title: RTTN Mutations Cause Primary Microcephaly and Primordial Dwarfism in Humans.
abstract: Primary microcephaly is a developmental brain anomaly that results from defective proliferation of neuroprogenitors in the germinal periventricular zone. More than a dozen genes are known to be mutated in autosomal-recessive primary microcephaly in isolation or in association with a more generalized growth deficiency (microcephalic primordial dwarfism), but the genetic heterogeneity is probably more extensive. In a research protocol involving autozygome mapping and exome sequencing, we recruited a multiplex consanguineous family who is affected by severe microcephalic primordial dwarfism and tested negative on clinical exome sequencing. Two candidate autozygous intervals were identified, and the second round of exome sequencing revealed a single intronic variant therein (c.2885+8A>G [p.Ser963(∗)] in RTTN exon 23). RT-PCR confirmed that this change creates a cryptic splice donor and thus causes retention of the intervening 7 bp of the intron and leads to premature truncation. On the basis of this finding, we reanalyzed the exome file of a second consanguineous family affected by a similar phenotype and identified another homozygous change in RTTN as the likely causal mutation. Combined linkage analysis of the two families confirmed that RTTN maps to the only significant linkage peak. Finally, through international collaboration, a Canadian multiplex family affected by microcephalic primordial dwarfism and biallelic mutation of RTTN was identified. Our results expand the phenotype of RTTN-related disorders, hitherto limited to polymicrogyria, to include microcephalic primordial dwarfism with a complex brain phenotype involving simplified gyration.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Hanan
authors.initials: H
authors.lastname: Shamseldin
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Anas M
authors.initials: AM
authors.lastname: Alazami
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Manning
authors.affiliation: Department of Pediatrics, Prince Sultan Military Medical City, Riyadh 11159, Saudi Arabia.
authors.forename: Amal
authors.initials: A
authors.lastname: Hashem
authors.affiliation: Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2R3, Canada.
authors.forename: Oana
authors.initials: O
authors.lastname: Caluseiu
authors.affiliation: Department of Pediatrics, Prince Sultan Military Medical City, Riyadh 11159, Saudi Arabia.
authors.forename: Brahim
authors.initials: B
authors.lastname: Tabarki
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Esplin
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Schelley
authors.affiliation: Department of Medical Genetics, University of Calgary, Calgary, AB T2N 1N4, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 1N4, Canada.
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.affiliation: Department of Medical Genetics, University of Calgary, Calgary, AB T2N 1N4, Canada.
authors.forename: Jillian S
authors.initials: JS
authors.lastname: Parboosingh
authors.affiliation: Department of Medical Genetics, University of Calgary, Calgary, AB T2N 1N4, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 1N4, Canada.
authors.forename: Ryan
authors.initials: R
authors.lastname: Lamont
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC H3A 0G4, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Department of Medical Genetics, University of Calgary, Calgary, AB T2N 1N4, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 1N4, Canada.
authors.forename: Francois P
authors.initials: FP
authors.lastname: Bernier
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia. Electronic address: falkuraya@kfshrc.edu.sa.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000002:abnormalities / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004392:Dwarfism / Q000235:genetics* / Q000473:pathology; D059472:Exome; D005091:Exons; D015870:Gene Expression; D006720:Homozygote; D006801:Humans; D007438:Introns; D008297:Male; D008831:Microcephaly / Q000235:genetics / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D016415:Sequence Alignment
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C576561:RTTN protein, human
keywords: ciliopathy; lissencephaly; primary cilium; primordial dwarfism; rotatin