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PURPOSE: Increasing usage of multigene panel testing has identified more patients with pathogenic or likely pathogenic (P or LP) variants in low-moderate penetrance genes or variants of uncertain significance (VUS). Our study evaluates the association between genetic test results and contralateral prophylactic mastectomy (CPM) among patients with breast cancer. METHODS: We conducted a retrospective cohort study among women diagnosed with unilateral stage 0-III breast cancer between 2013 and 2020 who underwent genetic testing. We examined whether genetic test results were associated with CPM using multivariable logistic regression models. RESULTS: Among 707 racially or ethnically diverse women, most had benign or likely benign (B or LB) variants, whereas 12.5% had P or LP and 17.9% had VUS. Racial or ethnic minorities were twice as likely to receive VUS. Patients with P or LP variants had higher CPM rates than VUS or B or LB (64.8% v 25.8% v 25.9%), and highest among women with P or LP variants in high-penetrance genes (74.6%). On multivariable analysis, P or LP compared with B or LB variants were significantly associated with CPM (odds ratio = 4.24; 95% CI, 2.48 to 7.26). CONCLUSION: Women with P or LP variants on genetic testing were over four times more likely to undergo CPM than B or LB. Those with VUS had similar CPM rates as B or LB. Our findings suggest appropriate genetic counseling and communication of cancer risk to multiethnic breast cancer survivors.

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.

Phosphatidylinositol Glycan Anchor Biosynthesis class H (PIGH) is an essential player in the glycosylphosphatidylinositol (GPI) synthesis, an anchor for numerous cell membrane‐bound proteins. PIGH deficiency is a newly described and rare disorder associated with developmental delay, seizures and behavioral difficulties. Herein, we report three new unrelated families with two different bi‐allelic PIGH variants, including one new variant p.(Arg163Trp) which seems associated with a more severe phenotype. The common clinical features in all affected individuals are developmental delay/intellectual disability and hypotonia. Variable clinical features include seizures, autism spectrum disorder, apraxia, severe language delay, dysarthria, feeding difficulties, facial dysmorphisms, microcephaly, strabismus, and musculoskeletal anomalies. The two siblings homozygous for the p.(Arg163Trp) variant have severe symptoms including profound psychomotor retardation, intractable seizures, multiple bone fractures, scoliosis, loss of independent ambulation, and delayed myelination on brain MRI. Serum iron levels were significantly elevated in one individual. All tested individuals with PIGH deficiency had normal alkaline phosphatase and CD16, a GPI‐anchored protein (GPI‐AP), was found to be decreased by 60% on granulocytes from one individual. This study expands the PIGH deficiency phenotype range toward the severe end of the spectrum with the identification of a novel pathogenic variant., GPIs are synthetized by the GPI‐GnT, comprising PIGH, on the cytoplasmic membrane of ER from a phosphatidylinositol and a N‐acetylglucosamine. Once flipped to the luminal side of the ER and further synthesized, GPIs are added to proteins to form GPI‐APs. GPI‐APs are transported to the cytoplasmic membrane via the Golgi. Features of individuals with bi‐allelic PIGH variants are presented according to their frequency.

Background: Contralateral prophylactic mastectomy (CPM) is a risk-reducing surgery offered to women with unilateral breast cancer intended to reduce the risk of contralateral breast cancer. The rate of CPM among women with unilateral early-stage breast cancer has risen in the United States over the past two decades, despite limited evidence for a survival benefit in the majority of patients. We evaluated sociodemographic and clinical factors, including receipt and results of BRCA1/2 genetic testing or multigene panel testing, associated with CPM among young women with unilateral early-stage breast cancer. Methods: We conducted a retrospective cohort study of women diagnosed with unilateral stage 0-III breast cancer at age ≤ 50 years between January 2007 and December 2017 at Columbia University Irving Medical Center (CUIMC) in New York, NY. Patients with bilateral breast cancer, male breast cancer, metastatic disease, or missing breast surgery information were excluded from the analysis. Demographics (age, race/ethnicity, marital status, primary health insurance) and clinical information (stage and year of diagnosis, family history of breast cancer) were collected from the electronic health record (EHR) and New York Presbyterian Hospital (NYPH) Tumor Registry. We also determined receipt of genetic testing (yes/no) and results (pathogenic/likely pathogenic [P/LP], variant of uncertain significance [VUS], negative). The primary outcome of interest was receipt of CPM. Multivariable logistic regression models were used to assess the association between demographic and clinical factors, including receipt and results of genetic testing, and CPM. Results: Among the 1207 women who met inclusion criteria, median age was 42.9 years (standard deviation [SD], 5.7 years), and 43% identified as non-Hispanic white, 27% Hispanic, 13% non-Hispanic black, 10% Asian, and 7% other. Nearly half (49.5%, N=597) underwent germline genetic testing for cancer susceptibility genes, and of those tested, 12.6% had P/LP variants (of which 69.3% were in BRCA1/2), 14.2% had VUSs, and 73.2% had negative results. Over one-quarter (27.7%, N = 334) underwent CPM, 29.8% had a unilateral mastectomy and 42.5% had lumpectomy. In multivariable analysis, women with a younger age at diagnosis, more advanced stage disease, and a family history of breast cancer were more likely to undergo CPM. There were no differences in CPM rates by primary health insurance. Asian women were less likely to undergo CPM compared to non-Hispanic white women (odds ratio [OR]=0.56, 95% confidence interval [CI]=0.34-0.95). Compared to women who did not undergo genetic testing, CPM rates were higher among those who had a P/LP variant (OR=5.12, 95% CI=2.94-8.89), those who had a VUS (OR=1.94, 95% CI=1.23-3.36) or negative results (OR=1.51, 95% CI=1.09-2.09). From 2007 to 2017, rates of genetic testing uptake in the study population increased from 17.9% to 67.1%, and CPM rates increased from 15.2% to 30.0%. Conclusions: Among young women with unilateral early-stage breast cancer, CPM rates were relatively high and increased over time. Women with P/LP variants were over 5 times more likely to undergo CPM compared to those who did not undergo genetic testing, however, even those with VUS or negative results were over 50% more likely to undergo CPM. The American Society of Breast Surgeons now recommends genetic testing for hereditary breast cancer among all women diagnosed with breast cancer. As multigene panel testing is increasingly utilized among women with breast cancer, further evaluation of its role in decisions regarding risk-reducing surgery such as CPM is warranted, particularly given the unclear implications of moderate-risk pathogenic variants and VUS results on contralateral breast cancer risk. Citation Format: Julia E McGuinness, Boya Guo, Meghna S Trivedi, Tarsha Jones, Wendy K Chung, Roshni Rao, Elana Levinson, Carrie Koval, Donna Russo, Ilana Chilton. Association between genetic testing for hereditary breast cancer and contralateral prophylactic mastectomy among young women diagnosed with early-stage breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-11.

