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Novel FRMD7 mutations and genomic rearrangement expand the molecular pathogenesis of X-linked idiopathic infantile nystagmus

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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.
Keywords
idiopathic infantile nystagmus, FRMD7 mutations, next generation sequencing, MLPA, genomic rearrangement, CONGENITAL NYSTAGMUS, FERM DOMAIN, CHINESE FAMILY, AROMATIC INTERACTIONS, PROTEINS, IDENTIFICATION, MEMBRANE, DELETION, GENE

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Chicago
Almoallem Mohammed, Basamat, Miriam Bauwens, SOPHIE WALRAEDT, Patricia Delbeke, Julie De Zaeytijd, Philippe Kestelyn, Françoise Meire, et al. 2015. “Novel FRMD7 Mutations and Genomic Rearrangement Expand the Molecular Pathogenesis of X-linked Idiopathic Infantile Nystagmus.” Investigative Ophthalmology & Visual Science 56 (3): 1701–1710.
APA
Almoallem Mohammed, B., Bauwens, M., WALRAEDT, S., Delbeke, P., De Zaeytijd, J., Kestelyn, P., Meire, F., et al. (2015). Novel FRMD7 mutations and genomic rearrangement expand the molecular pathogenesis of X-linked idiopathic infantile nystagmus. INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 56(3), 1701–1710.
Vancouver
1.
Almoallem Mohammed B, Bauwens M, WALRAEDT S, Delbeke P, De Zaeytijd J, Kestelyn P, et al. Novel FRMD7 mutations and genomic rearrangement expand the molecular pathogenesis of X-linked idiopathic infantile nystagmus. INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE. 2015;56(3):1701–10.
MLA
Almoallem Mohammed, Basamat, Miriam Bauwens, SOPHIE WALRAEDT, et al. “Novel FRMD7 Mutations and Genomic Rearrangement Expand the Molecular Pathogenesis of X-linked Idiopathic Infantile Nystagmus.” INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 56.3 (2015): 1701–1710. Print.
@article{5909590,
  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{\textrangle}A and c.875T{\textrangle}C, splice-site mutation c.497\_5G{\textrangle}A, and one genomic rearrangement (1.29 Mb deletion) in a syndromic case. Additionally, four known mutations were found: c.70G{\textrangle}A, c.886G{\textrangle}C, c.910C{\textrangle}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.},
  author       = {Almoallem Mohammed, Basamat and Bauwens, Miriam and WALRAEDT, SOPHIE and Delbeke, Patricia and De Zaeytijd, Julie and Kestelyn, Philippe and Meire, Fran\c{c}oise and Janssens, Sandra and Van Cauwenbergh, Caroline and Verdin, Hannah and Hooghe, Sally and Thakur, Prasoon Kumar and Coppieters, Frauke and De Leeneer, Kim and Devriendt, Koenraad and Leroy, Bart and De Baere, Elfride},
  issn         = {0146-0404},
  journal      = {INVESTIGATIVE OPHTHALMOLOGY \& VISUAL SCIENCE},
  keyword      = {idiopathic infantile nystagmus,FRMD7 mutations,next generation sequencing,MLPA,genomic rearrangement,CONGENITAL NYSTAGMUS,FERM DOMAIN,CHINESE FAMILY,AROMATIC INTERACTIONS,PROTEINS,IDENTIFICATION,MEMBRANE,DELETION,GENE},
  language     = {eng},
  number       = {3},
  pages        = {1701--1710},
  title        = {Novel FRMD7 mutations and genomic rearrangement expand the molecular pathogenesis of X-linked idiopathic infantile nystagmus},
  url          = {http://dx.doi.org/10.1167/iovs.14-15938},
  volume       = {56},
  year         = {2015},
}

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