Clinical practice guidelines for BRCA1 and BRCA2 genetic testing

BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices

A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome

International audienceCornelia de Lange syndrome is a multisystemic developmental disorder mainly related to de novo heterozygous NIPBL mutation. Recently, NIPBL somatic mosaicism has been highlighted through buccal cell DNA study in some patients with a negative molecular analysis on leukocyte DNA. Here, we present a series of 38 patients with a Cornelia de Lange syndrome related to an heterozygous NIPBL mutation identified by Sanger sequencing. The diagnosis was based on the following criteria: 1) intrauterine growth retardation and postnatal short stature, 2) feeding difficulties and/or gastro-oesophageal reflux, 3) microcephaly, 4) intellectual disability and 5) characteristic facial features. We identified 37 novel NIPBL mutations including 34 in leukocytes and three in buccal cells only. All mutations shown to have arisen de novo when parent blood samples were available. The present series confirms the difficulty in predicting the phenotype according to the NIPBL mutation. Until now, somatic mosaicism has been observed for twenty cases which does not seem to be consistently associated with a milder phenotype. Besides, several reports support a postzygotic event for those cases. Considering these elements, we recommend a first-line buccal cell DNA analysis in order to improve gene testing sensitivity in Cornelia de Lange syndrome and genetic counselin