TP53 missense allele predisposing to high risk of breast cancer but not pediatric cancers.

Pathogenic TP53 germline variants cause young-onset breast cancer and other cancers of the Li-Fraumeni syndrome (LFS) spectrum, but the clinical consequences of partial-loss-of function TP53 variants are incompletely understood. In the consecutive cohort of Palestinian breast cancer patients of the Middle East Breast Cancer Study (MEBCS), breast cancer risk among TP53 p. R181C heterozygotes was 50% by age 50 y and 81% by age 80 y.

Long-read DNA and cDNA sequencing identify cancer-predisposing deep intronic variation in tumor-suppressor genes.

The vast majority of deeply intronic genomic variants are benign, but some extremely rare or private deep intronic variants lead to exonification of intronic sequence with abnormal transcriptional consequences. Damaging variants of this class are likely underreported as causes of disease for several reasons: Most clinical DNA and RNA testing does not include full intronic sequences; many of these variants lie in complex repetitive regions that cannot be aligned from short-read whole-genome sequence; and, until recently, consequences of deep intronic variants were not accurately predicted by in silico tools. We evaluated the frequency and consequences of rare deep intronic variants for families severely affected with breast, ovarian, pancreatic, and/or metastatic prostate cancer, but with no causal variant identified by any previous genomic or cDNA-based approach.

Association of Genetic Diagnoses for Childhood-Onset Hearing Loss With Cochlear Implant Outcomes.

Importance: In the US, most childhood-onset bilateral sensorineural hearing loss is genetic, with more than 120 genes and thousands of different alleles known. Primary treatments are hearing aids and cochlear implants. Genetic diagnosis can inform progression of hearing loss, indicate potential syndromic features, and suggest best timing for individualized treatment.

Molecular diagnosis of childhood immune dysregulation, polyendocrinopathy, and enteropathy, and implications for clinical management.

Background: Most patients with childhood-onset immune dysregulation, polyendocrinopathy, and enteropathy have no genetic diagnosis for their illness. These patients may undergo empirical immunosuppressive treatment with highly variable outcomes.

Objective: We sought to determine the genetic basis of disease in patients referred with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like (IPEX-like) disease, but with no mutation in FOXP3; then to assess consequences of genetic diagnoses for clinical management.

Inherited predisposition to breast cancer in the Carolina Breast Cancer Study.

The Carolina Breast Cancer Study (CBCS) phases I-II was a case-control study of biological and social risk factors for invasive breast cancer that enrolled cases and controls between 1993 and 1999. Case selection was population-based and stratified by ancestry and age at diagnosis. Controls were matched to cases by age, self-identified race, and neighborhood of residence.

Spectrum of genes for inherited hearing loss in the Israeli Jewish population, including the novel human deafness gene ATOH1.

Mutations in more than 150 genes are responsible for inherited hearing loss, with thousands of different, severe causal alleles that vary among populations. The Israeli Jewish population includes communities of diverse geographic origins, revealing a wide range of deafness-associated variants and enabling clinical characterization of the associated phenotypes. Our goal was to identify the genetic causes of inherited hearing loss in this population, and to determine relationships among genotype, phenotype, and ethnicity.

Genomic analysis of inherited hearing loss in the Palestinian population.

The genetic characterization of a common phenotype for an entire population reveals both the causes of that phenotype for that place and the power of family-based, population-wide genomic analysis for gene and mutation discovery. We characterized the genetics of hearing loss throughout the Palestinian population, enrolling 2,198 participants from 491 families from all parts of the West Bank and Gaza. In Palestinian families with no prior history of hearing loss, we estimate that 56% of hearing loss is genetic and 44% is not genetic.

Inherited mutations in fallopian tube, ovarian and primary peritoneal carcinoma: Changes in diagnoses and mutational frequency over 20 years.

Objectives: Women with fallopian tube carcinoma (FTC) are reported to have a higher frequency of inherited BRCA mutations than those with ovarian carcinoma (OC) or primary peritoneal carcinoma (PPC). We hypothesized that routine serial sectioning of fallopian tubes would increase the proportion of cases designated as FTC and change the frequency of inherited mutations between carcinoma types.

Methods: Eight hundred and sixty-seven women diagnosed from 1998 to 2018 were enrolled at diagnosis into an institutional tissue bank.

