RESUMO
PURPOSE: BRCA1/2 founder pathogenic variants (PVs) occur in various populations, but data on the mutational spectrum in Africans are limited. We examined BRCA1/2 PVs in breast cancer patients of Ethiopian Jewish (EJ) origin. METHODS: We retrospectively analyzed BRCA1/2 test results and clinical features of EJ breast cancer patients from seven medical institutions. We obtained heterozygote carrier rates in affected individuals from the laboratories of the largest Israeli HMO (Clalit). Population carrier frequency was determined in EJ controls. RESULTS: We identified three recurrent BRCA2 PVs in 11 EJ breast cancer patients (9 females, 2 males): c.7579delG, c.5159C > A, and c.9693delA. Only c.5159C > A was previously reported in Africans. In women, mean age at diagnosis was 35.7y; 8/9 were diagnosed with advanced disease. All tumors were invasive, 4/9 were triple negative. Only 3/11 carriers had relevant family history. Carrier rate in high-risk breast cancer patients was 11% (3/28; 95%CI [2.3%, 28.2%]). Combined carrier rate among controls was 1.8% (5/280; 95%CI [0.6%, 4.1%]). CONCLUSION: EJs harbor 3 recurrent BRCA2 PVs presenting with relatively severe breast cancer morbidity. Combined with the high BRCA2 carrier rate in the EJ population, these findings merit increasing awareness in this community and suggest that a culturally adapted population screening approach may be warranted.
Assuntos
Proteína BRCA2 , Neoplasias da Mama Masculina , Neoplasias da Mama , Judeus , Proteína BRCA2/genética , Neoplasias da Mama/etnologia , Neoplasias da Mama/genética , Neoplasias da Mama Masculina/etnologia , Neoplasias da Mama Masculina/genética , Etiópia/epidemiologia , Feminino , Efeito Fundador , Predisposição Genética para Doença , Humanos , Judeus/genética , Masculino , Estudos RetrospectivosRESUMO
Lynch syndrome is an inherited cancer predisposition syndrome caused by germline defects in any of the mismatch repair (MMR) genes. Diagnosis of carriers makes precision prevention, early detection, and tailored treatment possible. Herein we report a novel founder deletion of 18,758 bp, mediated by Alu repeats on both sides, detected in Ethiopian Jews. The deletion, which encompasses exon 9-10 of the MSH2 coding sequence, is associated mainly with early-onset MSH2/MSH6-deficient colorectal cancer (CRC) and liposarcoma. Testing of 35 members of 5 seemingly unrelated families of Ethiopian origin yielded 10/21 (48%) carriers, of whom 9 had CRC. Age at first tumor diagnosis ranged from 16 to 89 years. Carriers from the oldest generations were diagnosed after age 45 years (mean 57), and carriers from the younger generation were diagnosed before age 45 years (mean 30). Awareness of this founder deletion is important to improve patient diagnosis, institute surveillance from an early age, and refer patients for genetic counseling addressing the risk of bi-allelic constitutional MMR deficiency syndrome.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Reparo de Erro de Pareamento de DNA/genética , Etiópia , Mutação em Linhagem Germinativa , Humanos , Judeus/genética , Pessoa de Meia-Idade , Proteína 2 Homóloga a MutS/genética , Adulto JovemRESUMO
Mutations of several genes have been implicated in autosomal recessive osteopetrosis (OP), a disease caused by impaired function and differentiation of osteoclasts. Severe combined immune deficiencies (SCID) can likewise result from different genetic mutations. We report two siblings with SCID and an atypical phenotype of OP. A biallelic microdeletion encompassing the 5' region of TRAF6, RAG1 and RAG2 genes was identified. TRAF6, a tumor necrosis factor receptor-associated family member, plays an important role in T cell signaling and in RANKL-dependent osteoclast differentiation and activation but its role in human OP has not been previously reported. The RAG proteins are essential for recombination of B and T cell receptors, and for the survival and differentiation of these cells. This is the first study to report a homozygous deletion of TRAF6 as a cause of human disease.
Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Homeodomínio/genética , Proteínas Nucleares/genética , Osteopetrose/genética , Imunodeficiência Combinada Severa/genética , Fator 6 Associado a Receptor de TNF/genética , Regiões 5' não Traduzidas/genética , Diferenciação Celular/genética , Feminino , Predisposição Genética para Doença , Homozigoto , Humanos , Lactente , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Mutação , Osteoclastos/metabolismo , Osteopetrose/patologia , Receptores de Antígenos de Linfócitos T/genética , Deleção de Sequência/genética , Imunodeficiência Combinada Severa/patologia , Transdução de Sinais/genéticaRESUMO
Little is known about the courses, causes, and clinical features of anaphylaxis in children outside the USA and Europe. Our objective was to evaluate the events of anaphylaxis in children admitted to the Schneider Children's Medical Center of Israel, a major tertiary facility, over a 12-year period. Ninety-two children with anaphylaxis (50 boys, 42 girls) aged 14 days to 18 yr (mean, 7.4 yr) were hospitalized during the study period. The event occurred at home in 52 children (56%), in a medical institution in 24 (26%), outdoors in 13 (15%), at school in 2 (2%), and in an unspecified location in 1 (1%). The main causes were foods (43%), mainly milk and nuts, medications (22%), and hymenoptera venom (11%); in five children, anaphylaxis occurred during general anesthesia, and in 5, the causative agent could not be determined. Food-induced anaphylaxis tended to occur in younger children. Forty-eight children (52%) had a history of atopy (mainly asthma). Hospital treatment consisted of corticosteroids (85%), antihistamines (75%), epinephrine (72%), and ß2 agonists (42%). Seven patients were admitted to intensive care units. There were no fatalities. EpiPen was used by only one of the 16 patients with more than one episode of anaphylaxis, indicating that patient and parent education in the application of the EpiPen needs to be improved.
