Submission Details

Variants in the FLNA gene were first reported in relation to X-linked periventricular nodular heterotopia in 1998 (Fox et al., PMID: 9883725). The majority of the affected individuals are female, while the affected males are typically prenatally or neonatally lethal. Common features include periventricular nodular heterotopia and epilepsy, while additional features such as cardiovascular abnormalities, connective tissue abnormalities, intellectual disability, and developmental delay have also been reported in some patients (Reinstein et al., PMID: 23032111; Parrini et al., PMID: 16684786; Tsuneda et al., PMID: 18427995). Evidence supporting this gene-disease relationship includes case-level data. FLNA variants leading to periventricular nodular heterotopia have been reported in more than one hundred probands in the literature (PMID: 16684786, 18427995, 19917821, 23032111, 24089482, 26471271, and 29449050). Additionally, evidence supporting this gene-disease relationship includes animal models and in vitro rescue experiments (PMID: 16825286, 17172441, 22076441, and 24089482). Defects in the FLNA gene may also result in FG syndrome 2, X-linked cardiac valvular dysplasia, congenital short bowel syndrome, and neuronal intestinal pseudoobstruction, which all share overlapping phenotypes with some patients with periventricular nodular heterotopia (OMIM *300017). Of note, while loss-of-function variants in the FLNA gene lead to periventricular nodular heterotopia, gain-of-function variants cause X-linked otopalatodigital spectrum disorders (https://www.ncbi.nlm.nih.gov/books/NBK1393/). In summary, FLNA is definitively associated with X-linked periventricular nodular heterotopia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 12/27/20 (SOP Version 8).