Basamat AlMoallem1, Miriam Bauwens2, Sophie Walraedt3, Patricia Delbeke3, Julie De Zaeytijd3, Philippe Kestelyn3, Françoise Meire4, Sandra Janssens2, Caroline van Cauwenbergh2, Hannah Verdin2, Sally Hooghe2, Prasoon Kumar Thakur2, Frauke Coppieters2, Kim De Leeneer2, Koenraad Devriendt5, Bart P Leroy6, Elfride De Baere2. 1. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium Department of Ophthalmology, King Abdul-Aziz University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia. 2. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium. 3. Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium. 4. Department of Ophthalmology, Queen Fabiola Children's University Hospital, Brussels, Belgium. 5. Center for Human Genetics, Leuven University Hospitals, Leuven, Belgium. 6. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States.
Abstract
PURPOSE: Idiopathic infantile nystagmus (IIN; OMIM 31700) with X-linked inheritance is one of the most common forms of infantile nystagmus. Up to date, three X-linked loci have been identified, Xp11.4-p11.3 (calcium/calmodulin-dependent serine protein kinase [CASK]), Xp22 (GPR143), and Xq26-q27 (FRMD7), respectively. Here, we investigated the role of mutations and copy number variations (CNV) of FRMD7 and GPR143 in the molecular pathogenesis of IIN in 49 unrelated Belgian probands. METHODS: We set up a comprehensive molecular genetic workflow based on Sanger sequencing, targeted next generation sequencing (NGS) and CNV analysis using multiplex ligation-dependent probe amplification (MLPA) for FRMD7 (NM_194277.2) and GPR143 (NM_000273.2). RESULTS: In 11/49 probands, nine unique FRMD7 changes were found, five of which are novel: frameshift mutation c.2036del, missense mutations c.801C>A and c.875T>C, splice-site mutation c.497+5G>A, and one genomic rearrangement (1.29 Mb deletion) in a syndromic case. Additionally, four known mutations were found: c.70G>A, c.886G>C, c.910C>T, and c.660del. The latter was found in three independent families. In silico predictions and segregation testing of the novel mutations support their pathogenic effect. No GPR143 mutations or CNVs were found in the remainder of the probands (38/49). CONCLUSIONS: Overall, genetic defects of FRMD7 were found in 11/49 (22.4%) probands, including the first reported genomic rearrangement of FRMD7 in IIN, expanding its mutational spectrum. Finally, we generate a discovery cohort of IIN patients potentially harboring either hidden a variation of FRMD7 or mutations in genes at known or novel loci sustaining the genetic heterogeneity of IIN. Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.
PURPOSE:Idiopathic infantile nystagmus (IIN; OMIM 31700) with X-linked inheritance is one of the most common forms of infantile nystagmus. Up to date, three X-linked loci have been identified, Xp11.4-p11.3 (calcium/calmodulin-dependent serine protein kinase [CASK]), Xp22 (GPR143), and Xq26-q27 (FRMD7), respectively. Here, we investigated the role of mutations and copy number variations (CNV) of FRMD7 and GPR143 in the molecular pathogenesis of IIN in 49 unrelated Belgian probands. METHODS: We set up a comprehensive molecular genetic workflow based on Sanger sequencing, targeted next generation sequencing (NGS) and CNV analysis using multiplex ligation-dependent probe amplification (MLPA) for FRMD7 (NM_194277.2) and GPR143 (NM_000273.2). RESULTS: In 11/49 probands, nine unique FRMD7 changes were found, five of which are novel: frameshift mutation c.2036del, missense mutations c.801C>A and c.875T>C, splice-site mutation c.497+5G>A, and one genomic rearrangement (1.29 Mb deletion) in a syndromic case. Additionally, four known mutations were found: c.70G>A, c.886G>C, c.910C>T, and c.660del. The latter was found in three independent families. In silico predictions and segregation testing of the novel mutations support their pathogenic effect. No GPR143 mutations or CNVs were found in the remainder of the probands (38/49). CONCLUSIONS: Overall, genetic defects of FRMD7 were found in 11/49 (22.4%) probands, including the first reported genomic rearrangement of FRMD7 in IIN, expanding its mutational spectrum. Finally, we generate a discovery cohort of IIN patients potentially harboring either hidden a variation of FRMD7 or mutations in genes at known or novel loci sustaining the genetic heterogeneity of IIN. Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.
Authors: Junwon Lee; Han Jeong; Dongju Won; Saeam Shin; Seung-Tae Lee; Jong Rak Choi; Suk Ho Byeon; Helen J Kuht; Mervyn G Thomas; Jinu Han Journal: Transl Vis Sci Technol Date: 2022-06-01 Impact factor: 3.048