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BackgroundLi-Fraumeni (LFS) and Li-Fraumeni-like (LFL) syndromes are associated to germline TP53 mutations, and are characterized by the development of central nervous system tumors, sarcomas, adrenocortical carcinomas, and other early-onset tumors. Due to the high frequency of breast cancer in LFS/LFL families, these syndromes clinically overlap with hereditary breast cancer (HBC). Germline point mutations in BRCA1, BRCA2, and TP53 genes are associated with high risk of breast cancer. Large rearrangements involving these genes are also implicated in the HBC phenotype.MethodsWe have screened DNA copy number changes by MLPA on BRCA1, BRCA2, and TP53 genes in 23 breast cancer patients with a clinical diagnosis consistent with LFS/LFL; most of these families also met the clinical criteria for other HBC syndromes.ResultsWe found no DNA copy number alterations in the BRCA2 and TP53 genes, but we detected in one patient a 36.4 Kb BRCA1 microdeletion, confirmed and further mapped by array-CGH, encompassing exons 9–19. Breakpoints sequencing analysis suggests that this rearrangement was mediated by flanking Alu sequences.ConclusionThis is the first description of a germline intragenic BRCA1 deletion in a breast cancer patient with a family history consistent with both LFL and HBC syndromes. Our results show that large rearrangements in these known cancer predisposition genes occur, but are not a frequent cause of cancer susceptibility.

Copy number variations (CNVs) have been previously associated with several different neurodevelopmental psychiatric disorders, such as autism, schizophrenia, and attention deficit hyperactivity disorder (ADHD). The present study consisted of a pilot genome-wide screen for CNVs in a cohort of 16 patients with early-onset obsessive-compulsive disorder (OCD) and 12 mentally healthy individuals, using array-based comparative genomic hybridization (aCGH) on 44K arrays. A small rare paternal inherited microdeletion (∼64 kb) was identified in chromosome 15q13.3 of one male patient with very early onset OCD. The father did not have OCD. The deletion encompassed part of the FMN1 gene, which is involved with the glutamatergic system. This finding supports the hypothesis of a complex network of several genes expressed in the brain contributing for the genetic risk of OCD, and also supports the glutamatergic involvement in OCD, which has been previously reported in the literature.

Patients harboring rare CNVs exhibited a decreased age of disease onset, in addition to an overall higher skin cancer predisposition. Our findings suggest that rare CNVs contribute to melanoma susceptibility, and should be taken into account when investigating cancer risk factors.

Our results suggest that constitutive CNVs contribute to the etiology of pediatric neoplasms, revealing new candidate genes for tumorigenesis.

Myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukemia (JMML) are rare clonal hematopoietic diseases presented in the childhood. Both diseases exhibit abnormal karyotype and/or monosomy of chromosome 7 in a subgroup of patients. We screened for copy number variations (CNVs) by array-comparative genomic hybridization (aCHG) the DNA from bone marrow of six MDS and four JMML pediatric patients. Array-CGH analysis identified five cases (50%) with monosomy 7, disclosing the chromosome 7 monosomy in two patients whose samples could not be evaluated by other methods. We identified CNVs in six patients, one of which displayed loss of LMO2, an oncogene that plays a central role in hematopoietic development. Our results suggest that array-CGH is a reliable and accurate technique to identify genomic alterations in MDS and JMML.

The majority of familial cancer remains with unknown genetic aetiology. Issues impairing the discovery of new genes in complex diseases such as cancer include multifactorial origin, incomplete penetrance of the disease and late‐onset. The authors present an outline of the contribution of constitutive deoxyribonucleic acid copy number variations (CNVs) in cancer predisposition. Even though the mechanisms by which germline CNVs influence disease are hitherto largely speculative, nowadays it is consensual that they play a major role in a range of human pathologies. Point mutations have been far more commonly described, mainly because sequencing is the first‐tier diagnostic test, but deletions and duplications of known cancer genes have been reported as an alternative mechanism for cancer susceptibility. Additionally, CNV screening in familial cancer cohorts with unknown genetic aetiology has pointed to new candidate genes for high cancer risk. Therefore, this type of genomic variation must be taken into account in the cancer risk assessment. Key Concepts: Structural variation, including copy number variation (CNV), is responsible for a large fraction of the genetic diversity of the human genome. CNVs can be inherited in a Mendelian fashion or occur de novo . Germline CNVs play an important role in a range of human pathologies through several mechanisms, mainly affecting gene dosage or function. Nearly half of the approximately 100 Mendelian cancer predisposition genes were also reported as rare pathogenic germline CNVs. Next‐generation sequencing (NGS) combined with automated high throughput data analysis is the most promising approach for elucidating the contribution of both CNVs and point mutations to cancer predisposition.

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