Submission Details

B4GALT7 was first reported in relation to autosomal recessive Ehlers-Danlos Syndrome, Spondylodysplastic Type in 1999 (Almeida et al., PMID: 10473568; and Okajima et al., PMID: 10506123). Prenatal features of this condition may include increased nuchal translucency, edema, cystic hygroma, absent digits on hands, and pulmonary hypoplasia. Features have manifested as early as 10 weeks gestation (PMIDs: 26940150, 27320698, 31278392). Additionally, B4GALT7 is associated with perinatal lethality, including spontaneous abortion, in some cases, as well as low birth weight and preterm birth. 12 variants (missense, nonsense, frameshift) that have been reported in at least 14 probands in 9 publications (PMIDs: 10506123, 23956117, 26940150, 27320698, 28882145, 30914273, 31278392, 31614862, 34193099) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (zebrafish and horse models; PMIDs: 27793082, 31862401). In the horse model, the mutants exhibited short stature, pectus excavatum, and hypermobility. In the zebrafish model, the mutants showed reduced body and head length, as well as craniofacial and morphological anomalies. Both of these phenotypes overlap with the human phenotype. In summary, there is definitive evidence supporting the relationship between B4GALT7 and autosomal recessive Ehlers-Danlos Syndrome, Spondylodysplastic Type. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date 8/5/2024 (SOP Version 10).