Aidan Thomas

Publications (3)48.53 Total impact

• Article: Mutations in origin recognition complex gene ORC4 cause Meier-Gorlin syndrome.

  Duane L Guernsey, Makoto Matsuoka, Haiyan Jiang, Susan Evans, Christine Macgillivray, Mathew Nightingale, Scott Perry, Meghan Ferguson, Marissa LeBlanc, Jean Paquette, [......], Andrew Orr, Chris R McMaster, Jacques L Michaud, Cheri Deal, Sylvie Langlois, Duane W Superneau, Sandhya Parkash, Mark Ludman, David L Skidmore, Mark E Samuels
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  ABSTRACT: Meier-Gorlin syndrome is a rare autosomal recessive genetic condition whose primary clinical hallmarks include small stature, small external ears and small or absent patellae. Using marker-assisted mapping in multiple families from a founder population and traditional coding exon sequencing of positional candidate genes, we identified three different mutations in the gene encoding ORC4, a component of the eukaryotic origin recognition complex, in five individuals with Meier-Gorlin syndrome. In two such individuals that were negative for mutations in ORC4, we found potential mutations in ORC1 and CDT1, two other genes involved in origin recognition. ORC4 is well conserved in eukaryotes, and the yeast equivalent of the human ORC4 missense mutation was shown to be pathogenic in functional assays of cell growth. This is the first report, to our knowledge, of a germline mutation in any gene of the origin recognition complex in a vertebrate organism.
  Nature Genetics 02/2011; 43(4):360-4. · 35.53 Impact Factor
• Article: Mutations in centrosomal protein CEP152 in primary microcephaly families linked to MCPH4.

  Duane L Guernsey, Haiyan Jiang, Julie Hussin, Marc Arnold, Khalil Bouyakdan, Scott Perry, Tina Babineau-Sturk, Jill Beis, Nadine Dumas, Susan C Evans, [......], Lysanne Patry, Andrea L Rideout, Aidan Thomas, Andrew Orr, Ingrid Hoffmann, Jacques L Michaud, Philip Awadalla, David C Meek, Mark Ludman, Mark E Samuels
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  ABSTRACT: Primary microcephaly is a rare condition in which brain size is substantially diminished without other syndromic abnormalities. Seven autosomal loci have been genetically mapped, and the underlying causal genes have been identified for MCPH1, MCPH3, MCPH5, MCPH6, and MCPH7 but not for MCPH2 or MCPH4. The known genes play roles in mitosis and cell division. We ascertained three families from an Eastern Canadian subpopulation, each with one microcephalic child. Homozygosity analysis in two families using genome-wide dense SNP genotyping supported linkage to the published MCPH4 locus on chromosome 15q21.1. Sequencing of coding exons of candidate genes in the interval identified a nonconservative amino acid change in a highly conserved residue of the centrosomal protein CEP152. The affected children in these two families were both homozygous for this missense variant. The third affected child was compound heterozygous for the missense mutation plus a second, premature-termination mutation truncating a third of the protein and preventing its localization to centrosomes in transfected cells. CEP152 is the putative mammalian ortholog of Drosphila asterless, mutations in which affect mitosis in the fly. Published data from zebrafish are also consistent with a role of CEP152 in centrosome function. By RT-PCR, CEP152 is expressed in the embryonic mouse brain, similar to other MCPH genes. Like some other MCPH genes, CEP152 shows signatures of positive selection in the human lineage. CEP152 is a strong candidate for the causal gene underlying MCPH4 and may be an important gene in the evolution of human brain size.
  The American Journal of Human Genetics 07/2010; 87(1):40-51. · 10.60 Impact Factor
• Article: Sotos syndrome: antenatal presentation.

  Aidan Thomas, Edmond G Lemire
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  ABSTRACT: There is little published information regarding the clinical presentation of Sotos syndrome in pregnancy. In this report, we describe the antenatal presentation of a child subsequently diagnosed with Sotos syndrome by molecular analysis. The pregnancy was complicated by a positive maternal serum screen and abnormal ultrasound findings including macrocephaly, polyhydramnios and decreased fetal movements. This is the first report of an elevated Down syndrome risk in a pregnancy with confirmed Sotos syndrome. Sotos syndrome should be included in the differential diagnosis of newborns with a normal karyotype where the pregnancy has demonstrated an increased risk for Down syndrome by maternal serum screening, especially in the presence of supportive ultrasound findings.
  American Journal of Medical Genetics Part A 06/2008; 146A(10):1312-3. · 2.39 Impact Factor