Optic nerve hypoplasia in children - prevalence, associated disorders and genetic causes

Optic nerve hypoplasia (ONH) is a congenital ocular malformation with a thin optic nerve in one or both eyes. ONH has been associated with neurodevelopmental disorders and pituitary dysfunction, but the prevalence of these comorbidities are still unknown, especially in children with less severe visual impairment and unilateral disease. The aims of this thesis were to examine the prevalence of ONH in children, to determine the prevalence of intellectual disability, autism spectrum disorder, motor impairment, and pituitary dysfunction in unilateral and bilateral disease, as well as to identify genetic variants underlying ONH. Methods: In study I, a population-based cohort of patients with ONH was established including patients who were diagnosed with ONH, below 20 years of age, and living in Stockholm in December 2009. Ophthalmological assessments were performed, and the Five to Fifteen parent questionnaire (FTF) was used to screen for developmental problems. Subsequently, study II and study III were population-based cross-sectional cohort studies. In study II, neurodevelopmental disorders were confirmed by the FTF, neurological assessments, reviewing previous neuropsychological investigations, or conducting neuropsychological tests. In study III, motor impairments were assessed using a specific protocol and previous neuroradiology was reviewed. Blood sampling was performed to screen for pituitary dysfunction together with analysis of growth curves and medical history. Study IV included 29 patients with ONH who were analysed with array comparative genomic hybridization followed by whole genome sequencing and in silico filtering of single nucleotide variants in 42 candidate genes. Rare variants were verified by Sanger sequencing. Results: The prevalence of ONH in children in Stockholm was 17.3/100 000. Unilateral ONH was almost as common as bilateral (45%). Intellectual disability was more common in bilateral ONH than in unilateral ONH (56% vs 9%, p< 0.001). Autism spectrum disorders were diagnosed in 17%, without correlation to laterality. Motor impairments were identified in 47% of the patients and were significantly more prevalent in bilateral ONH. In contrast, pituitary hormone deficiency (PHD) was confirmed in 29% of the cohort and 19% had multiple PHD, without correlation to laterality. Furthermore, presence of structural pituitary abnormalities had a very high sensitivity for PHD. Finally, we identified three rare variants in COL4A1 and three rare variants in COL4A2, of which two were assessed as likely pathogenic. In addition, we found an interesting rare variant in OPA1 and two other likely pathogenic variants in SOX5 and PAX6. Conclusions: ONH is a common ocular malformation in children, with a prevalence of 17.3/100 000 in Stockholm. Unilateral ONH seems to be as common as bilateral. Children with both unilateral and bilateral ONH have a high risk of neurodevelopmental disorders and PHD, but bilateral ONH increases the risk of intellectual disability, motor impairment, and brain abnormalities. These findings need to be considered when designing screening, care, and follow-up programs. Our genetic study suggests that a genetic cause of ONH is more common than previously reported and highlights COL4A1 and COL4A2 as candidate genes