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Marta Owczarek-Lipska, Christoph Jüschke, Lejla Mulahasanovic, Konstanze Hörtnagel, Saskia Biskup, Tobias Linden, Christoph G. Korenke, John Per Neidhardt; Whole exome sequencing towards a rapid identification of genetic variants associated with congenital nystagmus.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2785.
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© ARVO (1962-2015); The Authors (2016-present)
Congenital or early-onset nystagmus (CN) is characterized by involuntary eye movements and shows enormous clinical and genetic heterogeneity. CN may be an ambiguous sign of many different diseases, including retinal dysfunction / degeneration, ocular / oculocutaneous albinism, and severe central nervous system disorders, such as Pelizaeus-Merzbacher or Pelizaeus-Merzbacher-like diseases (PMLD).Due to enormous heterogeneity found among the diseases leading to CN, whole exome sequencing (WES) and panel-based bioinformatics was considered as an approach to rapidly identify disease-associated genetic sequence variants.
We analyzed 9 families with 16 CN-affected patients. The CN-affected index patients were analyzed using WES, while a co-segregation analysis in several family members was verified with Sanger sequencing.The patients were clinically investigated in detail.
The three patients presented here, were initially affected by CN, but developed further clinical symptoms of variables severities: one of these patients showed features of retinal dysfunction, including night blindness and myopia, while two other patients developed severe phenotypes including mental retardation or PMLD.WES identified four genetic variants in three genes associated with CN. The first patient showed a hemizygous splice-donor variant (c.2576+1G>A) in the calcium channel voltage-dependent alpha-1f subunit (CACNA1F) gene, the second patient carried a hemizygous variant (c.1403G>A, p.R468H) in the ferm domain-containing protein 7 (FRMD7) gene, and the third patient showed two heterozygous variants (c. 291C>G, p.Y97* and c.716T>C, p.V293A) in the gap junction protein gamma-2 (GJC2) gene. Sanger sequencing confirmed the WES-identified variants in the index patients and verified the co-segregation with the disease.
Our results suggested a beneficial role of WES to identify the molecular causes of CN and rapidly confirmed an initially unclear clinical diagnosis.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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