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Mike Stratton and colleague show that carriers of a germline copy number polymorphism involving APOBEC3A and APOBEC3B , which has been associated with increased risk of breast cancer, show more mutations characteristic of APOBEC-dependent mutational processes than cancers in non-carriers. The somatic mutations in a cancer genome are the aggregate outcome of one or more mutational processes operative through the lifetime of the individual with cancer 1 , 2 , 3 . Each mutational process leaves a characteristic mutational signature determined by the mechanisms of DNA damage and repair that constitute it. A role was recently proposed for the APOBEC family of cytidine deaminases in generating particular genome-wide mutational signatures 1 , 4 and a signature of localized hypermutation called kataegis 1 , 4 . A germline copy number polymorphism involving APOBEC3A and APOBEC3B , which effectively deletes APOBEC3B 5 , has been associated with modestly increased risk of breast cancer 6 , 7 , 8 . Here we show that breast cancers in carriers of the deletion show more mutations of the putative APOBEC-dependent genome-wide signatures than cancers in non-carriers. The results suggest that the APOBEC3A - APOBEC3B germline deletion allele confers cancer susceptibility through increased activity of APOBEC-dependent mutational processes, although the mechanism by which this increase in activity occurs remains unknown.

[...]studies have also suggested the utility of microarray testing in congenital heart disease2 and intrauterine growth restriction (IUGR) without congenital anomalies.3 Informed genetic consent needs to cover prognostication (most pathogenic copy number variants (CNVs) are associated with a significant risk of learning disability); potential implications for family members; incidental findings and the risk of identifying variants of uncertain significance (VUS). There was documented evidence of consent only in 62% of cases and only in 2% was consent informed with documented discussion about prognostic information, VUS, incidental findings and possible implications for family members (figure 1). Table 1 Indications and results of microarrays in neonatal inpatients over 1 year Indication Number of microarrays requested (%) Results Multiple congenital anomalies 21 (21%) 1: likely pathogenic CNV, 5: VUS 15: no abnormalities found Isolated congenital heart disease (CHD) 14 (14%) 1: likely pathogenic CNV 13: no abnormalities found Single congenital anomaly (not CHD) 30 (31%) 3: VUS 1: incidental finding—XYY karyotype 26: no abnormalities found Intrauterine growth restriction (IUGR), no congenital anomalies 23 (23%) 23: no abnormalities found High risk for trisomy on antenatal testing (no antenatal genetic test done) 3 (3%) 3: no abnormalities found Family history of CNV 1 (1%) 1: no abnormalities found Other 6 (6%) 6: no abnormalities found CHD, congenital heart disease; CNV, copy number variant; VUS, variant of uncertain significance.

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. Developmental disorders (DDs) are more prevalent in males, thought to be due to X-linked genetic variation. Here, the authors investigate the burden of X-linked coding variants in 11,044 DD patients, showing that this contributes to ~6% of both male and female cases and therefore does not solely explain male bias in DDs.

Background:Genome-wide high resolution array analysis is becoming established as a diagnostic test in the investigation of individuals with learning disability and congenital anomalies; many novel microdeletion and microduplication syndromes have already been identified. The diagnostic use of high resolution array genomic hybridisation analysis for prenatal testing remains to be systematically assessed.Methods:We studied 106 prenatal samples with abnormal ultrasound and a normal karyotype using the Affymetrix GeneChip 6.0 array. “Rare” DNA copy number variations (CNVs) were classified into three groups depending on their size, genomic location and the presence or absence of matched copy number changes in a large cohort of 3000 control samples analysed for copy number changes using genotyping arrays.Results:A total of 35 rare CNVs were identified. 10 (9%) of these are considered likely to represent pathogenic CNVs; 5 were syndromic and 5 were novel. 12 CNVs were detected in at least one control hybridisation and likely to be benign, and 13 CNVs were of unknown clinical significance. In addition, we identified one case of cryptic mosaicism for trisomy 10, one case of loss of heterozygosity (LOH), and showed that the Affymetrix GeneChip 6.0 array platform can detect triploidy.Conclusions:We conclude that careful implementation of high resolution array testing would benefit at least 10% of obstetric patients with abnormal ultrasound findings and a normal karyotype result.

Background: Oesophageal atresia (OA) and mandibulofacial dysostosis (MFD) are two congenital malformations for which the molecular bases of syndromic forms are being identified at a rapid rate. In particular, the EFTUD2 gene encoding a protein of the spliceosome complex has been found mutated in patients with MFD and microcephaly (MIM610536). Until now, no syndrome featuring both MFD and OA has been clearly delineated. Results: We report on 10 cases presenting with MFD, eight of whom had OA, either due to de novo 17q21.31 deletions encompassing EFTUD2 and neighbouring genes or de novo heterozygous EFTUD2 loss-of-function mutations. No EFTUD2 deletions or mutations were found in a series of patients with isolated OA or isolated oculoauriculovertebral spectrum (OAVS). Conclusions: These data exclude a contiguous gene syndrome for the association of MFD and OA, broaden the spectrum of clinical features ascribed to EFTUD2 haploinsufficiency, define a novel syndromic OA entity, and emphasise the necessity of mRNA maturation through the spliceosome complex for global growth and within specific regions of the embryo during development. Importantly, the majority of patients reported here with EFTUD2 lesions were previously diagnosed with Feingold or CHARGE syndromes or presented with OAVS plus OA, highlighting the variability of expression and the wide range of differential diagnoses.

The HTML and PDF versions of this Article were updated after publication to remove images of one individual from Figure 1.The HTML and PDF versions of this Article were updated after publication to remove images of one individual from Figure 1.

The original version of this Article contained an error in the spelling of the author Laurence Faivre, which was incorrectly given as Laurence Faive. This has now been corrected in both the PDF and HTML versions of the Article.

Large-scale copy number variation that is cytogenetically visible in normal individuals has been described as euchromatic variation but needs to be distinguished from pathogenic euchromatic deletion or duplication. Here, we report eight patients (three families and two individuals) with interstitial deletions of 9q13–q21.12. Fluorescence in situ hybridisation with a large panel of BACs showed that all the deleted clones were from extensive tracts of segmentally duplicated euchromatin, copies of which map to both the long and short arms of chromosome 9. The variety of reasons for which these patients were ascertained, and the phenotypically normal parents, indicates that this is a novel euchromatic variant with no phenotypic effect. Further, four patients with classical euchromatic variants of 9q12/qh or 9p12 were also shown to have duplications or triplications of this segmentally duplicated material common to both 9p and 9q. The cytogenetic boundaries between the segmentally duplicated regions and flanking unique sequences were mapped to 9p13.1 in the short arm (BAC RP11-402N8 at 38.7 Mb) and to 9q21.12 in the long arm (BAC RP11-88I18 at 70.3 Mb). The BACs identified in this study should in future make it possible to differentiate between clinically significant deletions or duplications and euchromatic variants with no established phenotypic consequences.