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Background: Risk-reducing mastectomy (RRM) is offered to women with a BRCA1 or BRCA2 pathogenic variant, however, there are limited data on the impact on breast cancer mortality. Methods: Participants were identified from a registry of women with BRCA1/2 pathogenic variants. We used a pseudo-randomised trial design and matched one woman with a RRM to one woman without a RRM on year of birth, gene, and country. We estimated the hazard ratio (HR) and 95% confidence intervals (CI) for dying of breast cancer in the follow-up period. Results: There were 1654 women included; 827 assigned to the RRM arm and 827 assigned to the control arm. After a mean follow-up of 6.3 years, there were 20 incident breast cancers (including 15 occult cancers) and two breast cancer deaths in the RRM arm, and 100 incident breast cancers and 7 breast cancer deaths in the control arm (HR = 0.26; 95% CI 0.05–1.35; p = 0.11). The probability of dying of breast cancer within 15 years after RRM was 0.95%. Conclusions: In women with a BRCA1 or BRCA2 pathogenic variant, RRM reduces the risk of breast cancer, and the probability of dying of breast cancer is low.

Background: The purpose of this study was to estimate the cumulative risks of all cancers in women from 50 to 75 years of age with a BRCA1 or BRCA2 pathogenic variant. Methods: Participants were women with BRCA1 or BRCA2 pathogenic variants from 85 centers in 16 countries. Women were eligible if they had no cancer before the age of 50 years. Participants completed a baseline questionnaire and follow-up questionnaires every 2 years. Women were followed from age 50 until a diagnosis of cancer, death, age 75, or last follow-up. The risk of all cancers combined from age 50 to 75 was estimated using the Kaplan-Meier method. Results: There were 2211 women included (1470 BRCA1 and 742 BRCA2). There were 379 cancers diagnosed in the cohort between 50 and 75 years. The actuarial risk of any cancer from age 50 to 75 was 49% for BRCA1 and 43% for BRCA2. Breast (n = 186) and ovarian (n = 45) were the most frequent cancers observed. For women who had both risk-reducing mastectomy and bilateral salpingo-oophorectomy before age 50, the risk of developing any cancer between age 50 and 75 was 9%. Conclusion: Women with a BRCA1 or BRCA2 pathogenic variant have a high risk of cancer between the ages of 50 and 75 years and should be counselled appropriately.

Contains fulltext : 196429.pdf (publisher's version ) (Open Access), BACKGROUND: ATP8A2 mutations have recently been described in several patients with severe, early-onset hypotonia and cognitive impairment. The aim of our study was to characterize the clinical phenotype of patients with ATP8A2 mutations. METHODS: An observational study was conducted at multiple diagnostic centres. Clinical data is presented from 9 unreported and 2 previously reported patients with ATP8A2 mutations. We compare their features with 3 additional patients that have been previously reported in the medical literature. RESULTS: Eleven patients with biallelic ATP8A2 mutations were identified, with a mean age of 9.4 years (range 2.5-28 years). All patients with ATP8A2 mutations (100%) demonstrated developmental delay, severe hypotonia and movement disorders, specifically chorea or choreoathetosis (100%), dystonia (27%) and facial dyskinesia (18%). Optic atrophy was observed in 78% of patients for whom funduscopic examination was performed. Symptom onset in all (100%) was noted before 6 months of age, with 70% having symptoms noted at birth. Feeding difficulties were common (91%) although most patients were able to tolerate pureed or thickened feeds, and 3 patients required gastrostomy tube insertion. MRI of the brain was normal in 50% of the patients. A smaller proportion was noted to have mild cortical atrophy (30%), delayed myelination (20%) and/or hypoplastic optic nerves (20%). Functional studies were performed on differentiated induced pluripotent cells from one child, which confirmed a decrease in ATP8A2 expression compared to control cells. CONCLUSIONS: ATP8A2 gene mutations have emerged as the cause of a novel neurological phenotype characterized by global developmental delays, severe hypotonia and hyperkinetic movement disorders, the latter being an important distinguishing feature. Optic atrophy is common and may only become apparent in the first few years of life, necessitating repeat ophthalmologic evaluation in older children. Early recognition o

