Kyphoscoliotic Ehlers‐Danlos syndrome caused by pathogenic variants in FKBP14: Further insights into the phenotypic spectrum and pathogenic mechanisms.

The Ehlers‐Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue diseases. The autosomal recessive kyphoscoliotic EDS results from deficiency of either lysyl hydroxylase 1 (encoded by PLOD1), crucial for collagen cross‐linking; or the peptidyl‐prolyl cis‐trans isomerase family FK506‐binding protein 22 kDa (FKBP22 encoded by FKBP14), a molecular chaperone of types III, IV, VI, and X collagen. This study reports the clinical manifestations of three probands with homozygous pathogenic FKBP14 variants, including the previously reported c.362dupC; p.(Glu122Argfs*7) variant, a novel missense variant (c.587A>G; p.(Asp196Gly)) and a start codon variant (c.2T>G; p.?). Consistent clinical features in the hitherto reported individuals (n = 40) are kyphoscoliosis, generalized joint hypermobility and congenital muscle hypotonia. Severe vascular complications have been observed in 12.5%. A previously unreported feature is microcornea observed in two probands reported here. Both the c.587A>G and the c.362dupC variant cause complete loss of FKBP22. With immunocytochemistry on dermal fibroblasts, we provide the first evidence for intracellular retention of types III and VI collagen in EDS‐FKBP14. Scratch wound assays were largely normal. Western blot of proteins involved in the unfolded protein response and autophagy did not reveal significant upregulation in dermal fibroblasts. [ABSTRACT FROM AUTHOR]