Global developmental delay (GDD) and intellectual disability (ID), which constitutes 3% of the pediatric population (1, 2), influences the physical and mental health of patients and their lives, bringing about heavy burdens for families and societies. Because the etiological diagnoses of GDD and ID overlap, the investigations leading up to a definitive diagnosis for these two diseases are naturally similar. Early detection and diagnosis are very important to the initiation of rehabilitative treatment as soon as possible. Genetic defects are responsible for the development of intellectual impairment in ~25% of patients, resulting in structural and/or functional defects of the central nervous system (3).

A previous study has described a family with a homozygous mutation in the FRMD4A gene, which resulted in a syndrome of congenital microcephaly, intellectual disability, and dysmorphism (4). In addition, FRMD4A polymorphisms have been suggested to be a genetic risk factor for Alzheimer's disease (5). We now report a novel compound heterozygous mutation in the FRMD4A gene in a child who has a GDD, ID, and corpus callosum anomaly.

We described a young boy with a syndrome of global developmental delay, intellectual disability, relative macrocephaly, and non-epileptic seizure. In fact, many studies on global developmental delay and intellectual disability are usually accompanied by macrocephaly (6–8). However, no other mutations assumed to be consistent with the autosomal recessive inheritance pattern of the family were identified by whole-exome sequencing, except a new compound heterozygous mutation of the FRMD4A gene. Remarkably, by contrast, previously described patients with the FRMD4A mutation presented microcephaly (4), not macrocephaly. This different clinical feature represents a possible novel phenotypic trait involving the FRMD4A mutation. Although the phenotype characteristic of head circumference was inconstant, we conclude that the association of epilepsy, intellectual disability/global developmental delay and ataxia is a recurrent clinical pattern in cases with FRMD4A mutations. To our knowledge, our patient is only the second case of the syndrome caused by the FRMD4A mutation in the literature (4), and the first case reported compound heterozygosity.

The FRMD4A protein, a member of the FERM superfamily, is localized in the cytoplasm and the cytoskeleton, where it binds molecules in the undercoat of the cell-to-cell adherens junction (9). The protein encoded by the FRMD4A gene is involved in cell structure, transport, and signal transduction, and it plays a role in the regulation of cell polarity in epithelial cells and neurons (10, 11). In addition, FRMD4A is expressed in many tissues, with higher levels in the brain (12, 13). More importantly, the relationship between the FRMD4A protein and the brain is not only reflected in the syndrome of microcephaly and intellectual disability caused by its mutation (4), but also in the phenotypes that are observed in carriers of its genomic copy number mutations that increase the risk of schizophrenia (14). Interestingly, other studies have reported that FRMD4A mutations are regarded as a genetic risk factor for late-onset Alzheimer's disease in that they can disrupt tau secretion by activating cytohesin–Arf6 signaling (5, 11).

In epithelial cells, FRMD4A was demonstrated to act as a scaffolding protein, regulating cell polarity by connecting the Par3–Par6–aPKCζ complex to Arf6 signaling through cytohesin-1 (10). Par polarity complex signaling plays an important role in neuronal polarization (15) but also in membrane trafficking, including vesicular secretion (16). The fact that FRMD4A binds to both Par3 and the ARF6 guanine nucleotide exchange factor (cytohesin-1) suggests that FRMD4A mediates their interaction and that the Par3–FRMD4A–cytohesin-1 complex ensures accurate activation of the ARF6 protein (17). On the other hand, in HEK293t cells, FRMD4A, a genetic risk factor for late-onset Alzheimer's disease, modulates cellular release of tau through cytohesins and Arf6 (11).

In summary, a compound heterozygote in the FRMD4A gene was identified in a 3-year-old male patient with a severe neurological phenotype of unique dysmorphism, and a novel missense mutation was suspected. The results were confirmed by Sanger sequencing. The source of mutations was investigated by two-generation pedigree analysis. The current results broaden the spectrum of FRMD4A mutations responsible for the neurological phenotype, and they have important implications for molecular diagnosis, treatment, and genetic counseling in the future.

The original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by the study was approved by the Ethics Committee of the Foshan Maternity & Child Healthcare Hospital to Southern Medical University. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

XY, XG, XZ, YL, JL, TY, and XH contributed to the acquisition and analysis of the clinical data. YP, FH, JZ, BW, and FX designed and performed the molecular analysis of the patient and patient's parents. All the authors contributed with the draft of the manuscript, and read and approved the final manuscript.

This work was supported by the National Natural Science Foundation of China (82171713, 31970558 and 81870755), Foshan Science and Technology Bureau (2020001003953), Natural Science Foundation of Guangdong Province (2020A1515010308), and Project of Foshan Genetic Disease Precision Diagnosis Engineering Technology Research Center (2020001003953).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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