Diverse Phenotypic Consequences of the Differential Splicing of FLNA Intronic Variants

Hemizygosity for a pathogenic loss‐of‐function FLNA ( Filamin A ) variant typically leads to male lethality in utero or early childhood. A small number of surviving males with loss of function variants have been reported, but these show either mosaicism for a variant at the genomic DNA level or are hypomorphic alleles. We present a surviving male proband with periventricular nodular heterotopia (PVNH) who is hemizygous at the genomic DNA level for a FLNA splice variant. In addition, we present a second surviving male proband who is also hemizygous at the genomic DNA level for a different FLNA splice variant, but whose RNA transcripts show opposite functional and hence phenotypic outcomes. RNA studies have shown that both patients have a complex pattern with multiple transcripts. In the patient with PVNH, the splice variant results in two abnormal transcripts: one frameshift variant arising from intron retention, and a three amino acid insertion assumed to provide enough functional compensation to be compatible with life. In the patient with frontometaphyseal dysplasia (FMD), leaky splicing results in a mixture of wild‐type transcripts (~70%), transcripts with a loss‐of‐function out‐of‐frame insertion due to an intronic cryptic acceptor site (~25%), and ~5% of transcripts with an in‐frame deletion due to the use of an exonic cryptic acceptor site, leading to a mixture of loss‐of‐function, gain‐of‐function, and wild‐type transcripts at the cellular level. In this latter patient, it is proposed that it is the small proportion of gain‐of‐function transcripts that solely impacted on the patient phenotype. This is the first reported case of male survivorship in a PVNH proband where differential splicing of an intronic variant produces two abnormal RNA transcripts but no wild‐type RNA transcripts. In the proband with FMD, RNA results showed both gain‐ and loss‐of‐function transcripts, with the least abundant transcript contributing solely to the phenotype. These cases highlight both the importance of the detection of FLNA intronic variants and the necessity of RNA studies to further increase our understanding of the complexity of FLNA genotype/phenotype correlations.