Novel FRMD7 Mutations and Genomic Rearrangement Expand the Molecular Pathogenesis of X-Linked Idiopathic Infantile Nystagmus.
Invest Ophthalmol Vis Sci
; 56(3): 1701-10, 2015 Feb 12.
Article
in En
| MEDLINE
| ID: mdl-25678693
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.Key words
Full text:
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
DNA Mutational Analysis
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Gene Rearrangement
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Nystagmus, Congenital
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Cytoskeletal Proteins
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Membrane Proteins
Type of study:
Diagnostic_studies
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Etiology_studies
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Incidence_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limits:
Adolescent
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Adult
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Aged80
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Child
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Child, preschool
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Female
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Humans
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Infant
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Male
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Middle aged
Country/Region as subject:
Europa
Language:
En
Journal:
Invest Ophthalmol Vis Sci
Year:
2015
Document type:
Article
Affiliation country:
Arabia Saudita