title: MKS1 mutations cause Joubert syndrome with agenesis of the corpus callosum.
abstract: Joubert syndrome (JS) is a clinically and genetically heterogeneous ciliopathy characterized by episodic hyperpnea and apnea, hypotonia, ataxia, cognitive impairment and ocular motor apraxia. The "molar tooth sign" is pathognomonic of this condition. Mutations in the MKS1 gene are a major cause of Meckel-Gruber syndrome (MKS), the most common form of syndromic neural tube defects, frequently resulting in perinatal lethality. We present the phenotype and genotype of a child with severe JS and agenesis of the corpus callosum (ACC). In our patient, a next generation sequencing (NGS) approach revealed the following two variants of the MKS1 gene: first, a novel missense variant [ c.240G > T (p.Trp80Cys)], which affects a residue that is evolutionarily highly conserved in mammals and ciliates; second, a 29 bp deletion in intron 15 [c.1408-35_1408-7del29], a founder mutation, which in a homozygous state constitutes the major cause of MKS in Finland. We review the MKS1-variants in all of the eleven JS patients reported to date and compare these patients to our case. To our knowledge, this is the first patient with Joubert syndrome and agenesis of the corpus callosum where a potentially causal genotype is provided.
authors.affiliation: Clinical Genetics Unit, Children's Hospital, Paracelsus Medical University, Salzburg, Austria; kbo-Kinderzentrum, Technische Universität München, Germany. Electronic address: i.bader@salk.at.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Bader
authors.affiliation: Bioscientia, Center for Human Genetics, Ingelheim, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Decker
authors.affiliation: Children's Hospital, Paracelsus Medical University, Salzburg, Austria.
authors.forename: J A
authors.initials: JA
authors.lastname: Mayr
authors.affiliation: Children's Hospital, Paracelsus Medical University, Salzburg, Austria.
authors.forename: V
authors.initials: V
authors.lastname: Lunzer
authors.affiliation: Children's Hospital, Paracelsus Medical University, Salzburg, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Koch
authors.affiliation: Children's University Hospital, Zürich, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Boltshauser
authors.affiliation: Children's Hospital, Paracelsus Medical University, Salzburg, Austria.
authors.forename: W
authors.initials: W
authors.lastname: Sperl
authors.affiliation: kbo-Kinderzentrum, Technische Universität München, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Pietsch
authors.affiliation: Institute for Clinical Radiology, Ludwig-Maximilians-University Munich, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Ertl-Wagner
authors.affiliation: Bioscientia, Center for Human Genetics, Ingelheim, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Bolz
authors.affiliation: Bioscientia, Center for Human Genetics, Ingelheim, Germany; Children's University Hospital, Zürich, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Bergmann
authors.affiliation: Clinical Genetics Unit, Children's Hospital, Paracelsus Medical University, Salzburg, Austria.
authors.forename: O
authors.initials: O
authors.lastname: Rittinger
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics*; D061085:Agenesis of Corpus Callosum / Q000235:genetics*; D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001921:Brain / Q000473:pathology; D002531:Cerebellum / Q000002:abnormalities*; D005124:Eye Abnormalities / Q000175:diagnosis* / Q000235:genetics*; D023061:Gene Order; D056426:Genetic Loci; D005838:Genotype; D006801:Humans; D007223:Infant; D052177:Kidney Diseases, Cystic / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D009154:Mutation; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D012160:Retina / Q000002:abnormalities*; D017422:Sequence Analysis, DNA
chemical_list: C509165:MKS1 protein, human; D011506:Proteins
keywords: Bioinformatics; Ciliopathy; Corpus-Callosum agenesis; Dysmorphology; Evolutionary conservation; Founder mutation; Genotype-phenotype correlation; Joubert syndrome; MKS1; Meckel-Gruber syndrome; Missense-mutation; Multiple sequence alignment; Syndromology