Postzygotic mutation and germline mosaicism in the otopalatodigital syndrome spectrum disorders

The otopalatodigital syndrome (OPD) spectrum disorders are a heterogeneous group of skeletal dysplasias caused by mutations in the X-linked gene, FLNA. All OPD spectrum disorders ( otopalatodigital syndromes types 1 and 2, frontometaphyseal dysplasia and Melnick-Needles syndrome) exhibit significant interfamilial variability in their expressivity, especially in female subjects. Factors contributing to this may include allelic heterogeneity, variation in the degree of skewing of X inactivation or, conceivably, mosaicism for the underlying causative mutation. We report here monozygotic twin sisters who are discordant for the severe phenotype, Melnick-Needles syndrome, associated with the heterozygous mutation, 3596C > T. We also describe two brothers with otopalatodigital syndrome type 1 due to the FLNA mutation 620G > A. The mutation is not detectable in the blood leucocytes of their clinically unaffected mother, indicating that she is a germline mosaic for the condition. The description of somatic mutations and germline mosaicism in FLNA has implications for clinical and molecular diagnosis, phenotypic expression and genetic counseling of families with these disorders.