Periventricular nodular heterotopias is associated with mutation at the FLNA locus-a case history and a literature review

FLNA is located in the q28 region of the X chromosome [1, 2]. It encodes a widely expressed filamentous protein that acts on intracellular actin binding, and is involved in cell migration, mechano sensing, and cell signaling [3]. FLNA variants trigger X-linked filopathies which affect all organs, including the brain, bones, heart, and skin [4]. Periventricular nodular heterotopia (PNH) is strongly associated with FLNA mutations, which causes a loss of protein function, meaning developing neuronsfail to differentiate or migrate to the cortex in a timely manner [5]. This causes bilateral gray matter ectopia at the lateral ventricular rim, combined with a large occipital cisterna and hypoplasia of the cerebellum and corpus callosum [1, 6]. As FLNA is located on the X chromosome and is prevalent in females, males with PNH may die from severe complications prenatally or at an early age [6]. It is worth noting that the relevance of approximately 1/3 of all FLNA mutations is unknown, and that the clinical heterogeneity of FLNA mutations is extremely high [7, 8]. Therefore, no genotype-phenotype correlations have been identified [8], which is reflected by a paucity of literature on the subject.

We identified PNH in a 26-month-old girl admitted to our hospital for febrile seizures. The patient’s father had febrile seizures when he was a child, and the patient’s aunt had severe epilepsy and died in infancy, so we did MRI and genetic tests for this patient. Genetic tests identified FLNA mutations in exon 31, however, no mutational information in this sub-region was available from the literature. Currently, the girl is not experiencing any epilepsy and no developmental delays. We believe this case report and our literature review could provide individualized treatment plans and better prognoses for patients with FLNA-associated PNH disease.

The female patient was 26 months old. She was admitted to the Department of Pediatrics of the Affiliated Hospital of Hangzhou Normal University in November 2022 with a “2 hour fever and one seizure episode”. The child had one febrile seizure when she was 12 months old, and her aunt (mother’s sister) died of a severe neurological developmental abnormality at a young age. The father had one febrile seizure as a young child. Previously, the girl raised head at 3 months, sat at 8 months, talked at 12 months, walked at 13 months, and currently understood simple vocabulary with no obvious signs of developmental delay. Neurological physical examinations were negative. Post-admission ancillary examinations using photo-stimulated electroencephalogram and 24 h video EEG showed no abnormalities, and no epileptiform discharges were captured. Cardiac ultrasound morphology, structure, and hemodynamics did not show any significant abnormalities. A cranial magnetic resonance imaging (MRI) examination suggested gray matter heterotopia, corpus callosum dysplasia, and an arachnoid cyst in the occipital greater cisterna (Fig. 1).

The study was approved by the Medical Ethics Committee of Hangzhou Normal University Hospital (approval number 2021-(E2)-hs-059) in accordance with the ethical guidelines of the Declaration of Helsinki. Written informed consent was obtained from the patient’s guardian. We performed trio whole exon sequencing using targeted region capture high-throughput sequencing, and observed two variants in the patient’s FLNA gene. After QC was used to assess the sequencing quality of raw sequencing data and remove low-quality and joint-contaminated reads. The filtered data were sequenced with the human HG19 reference genome using BWA software (Burrows Wheeler Aligner) and the capture effect was assessed. GATK software was used to analyze single nucletide Variant (SNV) and Inde (INSERTION and deletion). 1000 Genomes (1000 Human Genome Dataset), Genome Aggregation Database dataset 2.1.1 and ExAC (The Exome) were used Aggregation Consortium dataset (Aggregation Consortium DATASET) screened the SNV and Indel obtained by analysis. The pathogenicity of false sense mutation and shear mutation was predicted using dbNSFP database. Reported mutations were screened using the Human Mendelian Genetic Database (OMIM), human Gene Mutation Database (HGMD) and Clinvar database. All mutation sites were classified using ACMG genetic variation classification criteria and guidelines. Finally, all possible pathogenic sites were verified by Sanger sequencing. One was in exon31,c.5159dupA:p.Tyr1720* (nucleotide duplication in coding region 5159, resulting in termination at tyrosine 1720) and was considered a heterozygous nonsense mutation. The other occurred at exon36, c.5764G > A:p.Val1922Met (mutation in nucleotide 5764 in the coding region (guanine to adenine), resulting in the mutation of valine (1922) to methionine), and was considered a heterozygous missense mutation (presently not significant). Genetic verification of the patient’s family history revealed a heterozygous mutation in c.5764G > A in the patient’s mother, and a hemizygous mutation in c.5764G > A in the patient’s (maternal) grandfather. Both the mother and (maternal) grandfather underwent cranial MRI, but no PNH was identified; both had no history of epilepsy and were currently healthy. When we processed this information, we hypothesized the child’s PNH was associated with the nonsense mutation in exon 31 of FLNA (c.5159dupA). FLNA mutations in the patient, the patient’s mother, and the patient’s (maternal) grandfather are shown (Figs. 2 and 3), and the family tree is shown (Fig. 4).

Therefore, the patient had a heterozygous missense mutation in the coding region of FLNA at nucleotide 5764 (guanine to adenine), resulting in valine (1922) mutation to methionine. Her mother was heterozygous while her (maternal) grandfather was hemizygous for the mutation.

We searched PubMed for English-language studies published before February 20th, 2022, using “periventricular nodular heterotopias” AND “FLNA” OR “Grey matter heterotopias” AND “FLNA” terms. We sought studies on PNH associated with FLNA mutations, which provided mutation information, such as mutation type in exonic regions, descriptions of clinical symptoms, and images indicating cranial MRI alterations. We retrieved 19 publications covering diverse FLNA mutations in PNH patients (Fig. 5). Information on FLNA mutations, number of cases, patient gender, MRI imaging descriptions, clinical features, and levels of cognitive development were also gathered (Table 1).