The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

Stage IV breast cancer in the era of targeted therapy

general vie

Data from: Clonal relatedness between lobular carcinoma in situ and synchronous malignant lesions

INTRODUCTION: Lobular carcinoma in situ (LCIS) has been accepted as a marker of risk for the development of invasive breast cancer, yet modern models of breast carcinogenesis include LCIS as a precursor of low-grade carcinomas. We provide evidence favoring a clonal origin for LCIS and synchronous estrogen receptor-positive malignant lesions of the ductal and lobular phenotype. METHODS: Patients with prior LCIS undergoing mastectomy were identified preoperatively from 2003-2008. Specimens were widely sampled, and frozen blocks were screened for LCIS and co-existing malignant lesions, and subject to microdissection. Samples from 65 patients were hybridized to the Affymetrix SNP 6.0 array platform. Cases with both an LCIS sample and an associated ductal carcinoma in situ (DCIS) or invasive tumor sample were evaluated for patterns of somatic copy number changes to assess evidence of clonal relatedness. RESULTS: LCIS was identified in 44 of the cases, and among these, a DCIS and/or invasive lesion was also identified in 21 cases. A total of 17 tumor pairs had adequate DNA/array data for analysis, including 9 pairs of LCIS/invasive lobular cancer (ILC), 4 pairs of LCIS/DCIS, and 4 LCIS/invasive ductal cancer (IDC). Overall, 7 pairs (41%) were judged to be clonally related; in 5 (29%), evidence suggested clonality but was equivocal, and 5 (29%) were considered independent. Clonal pairs were observed with all matched lesion types and low and high histological grades. We also show anecdotal evidence of clonality between a patient-matched triplet of LCIS, DCIS, and IDC. CONCLUSIONS: Our results support the role of LCIS as a precursor in the development of both high- and low-grade ductal and lobular cancers

KingClonalityData3

Copy number log-ratio data for the 31 samples in the manuscript. It is a gzipped text file. This is part 3. Use cat to concatenate all 6 parts

KingClonalityCode

This file contains the R code used to preprocess the SNP array files (not submitted due to privacy issues) as well as the clonality analysis using the submitted log-ratio data

Data from: Clonal relatedness between lobular carcinoma in situ and synchronous malignant lesions

INTRODUCTION: Lobular carcinoma in situ (LCIS) has been accepted as a marker of risk for the development of invasive breast cancer, yet modern models of breast carcinogenesis include LCIS as a precursor of low-grade carcinomas. We provide evidence favoring a clonal origin for LCIS and synchronous estrogen receptor-positive malignant lesions of the ductal and lobular phenotype. METHODS: Patients with prior LCIS undergoing mastectomy were identified preoperatively from 2003-2008. Specimens were widely sampled, and frozen blocks were screened for LCIS and co-existing malignant lesions, and subject to microdissection. Samples from 65 patients were hybridized to the Affymetrix SNP 6.0 array platform. Cases with both an LCIS sample and an associated ductal carcinoma in situ (DCIS) or invasive tumor sample were evaluated for patterns of somatic copy number changes to assess evidence of clonal relatedness. RESULTS: LCIS was identified in 44 of the cases, and among these, a DCIS and/or invasive lesion was also identified in 21 cases. A total of 17 tumor pairs had adequate DNA/array data for analysis, including 9 pairs of LCIS/invasive lobular cancer (ILC), 4 pairs of LCIS/DCIS, and 4 LCIS/invasive ductal cancer (IDC). Overall, 7 pairs (41%) were judged to be clonally related; in 5 (29%), evidence suggested clonality but was equivocal, and 5 (29%) were considered independent. Clonal pairs were observed with all matched lesion types and low and high histological grades. We also show anecdotal evidence of clonality between a patient-matched triplet of LCIS, DCIS, and IDC. CONCLUSIONS: Our results support the role of LCIS as a precursor in the development of both high- and low-grade ductal and lobular cancers

KingClonalityData2

Copy number log-ratio data for the 31 samples in the manuscript. It is a gzipped text file. This is part 2. Use cat to concatenate all 6 parts

Reproductive parameters of female orangutans (Pongo pygmaeus wurmbii) 1971–2011, a 40-year study at Tanjung Puting National Park, Central Kalimantan, Indonesia

This study presents reproductive parameter data gathered by direct observation over a 40-year period (1971-2011) of the provisioned free-ranging population of orangutans at Camp Leakey in Tanjung Puting National Park, Central Kalimantan, Indonesia. Age at first reproduction, interbirth interval (IBI), sex ratio at birth, and infant mortality for 19 female orangutans (11 first-generation wild-born ex-captive mothers and 8 second-generation mothers) are included in this analysis. Age at first reproduction among the first-generation mothers was similar to that among wild orangutans, while second-generation mothers had a significantly earlier age at first reproduction. IBIs were similar among first- and second-generation mothers and were significantly shorter than those recorded in studies of wild orangutan populations. There was an expected male-biased sex ratio at birth and a slightly higher than expected rate of infant mortality when compared to wild populations. Infant mortality was primarily seen among second-generation mothers who gave birth before the age of 12, and among first births of some first-generation mothers. These results lend support to the ecological energetics hypothesis, which predicts that increased diet quality leads to a faster rate of reproduction

KingClonalityData5

Copy number log-ratio data for the 31 samples in the manuscript. It is a gzipped text file. This is part 5. Use cat to concatenate all 6 parts