Mutational analysis of two boys with the severe perinatally lethal Melnick-Needles syndrome
Helena H Santos1, Paula P Garcia, Latife Pereira
1Serviço Especial de Genética, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Abstract:
Melnick-Needles syndrome (MNS) (OMIM 309350) is a rare, X-linked dominant condition, caused by mutations in the filamin A gene (FLNA, on Xq28). In females, the syndrome presents with bone dysplasia and characteristic facial changes. Affected males may show two different phenotypes. One is similar to the female phenotype and is seen in children born to unaffected mothers and suggesting new mutations. Alternatively, males born to affected mothers have an embryonic or perinatally lethal disorder. It has been claimed that MNS constitutes part of a spectrum including frontometaphyseal dysplasia, otopalatodigital syndrome type 1 (OPD1) and otopalatodigital syndrome type 2 (OPD2). These conditions are produced by different mutations in the filamin A gene (FLNA). MNS is caused by three different mutations in FLNA exon 22, to date detected only in females. We describe the clinical manifestations and present the results of FLNA exon 22 mutations screening in two boys with the perinatally lethal form of MNS and their affected mothers. In order to obtain DNA amplification from paraffin-embedded tissues, we designed a new method based on hemi-nested PCR. One of the children (and his mother) had a previously undescribed mutation produced by a double SNP in the positions 3776 and 3777 of the gene and leading to an amino acid substitution (NP_001447:p.[Gly1176Asp]). The second child (and his mother) had an already known mutation (NP_001447.2:p[.Ser1199Leu]). This is the first report confirming the presence FLNA mutations in boys with the perinatally lethal phenotype of MNS. (
Insights
Melnick-Needles syndrome (MNS) is a rare X-linked disorder. This study confirms filamin A gene (FLNA) mutations in boys with the lethal form of MNS, identifying a new mutation.
Area of Science:
- Genetics
- Molecular Biology
- Medical Genetics
Background:
- Melnick-Needles syndrome (MNS) is a rare X-linked dominant disorder.
- It is caused by mutations in the filamin A gene (FLNA).
- MNS is part of a spectrum of related disorders including frontometaphyseal dysplasia and otopalatodigital syndromes.
Observation:
- MNS typically presents with bone dysplasia and facial changes in females.
- Affected males can have a similar phenotype or a perinatally lethal disorder.
- FLNA mutations in exon 22 have been identified in females with MNS.
Findings:
- This study reports FLNA exon 22 mutation screening in two boys with the perinatally lethal form of MNS and their mothers.
- A novel FLNA mutation (p.[Gly1176Asp]) was identified in one boy and his mother.
- A previously known FLNA mutation (p[.Ser1199Leu]) was found in the second boy and his mother.
- This is the first report confirming FLNA mutations in males with the perinatally lethal MNS phenotype.
Implications:
- These findings expand the understanding of FLNA mutations and their role in MNS.
- Confirms FLNA mutations as the cause of the perinatally lethal male phenotype of MNS.
- Highlights the importance of genetic testing for FLNA mutations in affected families.
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