ClinVar Genomic variation as it relates to human health

Burch et al. (1996, 1997) described a patient with Ehlers-Danlos syndrome (EDSCLL1; 606408) combined with congenital adrenal hyperplasia resulting from a 30-kb deletion in 6p21.3, which removed the functional 21-hydroxylase gene (CYP21; 613815) and produced partial duplication of the TNX gene, resulting in a nonfunctional fusion gene. The patient described by Burch et al. (1996, 1997) was referred to as the index patient by Schalkwijk et al. (2001) and was heterozygous for the 30-kb deletion. Patient 3 of a series of 5 patients with Ehlers-Danlos syndrome identified by Schalkwijk et al. (2001) was homozygous for this deletion, which explained both the presence of Ehlers-Danlos syndrome and congenital adrenal hyperplasia. Both her parents and 2 sibs were heterozygous for the deletion and were clinically normal, providing evidence of recessive inheritance in this family. Patient 2 of Schalkwijk et al. (2001) was heterozygous for the 30-kb deletion and did not have congenital adrenal hyperplasia. They were unable to identify a second TNX mutation in patient 2 and suggested that this patient, like the index patient (Burch et al., 1997), may have had a mutation in factors, not yet defined, that regulate the tenascin-X gene expression. Zweers et al. (2003) demonstrated that haploinsufficiency of TNXB resulting from heterozygosity for the 30-kb deletion results in Ehlers-Danlos syndrome. They measured serum TNX levels by ELISA in an unselected cohort of 80 patients with hypermobility-type EDS who were recruited through a Dutch organization for EDS patients. In all patients, the diagnosis was made by a medical specialist, and approximately 90% were female. In 6 of these patients (7.5%), all female, serum TNX levels were more than 2.5 SD below the mean for unaffected individuals. Clinically, patients with reduced TNX levels showed hypermobile joints, often associated with joint subluxations and chronic musculoskeletal pain. Patients with haploinsufficiency did not have skin hyperextensibility and lacked the easy bruising seen in patients with complete TNX deficiency. In addition, TNXB haploinsufficiency was autosomal dominant. Zweers et al. (2003) found that 1 of these 6 patients had the 30-kb deletion, which created a fusion gene of TNXB and XA, a partial duplicate of TNXB. The XA gene has an internal deletion that truncates its open reading frame, rendering it and the fusion gene nonfunctional (Gitelman et al., 1992). The deleted allele also lacked CYP21 (613815). (less)