Objective Growing use of clinical exome sequencing (CES) has led to an increased burden of genomic education. Self-guided educational tools can minimize the educational burden for genetic counselors (GCs). The effectiveness of these tools must be evaluated. Methods Parents of patients offered CES were randomized to watch educational videos before their visit or to receive routine care. Parents and GCs were surveyed about their experiences following the sessions. The responses of the video (n = 102) and no-video (n = 105) groups were compared. Results GCs reported no significant differences between parents in the video and no-video groups on genetics knowledge or CES knowledge. In contrast, parents’ scores on genetics knowledge questions were lower in the video than no-video group (p = 0.007). Most parents reported the videos were informative, and the groups did not differ in satisfaction with GCs or decisions to have CES. Conclusion GCs and parents perceived the videos to be beneficial. However, lower scores on genetics knowledge questions highlight the need for careful development of educational tools. Practice implications Educational tools should be developed and assessed for effectiveness with the input of all stakeholders before widespread implementation. Better measures of the effectiveness of these educational tools are needed.

CDC42BPB encodes MRCKβ (myotonic dystrophy-related Cdc42-binding kinase beta), a serine/threonine protein kinase, and a downstream effector of CDC42, which has recently been associated with Takenouchi-Kosaki syndrome, an autosomal dominant neurodevelopmental disorder. We identified 12 heterozygous predicted deleterious variants in CDC42BPB (9 missense, 2 frameshift, and 1 nonsense) in 14 unrelated individuals (confirmed de novo in 11/14) with neurodevelopmental disorders including developmental delay/intellectual disability, autism, hypotonia, and structural brain abnormalities including cerebellar vermis hypoplasia and agenesis/hypoplasia of the corpus callosum. The frameshift and nonsense variants in CDC42BPB are expected to be gene-disrupting and lead to haploinsufficiency via nonsense-mediated decay. All missense variants are located in highly conserved and functionally important protein domains/regions: 3 are found in the protein kinase domain, 2 are in the citron homology domain, and 4 in a 20-amino acid sequence between 2 coiled-coil regions, 2 of which are recurrent. Future studies will help to delineate the natural history and to elucidate the underlying biological mechanisms of the missense variants leading to the neurodevelopmental and behavioral phenotypes.

Whole-exome sequencing was used to identify the genetic etiology of a rapidly progressing neurological disease present in two of six siblings with early childhood onset of severe progressive spastic paraparesis and learning disabilities. A homozygous mutation (c.2005G>T, p, V669L) was found in VAC14, and the clinical phenotype is consistent with the recently described VAC14-related striatonigral degeneration, childhood-onset syndrome (SNDC) (MIM#617054). However, the phenotype includes a distinct clinical presentation of retinitis pigmentosa (RP), which has not previously been reported in association with VAC14 mutations. Brain magnetic resonance imaging (MRI) revealed abnormal magnetic susceptibility in the globus pallidus, which can be seen in neurodegeneration with brain iron accumulation (NBIA). RP is a group of inherited retinal diseases with phenotypic/genetic heterogeneity, and the pathophysiologic basis of RP is not completely understood but is thought to be due to a primary retinal photoreceptor cell degenerative process. Most cases of RP are seen in isolation (nonsyndromic); this is a report of RP in two siblings with VAC14-associated syndrome, and it is suggested that a connection between RP and VAC14-associated syndrome should be explored in future studies.

Background Myositis Ossificans Cicumscripta is a rare condition characterized by aberrant bone formation in paramuscular soft tissue of the extremities usually associated with trauma or a genetic mutation. Very few cases involve the head or neck and it is rarely found in the pediatric population. Objectives We present a case of a 5-month old with a rapidly growing posterior neck mass suspicious for neoplasia, which was treated with surgical resection and found to be a non-traumatic, non-genetic form of Myositis Ossificans. The workup, treatment, and findings of the patient are outlined and a review of the literature on this disease is discussed. Conclusion Myositis Ossificans is characterized by aberrant bone formation typically occurring after trauma but may be secondary to an underlying genetic abnormality. The case presented in the absence of trauma or an underlying genetic abnormality and is therefore an exceedingly rare instance of the sporadic form that presented spontaneously in the head and neck of a pediatric patient.