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Genetic counseling (GC) following abnormal Down syndrome (DS) screening tests aims to ensure learning of complex medical concepts and discussion of counselees' personal desires. Pre‐GC use of electronic learning tools (e‐learning tools) can facilitate GC sessions by allowing more time for dialogue rather than learning medical and genetic concepts, enabling greater focus on the counselee's decisional, psychological, and personal needs. Few studies have investigated such tools for DS screening tests and those who have focused on screening uptake rather than abnormal results and implications. This study evaluated prenatal GC outcomes following implementation of an e‐learning tool utilizing an educational animated movie for couples of varied ethnic backgrounds in northern Israel, with abnormal DS screening tests. E‐learning tool impact was assessed as knowledge level, informed choices, satisfaction with the intervention and GC process, the state of anxiety and duration of the GC meeting. The 321 study participants were randomized to three groups: animation movie, booklet, and control. All participants had been asked to complete pre‐ and post‐counseling questionnaires. Outcome scores were compared between the research groups. Results showed increased knowledge level in general among participants in the animation group; among minority participants, the highest knowledge level was in the animation group. Anxiety levels and informed choices were not statistically different among the groups. However, watching the animation, Jewish ethnicity, good level of genetic literacy, and academic degree were significant predictors of informed choice, and those who watched the animation were three times more likely to make an informed choice than the control group. Our findings suggest that this e‐learning tool is efficient and acceptable for the general population. Special attention is needed for minorities with lower genetic literacy and education. [ABSTRACT FROM AUTHOR]

Neurofibromatosis 1 (NF1) is caused by germline mutations in the NF1 gene and manifests as proliferation of various tissues, including plexiform neurofibromas. The plexiform neurofibroma phenotype varies from indolent to locally aggressive, suggesting contributions of other modifiers in addition to somatic loss of NF1. In this study, we investigated a life‐threatening plexiform neurofibroma in a 9‐month‐old female infant with NF1. Germline mutations in two RASopathy‐associated genes were identified using whole‐exome sequencing—a de novo pathogenic variant in the NF1 gene, and a known pathogenic variant in the LZTR1 gene. Somatic analysis of the plexiform neurofibroma revealed NF1 loss of heterozygosity and a variant in GNAZ, a gene encoding a G protein‐coupled receptor. Cells expressing mutant GNAZ exhibited increased ERK 1/2 activation compared to those expressing wild‐type GNAZ. Taken together, we suggest the variants in NF1, LZRT1 and GNAZ act synergistically in our patient, leading to MAPK pathway activation and contributing to the severity of the patient's plexiform neurofibromatosis. After treatment with the MEK inhibitor, trametinib, a prominent clinical improvement was observed in this patient. This case study contributes to the knowledge of germline and somatic non‐NF1 variants affecting the NF1 clinical phenotype and supports use of personalized, targeted therapy. [ABSTRACT FROM AUTHOR]

Acral peeling skin syndrome (APSS) is a heterogenous group of genodermatoses, manifested by peeling of palmo‐plantar skin and occasionally associated with erythema and epidermal thickening. A subset of APSS is caused by mutations in protease inhibitor encoding genes, resulting in unopposed protease activity and desmosomal degradation and/or mis‐localization, leading to enhanced epidermal desquamation. We investigated two Arab‐Muslim siblings with mild keratoderma and prominent APSS since infancy. Genetic analysis disclosed a homozygous mutation in SERPINB7, c.796C > T, which is the founder mutation in Nagashima type palmo‐plantar keratosis (NPPK). Although not previously formally reported, APSS was found in other patients with NPPK. We hypothesized that loss of SERPINB7 function might contribute to the peeling phenotype through impairment of keratinocyte adhesion, similar to other protease inhibitor mutations that cause APSS. Mis‐localization of desmosomal components was observed in a patient plantar biopsy compared with a biopsy from an age‐ and gender‐matched healthy control. Silencing of SERPINB7 in normal human epidermal keratinocytes led to increased cell sheet fragmentation upon mechanical stress. Immunostaining showed reduced expression of desmoglein 1 and desmocollin 1. This study shows that in addition to stratum corneum perturbation, loss of SERPINB7 disrupts desmosomal components, which could lead to desquamation, manifested by skin peeling. [ABSTRACT FROM AUTHOR]

As a result of the preference for consanguineous/endogamous marriages, the Israeli Arab population is composed of isolated communities with relatively frequent autosomal recessive (AR) conditions in each community. Clinical diagnosis of affected individuals has uncovered the pathogenic variants throughout the years. We investigated the diversity of pathogenic AR variants in a single village in northern Israel by exome analysis of 50 random, healthy adults descendants of the founders. Only likely pathogenic and pathogenic variants in known AR genes were selected. In this study 48 AR variants were found, of which 12 had been previously diagnosed in patients from this village, and for 11 with a frequency compatible with the frequency already known. Among the other 36 variants, 12 had been previously diagnosed in affected individuals in other Arab communities in Israel and 24 variants had not been previously characterized in this population. Of the 35 variants associated with conditions of moderate–severe medical consequences, only eight were known previously in this village. These findings emphasize the importance to better delineate the conditions at risk in a defined community, in particular for the development of preventive measures such as screening tests for reproductive couples, and for genetic counseling. [ABSTRACT FROM AUTHOR]