A comparison between the phenotype in HS (Hennekam lymphangiectasia-lymphedema syndrome 2) and VMS (Van Maldergem syndrome 2) shows a considerable overlap between the two entities. Facial resemblance is remarkable, and in both entities cognitive impairment, decreased height, microcephaly and distal limb anomalies (camptodactyly and syndactyly) are common. Most VMS patients with a FAT4 mutation have a severe intellectual disability, although milder intellectual disability does occur. In HS, the cognitive impairment is usually mild to moderate, and in some individuals cognition is even normal. A major sign in HS is the marked lymphatic vessel dysplasia which shows edema especially evident at the distal limbs but regularly is generalized. Lymphedema in HS caused by CCBE1 mutations always is present from birth on, but in HS caused by FAT4 mutations the lymphedema can also start later in life during childhood. Only in a single VMS individual pitting edema of one limb has been reported. In VMS a major sign is periventricular heterotopia. This has been reported once in a HS patient. Other manifestation characteristics for VMS such as tracheal anomalies, small kidneys, and osteoporosis are very uncommon or absent in HS. (Alders et al. 2014 and references therein, pubmed:24913602.)

Biallelic mutations in the FAT4 gene have been found in four unrelated families with VMS. However, FAT4 is also linked to the Hennekam lymphangiectasia-lymphedema syndrome (HS), first described in 1989, which shows combined symptoms of congenital lymphedema, intestinal lymphangiectasia (dilation of lymph vessels), facial anomalies and mental retardation. The whole-exome sequencing analyses have revealed a homozygous mutation in the FAT4 gene in the patients with HS. Both HS and VMS show overlapping phenotype including mental retardation and can be allelic to each other. (Adapted from Nakamura et al. 2017 and references therein, FBrf0236068.)

Planar cell polarity (PCP), the co-ordinated behaviour and polarity of cells within the plane of a tissue, is essential for the appropriate morphogenesis, and ultimately function of organs and tissues. Two clear examples of cellular polarization directed by the Daschous-Fat planar cell polarity pathway in vertebrates have been identified: Dchs1 and Fat4 regulate the orientation of cell divisions within the kidney tubule epithelium, and the collective migration of facial branchiomotor neurons within the hindbrain. (Mao et al. 2016 and references therein, pubmed:27145737.)

1 to 1: one human gene to 1 Drosophila gene.

Single, high-scoring ortholog of human FAT4.