title: Syndromic ciliopathies: From single gene to multi gene analysis by SNP arrays and next generation sequencing.
abstract: Joubert syndrome (JS) and related disorders (JSRD), Meckel syndrome (MKS) and Bardet-Biedl syndrome (BBS) are autosomal recessive ciliopathies with a broad clinical and genetic overlap. In our multiethnic cohort of 88 MKS, 61 JS/JSRD and 66 BBS families we performed genetic analyses and were able to determine mutation frequencies and detection rates for the most frequently mutated MKS genes. On the basis of determined mutation frequencies, a next generation gene panel for JS/JSRD and MKS was established. Furthermore 35 patients from 26 unrelated consanguineous families were investigated by SNP array-based homozygosity mapping and subsequent DNA sequencing of known candidate genes according to runs of homozygosity size in descending order. This led to the identification of the causative homozygous mutation in 62% of unrelated index cases. Based on our data we discuss various strategies for diagnostic mutation detection in the syndromic ciliopathies JS/JSRD, MKS and BBS.
authors.affiliation: Institute of Human Genetics, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany. Electronic address: cknopp@ukaachen.de.
authors.forename: C
authors.initials: C
authors.lastname: Knopp
authors.affiliation: Institute of Human Genetics, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany. Electronic address: srudnik-schoeneborn@ukaachen.de.
authors.forename: S
authors.initials: S
authors.lastname: Rudnik-Schöneborn
authors.affiliation: Institute of Human Genetics, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany. Electronic address: teggermann@ukaachen.de.
authors.forename: T
authors.initials: T
authors.lastname: Eggermann
authors.affiliation: Institute of Human Genetics, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany; Center for Human Genetics, Bioscientia, Konrad-Adenauer-Straße 17, 55218, Ingelheim, Germany. Electronic address: carsten.bergmann@bioscientia.de.
authors.forename: C
authors.initials: C
authors.lastname: Bergmann
authors.affiliation: Institute of Human Genetics, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany. Electronic address: mbegemann@ukaachen.de.
authors.forename: M
authors.initials: M
authors.lastname: Begemann
authors.affiliation: Institute of Pathology, UKGM University Hospital Marburg, Baldingerstraße, 35043, Marburg, Germany. Electronic address: schoner@med.uni-marburg.de.
authors.forename: K
authors.initials: K
authors.lastname: Schoner
authors.affiliation: Institute of Human Genetics, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany. Electronic address: kzerres@ukaachen.de.
authors.forename: K
authors.initials: K
authors.lastname: Zerres
authors.affiliation: Institute of Human Genetics, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany. Electronic address: nortiz-bruechle@ukaachen.de.
authors.forename: N
authors.initials: N
authors.lastname: Ortiz Brüchle
mesh_terms: D000015:Abnormalities, Multiple / Q000208:ethnology / Q000235:genetics*; D020788:Bardet-Biedl Syndrome / Q000208:ethnology / Q000235:genetics*; D002531:Cerebellum / Q000002:abnormalities*; D002925:Ciliary Motility Disorders / Q000208:ethnology / Q000235:genetics*; D003241:Consanguinity; D004677:Encephalocele / Q000208:ethnology / Q000235:genetics*; D005124:Eye Abnormalities / Q000208:ethnology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000208:ethnology / Q000235:genetics*; D008297:Male; D009154:Mutation; D059645:Mutation Rate; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010375:Pedigree; D007690:Polycystic Kidney Diseases / Q000208:ethnology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012160:Retina / Q000002:abnormalities*; D012174:Retinitis Pigmentosa; D017422:Sequence Analysis, DNA / Q000379:methods
keywords: Bardet-Biedl syndrome; Ciliopathy; Homozygosity mapping; Joubert syndrome and related disorders; Meckel syndrome; Mutation frequencies