Characterization of splice-altering mutations in inherited predisposition to cancer.

Mutations responsible for inherited disease may act by disrupting normal transcriptional splicing. Such mutations can be difficult to detect, and their effects difficult to characterize, because many lie deep within exons or introns where they may alter splice enhancers or silencers or introduce new splice acceptors or donors. Multiple mutation-specific and genome-wide approaches have been developed to evaluate these classes of mutations.

Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy.

Survival from malignant mesothelioma, particularly pleural mesothelioma, is very poor. For patients with breast, ovarian, or prostate cancers, overall survival is associated with increased sensitivity to platinum chemotherapy due to loss-of-function mutations in DNA repair genes. The goal of this project was to evaluate, in patients with malignant mesothelioma, the relationship between inherited loss-of-function mutations in DNA repair and other tumor suppressor genes and overall survival following platinum chemotherapy.

Inherited Breast Cancer in Nigerian Women.

Purpose: Among Nigerian women, breast cancer is diagnosed at later stages, is more frequently triple-negative disease, and is far more frequently fatal than in Europe or the United States. We evaluated the contribution of an inherited predisposition to breast cancer in this population.

Patients And Methods: Cases were 1,136 women with invasive breast cancer (mean age at diagnosis, 47.

Mutations in Homologous Recombination Genes and Outcomes in Ovarian Carcinoma Patients in GOG 218: An NRG Oncology/Gynecologic Oncology Group Study.

We hypothesized that mutations in homologous recombination repair (HRR) genes beyond and improve outcomes for ovarian carcinoma patients treated with platinum therapy and would impact the relative benefit of adding prolonged bevacizumab. We sequenced DNA from blood and/or neoplasm from 1,195 women enrolled in GOG-0218, a randomized phase III trial in advanced ovarian carcinoma of bevacizumab added to carboplatin and paclitaxel. Defects in HRR were defined as damaging mutations in 16 genes.

Genetic Predisposition to Breast Cancer Due to Mutations Other Than BRCA1 and BRCA2 Founder Alleles Among Ashkenazi Jewish Women.

Importance: Among Ashkenazi Jewish women, 3 mutations in BRCA1 and BRCA2 severely increase the risk of breast and ovarian cancer. However, among Ashkenazi Jewish patients with breast cancer who do not carry one of these founder mutations, the likelihood of carrying another pathogenic mutation in BRCA1 or BRCA2 or another breast cancer gene is not known. This information would be valuable to the patient and family for cancer prevention and treatment.

Bone marrow failure unresponsive to bone marrow transplant is caused by mutations in .

We report 5 individuals in 3 unrelated families with severe thrombocytopenia progressing to trilineage bone marrow failure (BMF). Four of the children received hematopoietic stem cell transplants and all showed poor graft function with persistent severe cytopenias even after repeated transplants with different donors. Exome and targeted sequencing identified mutations in the gene encoding thrombopoietin (): THPO R99W, homozygous in affected children in 2 families, and THPO R157X, homozygous in the affected child in the third family.

Genomic analysis of inherited breast cancer among Palestinian women: Genetic heterogeneity and a founder mutation in TP53.

Breast cancer among Palestinian women has lower incidence than in Europe or North America, yet is very frequently familial. We studied genetic causes of this familial clustering in a consecutive hospital-based series of 875 Palestinian patients with invasive breast cancer, including 453 women with diagnosis by age 40, or with breast or ovarian cancer in a mother, sister, grandmother or aunt ("discovery series"); and 422 women diagnosed after age 40 and with negative family history ("older-onset sporadic patient series"). Genomic DNA from women in the discovery series was sequenced for all known breast cancer genes, revealing a pathogenic mutation in 13% (61/453) of patients.

Vesicular acetylcholine transporter defect underlies devastating congenital myasthenia syndrome.

Objective: To identify the genetic basis of a recessive congenital neurologic syndrome characterized by severe hypotonia, arthrogryposis, and respiratory failure.

Methods: Identification of the responsible gene by exome sequencing and assessment of the effect of the mutation on protein stability in transfected rat neuronal-like PC12 cells.

Results: Two brothers from a nonconsanguineous Yemeni Jewish family manifested at birth with severe hypotonia and arthrogryposis.

Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease.

Mutations in nuclear genes required for the replication and maintenance of mitochondrial DNA cause progressive multisystemic neuromuscular disorders with overlapping phenotypes. Biallelic mutations in C10orf2, encoding the Twinkle mitochondrial DNA helicase, lead to infantile-onset cerebellar ataxia (IOSCA), as well as milder and more severe phenotypes. We present a 13-year-old girl with ataxia, severe hearing loss, optic atrophy, peripheral neuropathy, and hypergonadotropic hypogonadism.

Identifying Inherited and Acquired Genetic Factors Involved in Poor Stem Cell Mobilization and Donor-Derived Malignancy.

Analysis of the clinical characteristics of hematopoietic stem cell transplant (HSCT) donors has proven beneficial for identifying cases of heritable hematopoietic disorders. This study examines poor peripheral blood hematopoietic stem cell mobilization after granulocyte colony-stimulating factor administration among 328 donors as a potential marker for suspected familial predisposition to myeloid malignancies. Here, we present data comparing the clinical characteristics of poor-mobilizing versus nonpoor-mobilizing donors and the results of panel-based sequencing of hematopoietic genes in poor-mobilizing donors.

Comparison of clinical efficacy and renal safety of telbivudine and entecavir in chronic hepatitis B patients receiving cytotoxic chemotherapy.

Objective: Limited data is available on the clinical outcomes of telbivudine (LdT) and entecavir (ETV) in pre-emptive antiviral chemoprophylaxis. This study aimed to evaluate the clinical efficacy and renal safety of LdT and ETV in patients with chronic hepatitis B (CHB) who received cytotoxic chemotherapy.

Methods: Altogether 290 treatment-naïve CHB patients undergoing intense chemotherapy were enrolled to receive daily 600 mg of LdT or 0.

Mutation of KREMEN1, a modulator of Wnt signaling, is responsible for ectodermal dysplasia including oligodontia in Palestinian families.

Tooth development is controlled by the same processes that regulate formation of other ectodermal structures. Mutations in the genes underlying these processes may cause ectodermal dysplasia, including severe absence of primary or permanent teeth. Four consanguineous Palestinian families presented with oligodontia and hair and skin features of ectodermal dysplasia.

Improving performance of multigene panels for genomic analysis of cancer predisposition.

Purpose: Screening multiple genes for inherited cancer predisposition expands opportunities for cancer prevention; however, reports of variants of uncertain significance (VUS) may limit clinical usefulness. We used an expert-driven approach, exploiting all available information, to evaluate multigene panels for inherited cancer predisposition in a clinical series that included multiple cancer types and complex family histories.

Methods: For 1,462 sequential patients referred for testing by BROCA or ColoSeq multigene panels, genomic DNA was sequenced and variants were interpreted by multiple experts using International Agency for Research on Cancer guidelines and incorporating evolutionary conservation, known and predicted variant consequences, and personal and family cancer history.

Inherited Mutations in Women With Ovarian Carcinoma.

Importance: Germline mutations in BRCA1 and BRCA2 are relatively common in women with ovarian, fallopian tube, and peritoneal carcinoma (OC) causing a greatly increased lifetime risk of these cancers, but the frequency and relevance of inherited mutations in other genes is less well characterized.

Objective: To determine the frequency and importance of germline mutations in cancer-associated genes in OC.

Design, Setting, And Participants: A study population of 1915 woman with OC and available germline DNA were identified from the University of Washington (UW) gynecologic tissue bank (n = 570) and from Gynecologic Oncology Group (GOG) phase III clinical trials 218 (n = 788) and 262 (n = 557).

Genetic characterization of early onset ovarian carcinoma.

Objective: Ovarian carcinoma (OC) is rare in young women and the fraction of early onset OC attributable to inherited mutations in known OC genes is uncertain. We sought to characterize the fraction of OC that is heritable in women diagnosed with ovarian, fallopian tube, or peritoneal carcinoma at forty years of age or younger.

Methods: We sequenced germline DNA from forty-seven women diagnosed with OC at age 40 or younger ascertained through a gynecologic oncology tissue bank or referred from outside providers using BROCA, a targeted capture and massively parallel sequencing platform that can detect all mutation classes.