Additional file 2: Table S3. of Leveraging network analytics to infer patient syndrome and identify causal genes in rare disease cases

This table lists the detailed results used for benchmarking and comparison analysis. In particular, for all 27 patient cases it shows the observed clinical phenotypes used as input, as well as all corresponding previously known causal genes. It also shows ranking of causal genes in PDR (after running analyses in Ingenuity Variant Analysis taking whole genome data as input), the corresponding disease inferred by PDR, and causal variant properties. For comparison, the rank of the causal gene obtained from Phenolyzer is also shown. (XLSX 34 kb

Regions of homozygosity shared by the two affected siblings.

<p>The genotyping information is displayed as a B-allele frequency, with heterozygous SNPs plotted at 0.5, and homozygous plotted at 0 or 1. B-allele frequencies are shown for chromosome 13 (A) and 18 (B). For each chromosome, B-allele frequencies are shown for Patient 1 (top) and Patient 2 (bottom).</p

Countries of Birth for U.S. Participants.

<p>Countries of Birth for U.S. Participants.</p

Assessment of <i>SLX4</i> Mutations in Hereditary Breast Cancers

<div><p>Background</p><p><i>SLX4</i> encodes a DNA repair protein that regulates three structure-specific endonucleases and is necessary for resistance to DNA crosslinking agents, topoisomerase I and poly (ADP-ribose) polymerase (PARP) inhibitors. Recent studies have reported mutations in <i>SLX4</i> in a new subtype of Fanconi anemia (FA), FA-P. Monoallelic defects in several FA genes are known to confer susceptibility to breast and ovarian cancers.</p><p>Methods and Results</p><p>To determine if <i>SLX4</i> is involved in breast cancer susceptibility, we sequenced the entire <i>SLX4</i> coding region in 738 (270 Jewish and 468 non-Jewish) breast cancer patients with 2 or more family members affected by breast cancer and no known <i>BRCA1</i> or <i>BRCA2</i> mutations. We found a novel nonsense (c.2469G>A, p.W823*) mutation in one patient. In addition, we also found 51 missense variants [13 novel, 23 rare (MAF<0.1%), and 15 common (MAF>1%)], of which 22 (5 novel and 17 rare) were predicted to be damaging by Polyphen2 (score = 0.65–1). We performed functional complementation studies using p.W823* and 5 <i>SLX4</i> variants (4 novel and 1 rare) cDNAs in a human <i>SLX4</i>-null fibroblast cell line, RA3331. While wild type <i>SLX4</i> and all the other variants fully rescued the sensitivity to mitomycin C (MMC), campthothecin (CPT), and PARP inhibitor (Olaparib) the p.W823* <i>SLX4</i> mutant failed to do so.</p><p>Conclusion</p><p>Loss-of-function mutations in <i>SLX4</i> may contribute to the development of breast cancer in very rare cases.</p></div

Countries of Birth for U.S. Participants.

<p>Countries of Birth for U.S. Participants.</p

Loci with strongest P-values from admixture mapping of the Indigenous American component.

<p>*Fold-increased odds of ICP attributed to homozygosity for Indigenous American alleles at the locus, relative to zero Indigenous American alleles.</p><p>Note: genomic positions are derived from version GRCh37/hg19 of the human genome sequence.</p><p>Loci with strongest P-values from admixture mapping of the Indigenous American component.</p

Pregnancy and neonatal outcomes.

<p>Notes: ‘*’ = Excluding twins. Vaginal and Cesarean birth were analyzed using Fisher’s exact test, birth weight using the t-test, and gestational age using the Mann-Whitney test. Where ‘N’ for a cell is lower than the total N at the top of the column, N for that cell is indicated.</p><p>Pregnancy and neonatal outcomes.</p

Median laboratory findings.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0131211#pone.0131211.t003" target="_blank">Table 3</a> notes. For some biochemical parameters, results from medical records were available from a subset of controls; those data are not presented, as there is likely bias in selection of which control women would undergo testing for clinical purposes. Therefore, comparisons between cases and controls are performed only for data from the study samples. P-values are from the Mann-Whitney test.</p><p>Median laboratory findings.</p

Results of admixture mapping for the Indigenous American component.

<p>Fig 1A. X-axis: positions by chromosome. Y-axis: negative log₁₀ P-values for the association between ICP and locus-specific ancestry. Fig 1B. X-axis: genomic position in the chromosome 2 locus. Y-axis: Fold-increased or–decreased odds of ICP attributed to 1) risk associated with Indigenous American ancestry (black); 2) risk associated with European ancestry (red); and 3) risk associated with African ancestry (blue). The locus-specific ancestry is coded such that the OR is for 2 chromosomes from the population being tested (Indigenous American, European, or African) versus zero chromosomes from that population.</p

Participant and sampling characteristics.

<p>*Age at blood draw, or for retrospectively enrolled women, reported age during the ICP-affected study pregnancy. ^Data for 89 of 90 US cases is included, as due to sample labelling uncertainty, one sample could have come from either of 2 enrolled affected women, so data from that sample is excluded here. Maternal age was analyzed using the t-test, and other variables, using the Mann-Whitney test.</p><p>Participant and sampling characteristics.</p