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Published on: September 20, 2016
Expansion of the Spectrum of FLNA Mutations Associated with Melnick-Needles Syndrome
C Foley1, K Roberts, N Tchrakian
1Department of Neurology, St. Vincent's University Hospital, Dublin, Ireland.
Abstract:
Melnick-Needles syndrome (MNS) is a rare X-linked bone dysplasia characterised by facial dysmorphology and radiographic abnormalities [Melnick and Needles, 1966;97:39-48]. Previously, all published cases of MNS were associated with only 4 mutations [Robertson et al., 2003;33:487-491; Santos et al., 2010;152A:726-731], all localised within exon 22 of FLNA, the gene encoding the cytoskeletal protein filamin A. Here we report 3 new mutations in FLNA that are associated with MNS. One affected member of the first family with the mutation p.Y1229S presented with a stroke while this patient's daughter, previously known to be affected from a young age, developed multiple sclerosis. A second unrelated patient with a typical phenotype is shown to have the mutation c.1054G>T (p.G352W) within exon 7 of FLNA. A third individual with an atypical presentation but radiological findings very similar to those seen in classic MNS has a deletion likely to affect residues within repeat domain 14. These findings indicate that the mutational spectrum for MNS is wider than previously appreciated and has implications for genetic testing strategies employed to confirm a diagnosis of this rare disorder.
Insights
Melnick-Needles syndrome (MNS), a rare X-linked bone dysplasia, is now linked to more FLNA gene mutations beyond exon 22. This expands the known genetic causes and impacts diagnostic strategies for MNS.
Area of Science:
- Genetics
- Molecular Biology
- Rare Diseases
Background:
- Melnick-Needles syndrome (MNS) is a rare X-linked bone dysplasia.
- Previously, MNS was associated with only four mutations in the FLNA gene, all in exon 22.
Purpose of the Study:
- To identify new mutations in the FLNA gene associated with Melnick-Needles syndrome.
- To broaden the understanding of the FLNA mutational spectrum in MNS.
- To assess the implications for genetic testing strategies.
Main Methods:
- Genetic sequencing to identify mutations in the FLNA gene.
- Analysis of patient phenotypes and radiographic findings.
- Comparison of new mutations with previously reported cases.
Main Results:
- Three novel FLNA mutations associated with MNS were identified.
- One mutation (p.Y1229S) was found in a family with stroke and multiple sclerosis.
- Another mutation (p.G352W) was identified in a patient with a typical MNS phenotype.
- A deletion affecting repeat domain 14 was found in an individual with an atypical MNS presentation.
Conclusions:
- The mutational spectrum of FLNA in MNS is broader than previously recognized.
- New mutations expand the genetic basis of MNS.
- Findings necessitate updated genetic testing strategies for MNS diagnosis.
