Heterozygous Zinc Finger 469 Gene Changes Contribute to Ehlers-Danlos Syndrome, Hypermobile Type

The ZNF469 transcription factor and collagen-homologous matrix contributor, first related to recessively inherited brittle cornea syndrome, was found variant in 8 patients with Ehlers-Danlos syndrome and an additional 14 from the literature with related connective tissue findings. Systematic documentation of skin, skeletal, cardiovascular, and neuro-autonomic findings in the 8 patients supported the diagnosis of Ehlers-Danlos hypermobile type, component diagnoses of aneurysms-dissections or blue sclerae-skeletal change predominating in 9 patients having cardiovascular screening or 5 carriers among many in brittle cornea syndrome families. Locations of these 22 patient variants along with 60 related to EDS and 68 to brittle cornea syndrome from the ClinVar database were spread throughout the 3953 amino acid ZNF469 coding sequence. Heterozygous variants except for 3 in a zinc finger region were associated with diagnoses of Ehlers-Danlos syndrome or its component findings, all documented or inferred biallelic ZNF469 variations except for one associated with brittle cornea syndrome. Limitations of this study point to the need for matching of systematically evaluated patients with the multiple DNA variants inherent in complex disease, network action exemplified by the fibrillar participation and regulatory feedback of ZNF469.