PP05.6 – 2896: Genotype-phenotype correlations and counseling in carriers of Filamin A gene mutations

Abstract

Objective Mutations in the X-linked gene Filamin A (FLNA) are known to be linked to a broad clinical phenotype ranging from otopalatodigital syndromes (OPD1, OPD2) to frontometaphyseal dysplasia, Melnick-Needles syndrome and periventricular nodular heterotopia (PVNH). In the present study we investigate the phenotype-genotype correlation in carriers of FLNA mutations in order to improve the counseling of these patients and their relatives. Methods Clinical and neuroloradiological data from 16 FLNA mutation carriers were collected through retrospective analysis of their hospital files and a standardized questionnaire sent to the referring physician. These data were reviewed by a neurologist, molecular geneticists and a clinical geneticist. Results Fifteen of the carriers were female, as expected in dominant X-linked disorders. Half of the carriers belonged to a mother-child pair, with the mother being diagnosed secondary to the diagnosis in the child. Four carriers had the clinical diagnosis of OPD and their mutations were clustered in exons 3 and 4, whereas the mutations associated with PVNH were scattered throughout the gene. Besides the PVNH other findings on brain MRI included mega cisterna magna, corpus callosum and white matter anomalies. Cardiac investigations revealed aortic valve insufficiency and dilatation of the aorta, even at young age. In the majority of the patients, the clinical work-up focused on the primary indications for FLNA mutation analysis whereby other organs were not systematically investigated. Conclusion Although a lot is already known on the manifestations caused by FLNA mutations, and phenotype-genotype correlations can be made to a certain extent, many patients could benefit from a more extensive work-up and follow-up. This will not only lead to further improvement of our knowledge and understanding of the FLNA-related disorders, but will also allow us to anticipate on certain complications.