Otopalatodigital Spectrum Disorders, Periventricular Nodular Heterotopia and Cardiac Valvular Dystrophy via the FLNA Gene

Mutations in FLNA cause X-linked myxomatous cardiac valvular dystrophy, periventricular nodular heterotopia and otopalatodigital spectrum disorders. Otopalatodigital spectrum disorders are primarily characterized by skeletal dysplasia and include otopalatodigital syndrome type I (OPD1) and type II (OPD2), frontometaphyseal dysplasia (FMD), Melnick-Needles syndrome (MNS), and terminal osseous dysplasia with pigmentary skin defects (TOPD). OPD1 usually manifests at birth with females presenting with similar severity as related affected males. Symptoms include skeletal dysplasia, deafness, cleft palate, characteristic facial features, and oligohypodontia. In OPD2, males are severely affected and typically die within the first year of birth from pulmonary insufficiency while females typically have a subclinical phenotype. OPD2 features include skeletal dysplasia, cardiac septal defects, CNS abnormalities, and developmental delay. Males with MNS have a phenotype that is indistinguishable from OPD2. In FMD, females are less severely affected than related affected males. Females present with characteristic facial features found in FMD males. FMD males have skeletal dysplasia, oligohypodontia, deafness, and underdeveloped muscles around the shoulder girdle. Males with TOPD have not been described. Females have shortening and ossification of the carpals and metacarpals and characteristic facial findings. Periventricular nodular heterotopia is characterized by the presence of nodules on the surface of the lateral ventricles due to a failure in neuronal migration into the cerebral cortex. Affected females present with seizures in their teenage years. Females may also present with cardiovascular defects, such as patent ductus arteriosus, bicuspid aortic valve and dilation of the aorta. Males with periventricular nodular heterotopia show early lethality (Fox et al. Neuron 21(6):1315-1325, 1998). Myxomatous cardiac valvular dystrophy is characterized by mitral valve and/or aortic valve regurgitation. Only males are affected and carrier females are asymptomatic (Kyndt et al. Circulation 115(1):40-49, 2007). For more information, visit GeneReviews (Robertson. Otopalatodigital Spectrum Disorders, 2013).

FLNA-related disorders are inherited in an X-linked manner. FLNA encodes for filamin A, which cross-links the actin cytoskeleton. Loss of function mutations in FLNA lead to defects in vascular function, connective tissues and neuronal migration. Missense mutations in FLNA cause a spectrum of mutations in multiple organ systems, especially the skeleton. Otopalatodigital spectrum disorders and periventricular nodular heterotopia are inherited in an X-linked dominant manner. Females with an FLNA causative mutation have a range of phenotypic expression. Cardiac valvular dysplasia is inherited in an x-linked recessive manner (Kyndt et al., 2007). The majority of mutations in MNS females are localized to exon 22 (Robertson et al. Nat Genet 33(4):487-491, 2003; Santos et al. Am J Med Genet A 152A:726-731, 2010). Mutations in OPD1 and OPD2 cluster in exons 3-5, but pathogenic mutations in other exons have been found (Robertson, 2013).

Robertson et al. (2003) found mutations in FLNA in 26 out of 41 patients with FLNA-related disorders (OPD1, OPD2, FMD, MNS) (Robertson et al. Nat Genet 33:487-491, 2003).

Gross deletions of the FLNA gene have been identified in patients with otopalatodigital spectrum disorders. One family with cardiac valvular dystrophy has been found to have a 1944bp deletion in FLNA (Kyndt et al. Circulation 115(1):40-49, 2007). One report found 3 out of 35 patients with periventricular heterotopia to have gross deletions in FLNA (Clapham et al. Neurology 78:269-278, 2012).

This test provides full coverage of all coding exons of the FLNA gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.