Ehlers-Danlos Syndrome, Hypermobility Type, Is Linked to Chromosome 8p22-8p21.1 in an Extended Belgian Family.
Joint hypermobility is a common, mostly benign, finding in the general population. In a subset of individuals, however, it causes a range of clinical problems, mainly affecting the musculoskeletal system. Joint hypermobility often appears as a familial trait and is shared by several heritable connective tissue disorders, including the hypermobility subtype of the Ehlers-Danlos syndrome (EDS-HT) or benign joint hypermobility syndrome (BJHS). These hereditary conditions provide unique models for the study of the genetic basis of joint hypermobility. Nevertheless, these studies are largely hampered by the great variability in clinical presentation and the often vague mode of inheritance in many families. Here, we performed a genome-wide linkage scan in a unique three-generation family with an autosomal dominant EDS-HT phenotype and identified a linkage interval on chromosome 8p22-8p21.1, with a maximum two-point LOD score of 4.73. Subsequent whole exome sequencing revealed the presence of a unique missense variant in the LZTS1 gene, located within the candidate region. Subsequent analysis of 230 EDS-HT/BJHS patients resulted in the identification of three additional rare variants. This is the first reported genome-wide linkage analysis in an EDS-HT family, thereby providing an opportunity to identify a new disease gene for this condition.
Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
Delfien
D
Syx
Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
Sofie
S
Symoens
Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
Wouter
W
Steyaert
Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
Anne
A
De Paepe
Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
Paul J
PJ
Coucke
Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
Fransiska
F
Malfait
D000328:Adult; D002478:Cells, Cultured; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004535:Ehlers-Danlos Syndrome / Q000175:diagnosis / Q000235:genetics*; D059472:Exome; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D025521:Tumor Suppressor Proteins / Q000235:genetics
D004268:DNA-Binding Proteins; C118711:LZTS1 protein, human; D025521:Tumor Suppressor Proteins