BACKGROUND: ATP8A2 mutations have recently been described in several patients with severe, early-onset hypotonia and cognitive impairment. The aim of our study was to characterize the clinical phenotype of patients with ATP8A2 mutations. METHODS: An observational study was conducted at multiple diagnostic centres. Clinical data is presented from 9 unreported and 2 previously reported patients with ATP8A2 mutations. We compare their features with 3 additional patients that have been previously reported in the medical literature. RESULTS: Eleven patients with biallelic ATP8A2 mutations were identified, with a mean age of 9.4 years (range 2.5-28 years). All patients with ATP8A2 mutations (100%) demonstrated developmental delay, severe hypotonia and movement disorders, specifically chorea or choreoathetosis (100%), dystonia (27%) and facial dyskinesia (18%). Optic atrophy was observed in 78% of patients for whom funduscopic examination was performed. Symptom onset in all (100%) was noted before 6 months of age, with 70% having symptoms noted at birth. Feeding difficulties were common (91%) although most patients were able to tolerate pureed or thickened feeds, and 3 patients required gastrostomy tube insertion. MRI of the brain was normal in 50% of the patients. A smaller proportion was noted to have mild cortical atrophy (30%), delayed myelination (20%) and/or hypoplastic optic nerves (20%). Functional studies were performed on differentiated induced pluripotent cells from one child, which confirmed a decrease in ATP8A2 expression compared to control cells. CONCLUSIONS: ATP8A2 gene mutations have emerged as the cause of a novel neurological phenotype characterized by global developmental delays, severe hypotonia and hyperkinetic movement disorders, the latter being an important distinguishing feature. Optic atrophy is common and may only become apparent in the first few years of life, necessitating repeat ophthalmologic evaluation in older children. Early recognition o

Contains fulltext : 196429.pdf (publisher's version ) (Open Access), BACKGROUND: ATP8A2 mutations have recently been described in several patients with severe, early-onset hypotonia and cognitive impairment. The aim of our study was to characterize the clinical phenotype of patients with ATP8A2 mutations. METHODS: An observational study was conducted at multiple diagnostic centres. Clinical data is presented from 9 unreported and 2 previously reported patients with ATP8A2 mutations. We compare their features with 3 additional patients that have been previously reported in the medical literature. RESULTS: Eleven patients with biallelic ATP8A2 mutations were identified, with a mean age of 9.4 years (range 2.5-28 years). All patients with ATP8A2 mutations (100%) demonstrated developmental delay, severe hypotonia and movement disorders, specifically chorea or choreoathetosis (100%), dystonia (27%) and facial dyskinesia (18%). Optic atrophy was observed in 78% of patients for whom funduscopic examination was performed. Symptom onset in all (100%) was noted before 6 months of age, with 70% having symptoms noted at birth. Feeding difficulties were common (91%) although most patients were able to tolerate pureed or thickened feeds, and 3 patients required gastrostomy tube insertion. MRI of the brain was normal in 50% of the patients. A smaller proportion was noted to have mild cortical atrophy (30%), delayed myelination (20%) and/or hypoplastic optic nerves (20%). Functional studies were performed on differentiated induced pluripotent cells from one child, which confirmed a decrease in ATP8A2 expression compared to control cells. CONCLUSIONS: ATP8A2 gene mutations have emerged as the cause of a novel neurological phenotype characterized by global developmental delays, severe hypotonia and hyperkinetic movement disorders, the latter being an important distinguishing feature. Optic atrophy is common and may only become apparent in the first few years of life, necessitating repeat ophthalmologic evaluation in older children. Early recognition o

Contains fulltext : 196429.pdf (publisher's version ) (Open Access), BACKGROUND: ATP8A2 mutations have recently been described in several patients with severe, early-onset hypotonia and cognitive impairment. The aim of our study was to characterize the clinical phenotype of patients with ATP8A2 mutations. METHODS: An observational study was conducted at multiple diagnostic centres. Clinical data is presented from 9 unreported and 2 previously reported patients with ATP8A2 mutations. We compare their features with 3 additional patients that have been previously reported in the medical literature. RESULTS: Eleven patients with biallelic ATP8A2 mutations were identified, with a mean age of 9.4 years (range 2.5-28 years). All patients with ATP8A2 mutations (100%) demonstrated developmental delay, severe hypotonia and movement disorders, specifically chorea or choreoathetosis (100%), dystonia (27%) and facial dyskinesia (18%). Optic atrophy was observed in 78% of patients for whom funduscopic examination was performed. Symptom onset in all (100%) was noted before 6 months of age, with 70% having symptoms noted at birth. Feeding difficulties were common (91%) although most patients were able to tolerate pureed or thickened feeds, and 3 patients required gastrostomy tube insertion. MRI of the brain was normal in 50% of the patients. A smaller proportion was noted to have mild cortical atrophy (30%), delayed myelination (20%) and/or hypoplastic optic nerves (20%). Functional studies were performed on differentiated induced pluripotent cells from one child, which confirmed a decrease in ATP8A2 expression compared to control cells. CONCLUSIONS: ATP8A2 gene mutations have emerged as the cause of a novel neurological phenotype characterized by global developmental delays, severe hypotonia and hyperkinetic movement disorders, the latter being an important distinguishing feature. Optic atrophy is common and may only become apparent in the first few years of life, necessitating repeat ophthalmologic evaluation in older children. Early recognition o

