Familial periventricular nodular heterotopia, epilepsy and Melnick-Needles Syndrome caused by a single FLNA mutation with combined gain-of-function and loss-of-function effects

Loss-of-function mutations of the FLNA gene cause X-linked periventricular nodular heterotopia (PNH) while gain-of-function mutations cause the Otopalatodigital (OPD) spectrum. These two conditions are known to be mutually exclusive phenotypes. We describe a family in which a woman and her three daughters exhibited a phenotype combining PNH, epilepsy and Melnick-Needles syndrome, a skeletal disorder assigned to the OPD spectrum. All affected individuals harbored a novel non-conservative missense mutation in FLNA leading to two aberrant transcripts, one of which carries the missense mutation, plus a longer transcript resulting from intron 3 retention. Co-occurring gain-of and loss-of-function appears to cause the dual phenotype. (By Elena Parrini, http://jmg.bmj.com/content/early/2015/03/09/jmedgenet-2014-102959 )