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Background Breast cancer (BC) disparities may widen with genomic advances. We compared non-Hispanic white (NHW), Black, and Hispanic BC survivors for: 1) cancer risk management practices (CRM) among BRCA carriers; and 2) provider discussion and receipt of genetic testing. Methods A population-based sample of NHW, Black, and Hispanic women diagnosed with invasive BC ≤ age 50 in 2009–2012 were recruited through the state cancer registry. Using multiple logistic regression we compared CRM in BRCA carriers and association of demographic and clinical variables with provider discussion and receipt of testing. Results Of the 1622 participants, 36.1% (159/440) Blacks, 64.5% (579/897) NHW, 49.6% (58/117) Spanish-speaking Hispanics, and 69.0% (116/168) English-speaking Hispanics had BRCA testing, of whom 90 had a pathogenic BRCA mutation. Among BRCA carriers, RRM and RRSO rates were significantly lower among Blacks compared to Hispanics and NHW after controlling clinical and demographic variables (p=0.025 and 0.008, respectively). Compared to NHW, discussion of genetic testing with a provider was 16 times less likely among Blacks (p<0.0001) and nearly two times less likely among Spanish-speaking Hispanics (p=0.04) after controlling clinical and sociodemographic factors. Conclusions Our results suggest lower rates of RRSO among Black compared to Hispanic and NHW BRCA carriers, which is concerning as benefits from genetic testing arise from CRM options. Furthermore, lower BRCA testing rates among Blacks may partially be due to lower likelihood of provider discussion. Future studies are needed to improve cancer risk identification and management practices across all populations to prevent the widening of disparities.

Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl À /H þ exchanger, CLCN7 (ClC-7), encoded by CLCN7. The role of ClC-7 in maintaining lysosomal pH has been controversial. In this paper, we performed clinical and genetic evaluations of two children of different ethnicities. Both children had delayed myelination and development, organomegaly, and hypopigmentation, but neither had osteopetrosis. Whole-exome and-genome sequencing revealed a de novo c.2144A>G variant in CLCN7 in both affected children. This p.Tyr715Cys variant, located in the C-terminal domain of ClC-7, resulted in increased outward currents when it was heterologously expressed in Xenopus oocytes. Fibroblasts from probands displayed a lysosomal pH approximately 0.2 units lower than that of control cells, and treatment with chloroquine normalized the pH. Primary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys CLCN7 in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in Clcn7 variant exhibited hypopigmentation, hepatomegaly resulting from abnormal storage, and enlarged vacuoles in cultured fibroblasts. Our results show that p.Tyr715Cys is a gain-of-function CLCN7 variant associated with developmental delay, organomegaly, and hypopigmentation resulting from lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles. Our data supports the hypothesis that the ClC-7 antiporter plays a critical role in maintaining lysosomal pH.

Purpose Concerns about the potential for genomic advances to increase health disparities have been raised. Thus it is important to assess referral and uptake of genetic counseling (GC) and testing in minority populations at high risk for hereditary breast and ovarian cancer (HBOC). Methods Black women diagnosed with invasive breast cancer ≤ age 50 in 2009-2012 were recruited through the Florida State Cancer Registry 6-18 months following diagnosis and completed a baseline questionnaire. Summary statistics, Chi-square tests, and path modeling were conducted to examine which demographic and clinical variables were associated with referral and access to genetic services. Results Of the 440 participants, all met national criteria for GC yet only 224 (51%) were referred for or received GC and/or HBOC testing. Variables most strongly associated with healthcare provider referral for GC included having a college education (OR=2.1), diagnosis at or below age 45 (OR=2.0), and triple negative tumor receptor status (OR=1.7). The strongest association with receipt of GC and/or HBOC testing was healthcare provider referral (OR=7.9), followed by private health insurance at diagnosis (OR=2.8), and household income greater than $35,000 in the year prior to diagnosis (OR=2.0). Conclusions Study findings suggest efforts are needed to improve genetic services access among a population-based sample of high-risk Black women. These results indicate that socioeconomic factors and physician referral patterns contribute to disparities in access to genetic services within this underserved minority population.

Interferon regulatory factor 2 binding protein-like (IRF2BPL) encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals who carry damaging heterozygous variants in IRF2BPL and are affected with neurological symptoms. Five individuals who carry IRF2BPL nonsense variants resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The IRF2BPL bioinformatics signature based on population genomics is consistent with a gene that is intolerant to variation. We show that the fruit-fly IRF2BPL ortholog, called pits (protein interacting with Ttk69 and Sin3A), is broadly detected, including in the nervous system. Complete loss of pits is lethal early in development, whereas partial knockdown with RNA interference in neurons leads to neurodegeneration, revealing a requirement for this gene in proper neuronal function and maintenance. The identified IRF2BPL nonsense variants behave as severe loss-of-function alleles in this model organism, and ectopic expression of the missense variants leads to a range of phenotypes. Taken together, our results show that IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.

PURPOSE Black women are disproportionately affected with triple negative breast cancer and have relatively poor survival. It is not known to what extent differences in clinical presentation of breast cancer in Non-Hispanic White (NHW) women and Black women can be accounted for by the presence of mutations in the BRCA1 and BRCA2 (BRCA) genes. We sought to evaluate the frequency of BRCA pathogenic variants in a population-based sample of young Black women with breast cancer. PATIENTS AND METHODS Black women diagnosed with invasive breast cancer at or before age 50 from 2009 to 2012 were recruited to the study through the Florida Cancer Registry. Participants underwent genetic counseling, completed a study questionnaire and consented to release of their medical records. Saliva specimens were collected for BRCA sequencing and large rearrangement testing through MLPA. RESULTS A DNA sample was evaluated for 396 women of whom 49 (12.4%) had a mutation in BRCA1 or BRCA2. Eight recurrent mutations accounted for 49% of all pathogenic variants. CONCLUSIONS The prevalence of BRCA mutations among our Florida-based sample of young Black women with breast cancer exceeds that previously reported for NHW women. It is appropriate to recommend BRCA testing in all young Black women with invasive breast cancer.

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Patient now 19 years old has intellectual disability, developmental delay, absent speech, seizures, hypotonia, severe motor disability (non-ambulatory), short stature, relative macrocephaly. Patient uses gastric tube for feeding and has gastroesophageal reflux. Facial dysmorphisms include short palpebral fissures, large incisors, full eyebrows. Fingers are short and trident-shaped.Brain MRI revealed progressive cerebral and cerebellar volume loss, hypodensity in the left basal ganglia, unchanged and consistent with a lacune infarct (remote). There is a less conspicuous area of hypodensity on the contralateral side. There are hypodense white matter changes along the periventricular white matter and bilateral centrum semiovale.