Item does not contain fulltext, BACKGROUND: AUTS2 syndrome is an 'intellectual disability (ID) syndrome' caused by genomic rearrangements, deletions, intragenic duplications or mutations disrupting AUTS2. So far, 50 patients with AUTS2 syndrome have been described, but clinical data are limited and almost all cases involved young children. METHODS: We present a detailed clinical description of 13 patients (including six adults) with AUTS2 syndrome who have a pathogenic mutation or deletion in AUTS2. All patients were systematically evaluated by the same clinical geneticist. RESULTS: All patients have borderline to severe ID/developmental delay, 83-100% have microcephaly and feeding difficulties. Congenital malformations are rare, but mild heart defects, contractures and genital malformations do occur. There are no major health issues in the adults; the oldest of whom is now 59 years of age. Behaviour is marked by it is a friendly outgoing social interaction. Specific features of autism (like obsessive behaviour) are seen frequently (83%), but classical autism was not diagnosed in any. A mild clinical phenotype is associated with a small in-frame 5' deletions, which are often inherited. Deletions and other mutations causing haploinsufficiency of the full-length AUTS2 transcript give a more severe phenotype and occur de novo. CONCLUSIONS: The 13 patients with AUTS2 syndrome with unique pathogenic deletions scattered around the AUTS2 locus confirm a phenotype-genotype correlation. Despite individual variations, AUTS2 syndrome emerges as a specific ID syndrome with microcephaly, feeding difficulties, dysmorphic features and a specific behavioural phenotype.

Item does not contain fulltext, BACKGROUND: AUTS2 syndrome is an 'intellectual disability (ID) syndrome' caused by genomic rearrangements, deletions, intragenic duplications or mutations disrupting AUTS2. So far, 50 patients with AUTS2 syndrome have been described, but clinical data are limited and almost all cases involved young children. METHODS: We present a detailed clinical description of 13 patients (including six adults) with AUTS2 syndrome who have a pathogenic mutation or deletion in AUTS2. All patients were systematically evaluated by the same clinical geneticist. RESULTS: All patients have borderline to severe ID/developmental delay, 83-100% have microcephaly and feeding difficulties. Congenital malformations are rare, but mild heart defects, contractures and genital malformations do occur. There are no major health issues in the adults; the oldest of whom is now 59 years of age. Behaviour is marked by it is a friendly outgoing social interaction. Specific features of autism (like obsessive behaviour) are seen frequently (83%), but classical autism was not diagnosed in any. A mild clinical phenotype is associated with a small in-frame 5' deletions, which are often inherited. Deletions and other mutations causing haploinsufficiency of the full-length AUTS2 transcript give a more severe phenotype and occur de novo. CONCLUSIONS: The 13 patients with AUTS2 syndrome with unique pathogenic deletions scattered around the AUTS2 locus confirm a phenotype-genotype correlation. Despite individual variations, AUTS2 syndrome emerges as a specific ID syndrome with microcephaly, feeding difficulties, dysmorphic features and a specific behavioural phenotype.

Contains fulltext : 97324.pdf (publisher's version ) (Closed access), BACKGROUND: Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch-repair genes and leads to a high risk of colorectal and endometrial cancer. We previously showed that constitutional 3' end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM-expressing tissues, resulting in tissue-specific MSH2 deficiency. We aim to establish the risk of cancer associated with such EPCAM deletions. METHODS: We obtained clinical data for 194 carriers of a 3' end EPCAM deletion from 41 families known to us at the Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands and compared cancer risk with data from a previously described cohort of 473 carriers from 91 families with mutations in MLH1, MSH2, MSH6, or a combined EPCAM-MSH2 deletion. FINDINGS: 93 of the 194 EPCAM deletion carriers were diagnosed with colorectal cancer; three of the 92 women with EPCAM deletions were diagnosed with endometrial cancer. Carriers of an EPCAM deletion had a 75% (95% CI 65-85) cumulative risk of colorectal cancer before the age of 70 years (mean age at diagnosis 43 years [SD 12]), which did not differ significantly from that of carriers of combined EPCAM-MSH2 deletion (69% [95% CI 47-91], p=0.8609) or mutations in MSH2 (77% [64-90], p=0.5892) or MLH1 (79% [68-90], p=0.5492), but was higher than noted for carriers of MSH6 mutation (50% [38-62], p<0.0001). By contrast, women with EPCAM deletions had a 12% [0-27] cumulative risk of endometrial cancer, which was lower than was that noted for carriers of a combined EPCAM-MSH2 deletion (55% [20-90], p<0.0001) or of a mutation in MSH2 (51% [33-69], p=0.0006) or MSH6 (34% [20-48], p=0.0309), but did not differ significantly from that noted for MLH1 (33% [15-51], p=0.1193) mutation carriers. This risk seems to be restricted to deletions that extend close to the MSH2 gene promoter. Of 194 carriers of an EPCAM deletion, three had duodenal cancer and four had pancreatic cancer. INTERPR

