Supplementary Material S2
Supplementary Material S3 details the syntenies of detected mouse CNVs in the human
genome, phenotype correlates in the human and the associated literature.
S3.1. Detailed description and visualization of syntenies and phenotype correlates
Legend to Figures.
Abbreviations: AMP, amplification; CC, corpus callosum; DEL, deletion; DN, de novo;
DUP, duplication; INV, inversion; SLEP, Sullivan Lab Evidence Project.
Colour code of the Database of Genomic Variants: Blue, loss; red, gain; brown, loss and
gain; purple, inversion.
Copy Number Variant 2.
CNV2 spanned exon 3 and 4 in the mouse and the syntenic human Auts2 gene (see Figure
2, main text). This locus has been associated with autism1, schizophrenia2, bipolar
disorder3, and attention deficit hyperacivity disorder4 in genome-wide linkage analyses.
While several small CNVs have been observed in the general population5-10, separate
aberrations within this gene and overlapping with CNV2 have been reported in cases with
neurodevelopmental diseases11-14 (Figure 2). Balanced translocations disrupting Auts2 have
been observed in additional cases with autism spectrum disorder and mental retardation15.
Additionally, larger aberrations encompassing Auts2 have been reported in cases with
mental retardation14, 16-18, Zellweger Syndrome19 and social cognitive delay20.
Syntenies of the remaining copy number variants are detailed below.
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Supplementary Material S2
CNV1 spanned twenty characterized genes on mouse chromosome 4 and their orthologs in
the syntenic region of this CNV in the human on chromosome 9. Within this region
amplifications and deletions have been observed. A gene encompassed by CNV1 (Sigmar1)
has been associated with alcoholism21, schizophrenia 22, dementia 23. Additional loci with
this region have been associated with galactosemia 24, Paget disease 25 and Fanconi Anemia
26, 27
.
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Supplementary Material S2
Syntenic regions to CNV3 and CNV4 were scattered over several chromosomes in the
human. However, Nlrp4, a gene encompassed by CNV3, mapped to human chromosome
19 and overlapped a large aberration in an individual with cerebral atrophy14. 14% of
CNV4 or three (Anxa11, Plac9 and D14Ertd449e) of the five genes affected by this CNV,
respectively, mapped to human chromosome 10. One patient with schizophrenia28 and two
with autism spectrum disorder14 carried aberrations <600kb in size, that also contained
these genes. Again larger structural aberration encompassing this region were reported in
cases with mental retardation14 and / or brain morphological abnormalities29.
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Supplementary Material S2
CNV5 mapped to a locus in human chromosome 8 that has been associated with
schizophrenia in a meta-analysis of genome wide linkage studies30. An aberration
containing this region was present in a patient with mental retardation14. Moreover, this
region lies in the core of the ‘8p duplication inversion deletion syndrome’ region31-35. This
syndrome is characterized by mental retardation and agenesis of the corpus callosum34, 36.
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Supplementary Material S2
CNV6 and 7 affected the Mid1 gene on chromosome X. In the mouse a pseudoautosomal
boundary is situated between exon 3 and 5 of Mid137. The region upstream of exon 3 is
specific to the X chromosome, while the region downstream of this exon is located on both
sex chromosomes37. The pseudoautosomal portion is highly variable within C57BL/6J38-40.
In our current study CNV6 spanned exons 2 and 3 and is, therefore, X-linked. The two
breakpoints for CNV7 were between exon 3 and 4 and approximately 11kb downstream of
this gene in the pseudoautosomal region. CNV6 and 7 map to the same location in Mid1 in
the human, where the entire gene is X-linked. Genetic loss of function mutations in Mid1,
have been found causative for the Opitz G/BBB Syndrome, which is characterized by a
varied phenotype that might include a range of midline birth defects and mental
retardation41. A patient with Opitz G/BBB syndrome as well as autism carried a discrete
deletion of Mid1 exon 2 (contained in CNV6)42. A separate case with autism but without
Opitz G/BBB syndrome carried a duplication that included the Mid1 gene from exon 2
onwards to a region approximately 500 kb downstream of his gene43, while a larger
aberration encompassing the Mid1 gene was evident in an individual with agenesis of the
corpus callosum14.
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Supplementary Material S2
S3.2. References associated with CNV syntenies in the human and phenotype
correlates
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