individuals with optic nerve hypoplasia (A). Of these four variants, two affected the collagen triple helix domain of COL4A1 or COL4A2, one affected the 7S domain of COL4A1, and one affected the noncollagenous (NC1) domain of COL4A2 (B).
Table 2.
Rare single nucleotide variants identified in the optic nerve hypoplasia cohort.
Fig 4.
Fundus photographs from Case 17 with bilateral optic nerve hypoplasia.
Case 17 was born full term and due to nystagmus bilateral optic nerve hypoplasia was diagnosed at one month of age. He was visually impaired with a BCVA of 0.15 right and 0.03 left eye at 12 years of age. Extreme thirst and weight gain at three months of age revealed a diabetes insipidus. In addition, he had adrenocorticotropic hormone deficiency. At ten years of age he was diagnosed with an autism spectrum disorder, but he has normal intelligence. Furthermore, he has hyposmia, mild gross motor function impairment, and jaw abnormalities.
Fig 5.
Fundus photographs from Case 21 with unilateral optic nerve hypoplasia left eye.
Fundus photographs from Case 21 with unilateral optic nerve hypoplasia and heterozygous missense variants in COL4A1 and OPA1 showing (A) a normal optic disc in the right eye and (B, magnified image) optic nerve hypoplasia in the left eye with a small optic disc (arrow) and a surrounding peripapillary atrophy. Case 21 was born full term and was treated with patching from 11 months of age because of strabismus (esotropia left eye). She was lost to follow-up and unilateral optic nerve hypoplasia was diagnosed after the visual screening at four years of age. The BCVA was 1.0 right and 0.03 left eye at 15 years of age. She had a precocious puberty from seven years of age and is normally developed.
Fig 6.
Fundus photographs from Case 27 with unilateral optic nerve hypoplasia right eye.
Case 27 was born at 37 weeks of gestation. She developed strabismus (exotropia right eye) and unilateral optic nerve hypoplasia was diagnosed at two years of age. The BCVA was 0.5 right and 1.0 left eye at 11 years of age. She has a mild intellectual disability.
Fig 7.
Fundus photographs from Case 29 with bilateral optic nerve hypoplasia.
Case 29 was born full term and came to Sweden from Iraq at four years of age. She had strabismus (exophoria left eye) and multiple brain malformations, including thin optic nerves, on magnetic resonance imaging. However, bilateral optic nerve hypoplasia was not diagnosed until she was 17 years of age. At 18 years of age the BCVA was 0.8 right and 0.5 left eye. She was further diagnosed with a moderate intellectual disability and has mild motor impairments.
Fig 8.
Fundus photographs from Case 5 with bilateral optic nerve hypoplasia.
Case 5 was born full term and had neonatal hypoglycemia and seizures. Bilateral optic nerve hypoplasia was diagnosed at two months of age due to lack of fixation and nystagmus. At the same age he was diagnosed with adrenocorticotropic hormone deficiency, and later on he was also treated for growth hormone deficiency and central hypothyroidism. The BCVA was 0.125 right and left eye at seven years of age. He is normally developed.
Fig 9.
Fundus photographs from Case 19 with unilateral optic nerve hypoplasia right eye.
Case 19 was born full term. He had severe strabismus (esotropia right eye) and was diagnosed with unilateral optic nerve hypoplasia at two months of age. He is blind in his right eye, but the BCVA was 1.0 left eye at 12 years of age. He is normally developed.
Fig 10.
Fundus photographs from Case 20 with unilateral optic nerve hypoplasia right eye.
Case 20 was born full term and unilateral optic nerve hypoplasia was discovered at the ophthalmology department after detection at the visual screening at four years of age. He had strabismus (esotropia right eye) and the BCVA was 0.1 right and 1.0 left eye at five years of age. He has normal intelligence.
Fig 11.
Fundus photographs from Case 14 with bilateral optic nerve hypoplasia.
Case 14 was born preterm at 27 weeks of gestation. He had strabismus and was diagnosed with left sided optic nerve hypoplasia at 13 months of age, which on closer assessment proved to be bilateral optic nerve hypoplasia when he was 13 years of age. The BCVA was 1.0 right and 0.1 left eye at eight years of age, but he had a significant visual field defect in his right eye. He is normally developed.