Resequencing of candidate genes for Keratoconus reveals a role for Ehlers-Danlos Syndrome genes

The involvement of genetic factors in the pathogenesis of KC has long been recognized but the identification of variants affecting the underlying protein functions has been challenging. In this study, we selected 34 candidate genes for KC based on previous whole-exome sequencing (WES) and the literature, and resequenced them in 745 KC patients and 810 ethnically matched controls from Belgium, France and Italy. Data analysis was performed using the single variant association test as well as gene-based mutation burden and variance components tests. In our study, we detected enrichment of genetic variation across multiple gene-based tests for the genes COL2A1, COL5A1, TNXB, and ZNF469. The top hit in the single variant association test was obtained for a common variant in the COL12A1 gene. These associations were consistently found across independent subpopulations. Interestingly, COL5A1, TNXB, ZNF469 and COL12A1 are all known Ehlers-Danlos Syndrome (EDS) genes. Though the co-occurrence of KC and EDS has been reported previously, this study is the first to demonstrate a consistent role of genetic variants in EDS genes in the etiology of KC. In conclusion, our data show a shared genetic etiology between KC and EDS, and clearly confirm the currently disputed role of ZNF469 in disease susceptibility for KC

Noot bij: HR 25 juni 2010, NTFR, 2010, 1500 (Renteafspraak door erfgenamen bij OBV was geen schenking (II))

Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseaseNeuro Imaging Researc

Rare genetic variations in MEPE are associated with otosclerosis and craniofacial bone disorder with facial paresis and mixed hearing loss

Craniofacial bone disorders comprise a group of diseases caused by abnormal growth and/or development of the head and facial bones, and can be associated with hearing loss due to abnormalities of the outer, middle or inner ear. In this study, we identified a heterozygous frameshift variant c.1273delC (p.Gln425Lysfs*38) in the MEPE gene in a family with non-progressive Hereditary Congenital Facial Paresis (HCFP) and mixed conductive-sensorineural hearing loss associated with diploic thickening and sclerosis of the skull. MEPE encodes a matrix extracellular phosphoglycoprotein and plays an inhibitory role in bone mineralization. Next, we hypothesized that this gene might also be important in otosclerosis bone remodeling disorder and screened for mutations in MEPE in 91 individuals with familial otosclerosis. We identified an additional heterozygous frameshift variant, c.199_202delGAAA (p.Lys70Ilefs*26), that segregated with the phenotype in two apparently unrelated families with otosclerosis, albeit with some reduced penetrance which is typically observed in otosclerosis families. Furthermore, we screened 1398 unrelated cases with otosclerosis and 1447 ethnically-matched controls. We observed the rare c.209_212del frameshift variant in eight affected individuals with otosclerosis only. None of the controls carried this variant (Fisher\u2019s Exact p = 0.003). Two other rare variants (c.184G>T: p.Glu62* and c.229G>A: p.Ala77Thr) were identified in cases and not in controls (cumulative Fisher\u2019s Exact p = 0.0008). Our results pinpoint MEPE as a key player in temporal bone and middle ear mineralization, which is involved in the pathogenesis of otosclerosis and other craniofacial bone disorders associated with mixed hearing loss