Genome Sequencing Finds Genetic Heterogeneity in Optic Nerve Hypoplasia

Using whole genome sequencing, researchers were able to determine genetic heterogeneity in patients with optic nerve hypoplasia (ONH), according to a study published in PLoS One.

ONH, a congenital malformation, is a common cause of visual impairment in children and is associated with brain malformations and neurodevelopmental disorders. The disease results in a reduced number of retinal ganglion cell axons in a thin optic nerve. Although the cause is unknown, environmental and genetic sources have been proposed in the past.

Researchers performed array comparative genomic hybridization and whole genome sequencing on 29 individuals with ONH in order to determine genetic heterogeneity. The population-based, cross-sectional cohort was selected from children and young adults with ONH from Stockholm, Sweden. Eighteen individuals with bilateral ONH and 11 with unilateral ONH were included.

Patients with ONH often have coexisting pituitary hormone deficiencies, intellectual disabilities, or other brain malformations. In the study, 10 participants (34%) had an intellectual disability, while 4 patients had an autism spectrum disorder.

Overall, 11 rare single nucleotide variants (SNVs) were identified in 10 individuals, including:

• A homozygous variant in KIF7 (previously associated with Joubert syndrome)
• A heterozygous de novo variant in COL4A1 (previously described in an individual with porencephaly)
• A homozygous variant in COL4A2
• A heterozygous deletion of 341 kb involving exons 7-18 of SOX5 (associated with Lamb-Schaffer syndrome)

“The overall diagnostic yield of pathogenic or likely pathogenic variants in individuals with ONH using whole genome sequencing was 4 out of 29 (14%),” researchers said. In addition to proving genetic causes of ONH are not rare, results indicate genetic testing may be valuable in a substantial proportion of individuals with ONH.

“In total, 4 out of 11 (36%) of all the rare SNVs identified were in COL4A1 or COL4A2,” researched found. They continued, “This is the first whole genome sequencing study of a cohort with ONH…Likely, ONH can be caused of monogenic, polygenic, and environmental factors, single or in combinations.”

Researchers believe increased use of whole genome sequencing in the future can lead to more individuals with ONH receiving a genetic diagnosis.

Reference

Dahl S, Pettersson M, Eisfeldt J, et al. Whole genome sequencing unveils genetic heterogeneity in optic nerve hypoplasia. PLoS One. 2020;15(2):e0228622. doi: 10.1371/journal.pone.0228622.