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

Basamat Almoallem Mohammed UGent, Miriam Bauwens UGent, SOPHIE WALRAEDT UGent, Patricia Delbeke, Julie De Zaeytijd, Philippe Kestelyn, Françoise Meire, Sandra Janssens, Caroline Van Cauwenbergh UGent, Hannah Verdin UGent, et al. (2015) INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE. 56(3). p.1701-1710
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
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
journal title
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
Invest. Ophthalmol. Vis. Sci.
volume
56
issue
3
pages
1701 - 1710
Web of Science type
Article
Web of Science id
000352137600041
JCR category
OPHTHALMOLOGY
JCR impact factor
3.427 (2015)
JCR rank
6/56 (2015)
JCR quartile
1 (2015)
ISSN
0146-0404
DOI
10.1167/iovs.14-15938
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
5909590
handle
http://hdl.handle.net/1854/LU-5909590
date created
2015-03-23 16:30:40
date last changed
2018-05-23 08:30:32
@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},
}

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.