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Study Description

The overall goal of this project is to investigate the etiology and pathogenesis of malformations (i.e., birth defects) of the limb, concentrating on abnormalities of limb patterning such as limb deficiency/duplications and multiple congenital contractures.

The exome sequences of two siblings and two unrelated individuals were obtained by massively parallel DNA sequencing. The four individuals were affected with Miller syndrome (OMIM: 263750).

Additionally, the whole-genome sequences of a family of four were obtained with the method of Complete Genomics Incorporated (CGI). The two offspring were both affected with Miller syndrome and is the same sibling pair mentioned previously from whom exome sequences were also obtained.

Authorized Access
Publicly Available Data (Public ftp)
Study Inclusion/Exclusion Criteria

Inclusion criteria: Exome sequencing: Two affected siblings and two affected unrelated individuals with Miller syndrome.

Whole genome sequencing: Family (mother and father) with two offspring affected with Miller syndrome.

Exclusion criteria: None.

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Whole Genome Sequencing Complete Genomics Assembler Version 1.2.0; File Format Version: July 2009 N/A N/A
Whole Genome Sequencing Illumina Genome Analyzer N/A N/A 76 bp single end reads, pipeline 1.0 or 1.3
Exome Sequencing Agilent Custom aCGH Array 244000 N/A ~244000 probes
Exome Capture Sequence Analysis Open Source Maq (0.7.1) N/A N/A
Exome Capture Sequence Analysis Open Source Cross_match (1.080812) N/A N/A
Study History

Miller syndrome is a very rare disease with a single-gene recessive mode of inheritance. A hypothesis was made that this gene would be identifiable as a gene common to all four individuals with Miller syndrome, wherein each individual had at least two novel, protein-changing variants in the gene after filtering against public SNP databases and HapMap exomes.

For analysis of whole genome data, a hypothesis was made that this gene would be identifiable as a gene shared by two siblings in a family with Miller syndrome. The gene should be in an IBD block. The defect in the gene should be detrimental. The variation responsible for the defect should be exceptionally rare. The two affected offspring in this family also have primary ciliary dyskinesia. Candidate genes identified in this study, consistent with a rare recessive inheritance mode, and shared by the two offspring include DHODH, DNAH5, KIAA0556, and CES1. DHODH was subsequently confirmed in additional affected individuals as being primarily responsible for Miller syndrome (PMID: 19915526). DNAH5 is responsible for primary ciliary dyskinesia (OMIM: 603335). The roles, if any, of KIAA0556 and CES1 in modulating phenotypes in this pedigree are currently unknown.

Selected Publications
Diseases/Traits Related to Study (MeSH terms)
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Study Attribution
  • Principal Investigators
    • Michael Bamshad, MD. Seattle Children's, Seattle, WA, USA.
    • Leroy Hood, MD, PhD. Institute for Systems Biology, Seattle, WA, USA.
    • David Galas, PhD. Institute for Systems Biology, Seattle, WA, USA.
  • Funding Sources
    • Institute for Systems Biology Program. University of Luxembourg, Luxembourg.
    • 5R01HL094976. National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
    • 5R21HG004749. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
    • 1RC2HG005608. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
    • 1R01HD048895. National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.