Whole genome sequencing unveils genetic heterogeneity in optic nerve hypoplasia
| Autor: | Kristina Teär Fahnehjelm, Ronny Wickström, Maria Pettersson, Anna Lindstrand, Jesper Eisfeldt, Sara Dahl, Anna Katharina Schröder, Britt-Marie Anderlid |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Retinal Ganglion Cells 0301 basic medicine genetic structures Blindness Nervous System Loss of heterozygosity 0302 clinical medicine Medicine and Health Sciences Optic Nerve Hypoplasia Genome Sequencing Child Visual Impairments Genetics Sanger sequencing Comparative Genomic Hybridization Optic nerve hypoplasia Multidisciplinary medicine.diagnostic_test Genomics Exons Pedigree Phenotype Neurology Pituitary Gland symbols Medicine Female Anatomy SOXD Transcription Factors Research Article Adult Heterozygote Adolescent Science Optic Neuropathy Endocrine System Biology Research and Analysis Methods Polymorphism Single Nucleotide Joubert syndrome Genetic Heterogeneity Young Adult 03 medical and health sciences symbols.namesake Genomic Medicine Ocular System medicine Humans Genetic Testing Molecular Biology Techniques Sequencing Techniques Molecular Biology Genetic testing Sweden Whole genome sequencing Whole Genome Sequencing Genome Human Genetic heterogeneity Biology and Life Sciences Computational Biology Optic Nerve Comparative Genomics medicine.disease eye diseases Neuropathy Neuroanatomy Ophthalmology Cross-Sectional Studies 030104 developmental biology Eyes sense organs Head 030217 neurology & neurosurgery Neuroscience Comparative genomic hybridization |
| Zdroj: | PLoS ONE PLoS ONE, Vol 15, Iss 2, p e0228622 (2020) |
| ISSN: | 1932-6203 |
| Popis: | Optic nerve hypoplasia (ONH) is a congenital malformation with a reduced number of retinal ganglion cell axons in a thin optic nerve. It is a common cause of visual impairment in children and ONH is associated with neurodevelopmental disorders, pituitary hormone deficiencies, and brain malformations. In most cases, the aetiology is unknown, but both environmental factors and genetic causes have been described. This study aimed to identify genetic variants underlying ONH in a well-characterised cohort of individuals with ONH. We performed array comparative genomic hybridization and whole genome sequencing in 29 individuals with ONH. Rare variants were verified by Sanger sequencing and inheritance was assessed in parental samples. We identified 11 rare single nucleotide variants (SNVs) in ten 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), and a homozygous variant in COL4A2. In addition, one individual harboured a heterozygous variant in OPA1 and a heterozygous variant in COL4A1, both were inherited and assessed as variants of unknown clinical significance. Finally, a heterozygous deletion of 341 kb involving exons 7-18 of SOX5 (associated with Lamb-Schaffer syndrome) was identified in one individual. The overall diagnostic yield of pathogenic or likely pathogenic variants in individuals with ONH using whole genome sequencing was 4/29 (14%). Our results show that there is a genetic heterogeneity in ONH and indicate that genetic causes of ONH are not rare. We conclude that genetic testing is valuable in a substantial proportion of the individuals with ONH, especially in cases with non-isolated ONH. |
| Databáze: | OpenAIRE |
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