Contains fulltext : 97324.pdf (publisher's version ) (Closed access), BACKGROUND: Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch-repair genes and leads to a high risk of colorectal and endometrial cancer. We previously showed that constitutional 3' end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM-expressing tissues, resulting in tissue-specific MSH2 deficiency. We aim to establish the risk of cancer associated with such EPCAM deletions. METHODS: We obtained clinical data for 194 carriers of a 3' end EPCAM deletion from 41 families known to us at the Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands and compared cancer risk with data from a previously described cohort of 473 carriers from 91 families with mutations in MLH1, MSH2, MSH6, or a combined EPCAM-MSH2 deletion. FINDINGS: 93 of the 194 EPCAM deletion carriers were diagnosed with colorectal cancer; three of the 92 women with EPCAM deletions were diagnosed with endometrial cancer. Carriers of an EPCAM deletion had a 75% (95% CI 65-85) cumulative risk of colorectal cancer before the age of 70 years (mean age at diagnosis 43 years [SD 12]), which did not differ significantly from that of carriers of combined EPCAM-MSH2 deletion (69% [95% CI 47-91], p=0.8609) or mutations in MSH2 (77% [64-90], p=0.5892) or MLH1 (79% [68-90], p=0.5492), but was higher than noted for carriers of MSH6 mutation (50% [38-62], p<0.0001). By contrast, women with EPCAM deletions had a 12% [0-27] cumulative risk of endometrial cancer, which was lower than was that noted for carriers of a combined EPCAM-MSH2 deletion (55% [20-90], p<0.0001) or of a mutation in MSH2 (51% [33-69], p=0.0006) or MSH6 (34% [20-48], p=0.0309), but did not differ significantly from that noted for MLH1 (33% [15-51], p=0.1193) mutation carriers. This risk seems to be restricted to deletions that extend close to the MSH2 gene promoter. Of 194 carriers of an EPCAM deletion, three had duodenal cancer and four had pancreatic cancer. INTERPR

Contains fulltext : 97324.pdf (publisher's version ) (Closed access), BACKGROUND: Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch-repair genes and leads to a high risk of colorectal and endometrial cancer. We previously showed that constitutional 3' end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM-expressing tissues, resulting in tissue-specific MSH2 deficiency. We aim to establish the risk of cancer associated with such EPCAM deletions. METHODS: We obtained clinical data for 194 carriers of a 3' end EPCAM deletion from 41 families known to us at the Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands and compared cancer risk with data from a previously described cohort of 473 carriers from 91 families with mutations in MLH1, MSH2, MSH6, or a combined EPCAM-MSH2 deletion. FINDINGS: 93 of the 194 EPCAM deletion carriers were diagnosed with colorectal cancer; three of the 92 women with EPCAM deletions were diagnosed with endometrial cancer. Carriers of an EPCAM deletion had a 75% (95% CI 65-85) cumulative risk of colorectal cancer before the age of 70 years (mean age at diagnosis 43 years [SD 12]), which did not differ significantly from that of carriers of combined EPCAM-MSH2 deletion (69% [95% CI 47-91], p=0.8609) or mutations in MSH2 (77% [64-90], p=0.5892) or MLH1 (79% [68-90], p=0.5492), but was higher than noted for carriers of MSH6 mutation (50% [38-62], p<0.0001). By contrast, women with EPCAM deletions had a 12% [0-27] cumulative risk of endometrial cancer, which was lower than was that noted for carriers of a combined EPCAM-MSH2 deletion (55% [20-90], p<0.0001) or of a mutation in MSH2 (51% [33-69], p=0.0006) or MSH6 (34% [20-48], p=0.0309), but did not differ significantly from that noted for MLH1 (33% [15-51], p=0.1193) mutation carriers. This risk seems to be restricted to deletions that extend close to the MSH2 gene promoter. Of 194 carriers of an EPCAM deletion, three had duodenal cancer and four had pancreatic cancer. INTERPR