AbstractBackgroundFilamin A, encoded by the X‐linked geneFLNA, links the cell membrane with the cytoskeleton and acts as a regulator of the actin cytoskeleton. Mutations inFLNAcause a large spectrum of congenital malformations during embryonic development, including Melnick–Needles syndrome (MNS). However, reports of MNS, especially in males, are rare, and the pathogenesis molecular mechanisms are not well understood.MethodsWe found a family with two consecutive miscarriages of similar fetuses with multiple malformations. DNA was extracted from peripheral blood and tissues, and whole exome sequencing was performed for genetic analysis. Then, we created a C57BL/6 mouse with a point mutation by CRISPR/Cas‐mediated genome engineering. The migration of primary abdominal muscle cell was detected by wound healing assay.ResultsThe first fetus showed congenital hygroma colli and omphalocele identified by ultrasound at 12 wks; the second fetus showed hygroma colli and thoraco abdominoschisis at 12 wks, with a new hemizygous mutation c.4420G>A in exon 26 of theFLNAgene, which is predicted to cause an amino acid substitution (p.Asp1474Asn). The mother and grandmother were both present in the c.4420G>A heterozygous state, and the mother's healthy brother had wild‐typeFLNA. TheseFLNA‐mutated mice exhibited a broader central gap between the rectus abdominis than the wild type (WT), similar to the midline structure dysplasia of the abdominal wall in the two fetuses. Wound healing assays showed the attenuated migration capacity of abdominal muscle cells in mice with mutatedFLNA. Finally, we summarized the cases of MNS withFLNAmutation from the accessible published literature thus far.ConclusionOur research revealed a mutation site of theFLNAfor MNS and explored the mechanism of midline structure dysplasia in the abdominal wall of male patients, which could provide more evidence for the clinical diagnosis and genetic counseling of families with these disorders.