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A Novel Intronic Variant in FRMPD4 Disrupts Splicing: Case Report of an X‐Linked Neurodevelopmental Disorder

Year: 2025

Type: article

Abstract: FRMPD4, a gene on the X-chromosome, encodes a neuronal scaffold protein, and six variants in this gene have been associated with X-linked neurodevelopmental disorder. We identified a novel intronic hemizygous variant (NM_014728.3:c.1198-6C>A) in FRMPD4 in a 2-year-old male patient with moderate developmental delay inherited from his asymptomatic heterozygous mother. Minigene assays in different cell lines demonstrated that this variant led to the consistent skipping of in-frame exon 12, which encodes 30 amino acids within the FERM domain. We speculated that this splicing defect may be due to the impaired recruitment of essential splicing factor U2AF2, as this C>A intronic variant is positioned at the center of the uridine-rich polypyrimidine tract, adjacent to the 3'-splice site. Structural modeling predicted that the loss of this region would disrupt the integrity of the FERM domain. Given that FRMPD4 mediates metabotropic glutamate receptor signaling via its FERM domain, we conclude that this intronic variant is likely pathogenic.

Source: American Journal of Medical Genetics Part A

DOI: 10.1002/ajmg.a.64306

Authors: Tomoko Satake, Yasuhiro Kawai, Koki Nagai, Takuya Naruto, Yukiko Kuroda

Institution: Kanagawa Children's Medical Center

Language: English

Topic: Genetics and Neurodevelopmental Disorders

Subfield: Genetics

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: bronze

Funders: Japan Agency for Medical Research and Development, Ministry of Health, Labour and Welfare, Japan Society for the Promotion of Science