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As multigene panel testing is becoming routine in clinical care, there are recommendations at national and international level, as to which genes should be analyzed in the context of a hereditary breast and ovarian cancer (HBOC). However, the individual composition of gene panels offered by testing laboratories vary, resulting in a different variant diagnostic rate. Therefore, we performed a retrospective NGS dataset analysis of suspected HBOC patients who had been tested at different German diagnostic laboratories that are part of the NASGE network. We collected 29,317 HBOC datasets and compared the diagnostic yield applying the most common panel recommendations and an internal HBOC gene panel. Additionally, we analyzed the data concerning other potential tumor risk syndromes (TRS) not caused by pathogenic variants in the core panel genes. At least one pathogenic variant causative for an autosomal-dominant TRS was identified in 4235 datasets, resulting in an overall diagnostic yield of 14.4 %. The diagnostic yield of pathogenic variants varied depending on the applied HBOC panel (between 5 and 26 genes) from 9.0 % to 13.8 % with the internal HBOC panel having a yield of 12.7 %. Notably, in about 1 % of cases, a pathogenic variant outside the established HBOC core genes was identified, indicating the presence of other TRS. These results are consistent with previous observations that a significant proportion of patients with HBOC predisposition were not detected by the guideline-based gene panels and suggest that expanded diagnostics compared to currently recommended multigene panels may identify additional patients at high risk for developing cancer., Competing Interests: Declaration of competing interest All the authors declare no support from any organization for the submitted work., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pathogenic variants in the leucine zipper-like transcriptional regulator 1 gene ( LZTR1 ) have been identified in schwannomatosis and Noonan syndrome. Here, we expand the phenotype spectrum of LZTR1 variants. We identified four loss-of-function heterozygous LZTR1 variants in five children with multiple café au lait macules and one adult with multiple café au lait macules and axillar freckling, by applying gene panel analysis in four families. The three LZTR1 variants, namely, c.184del/p.Glu62Ser fs *39, c.1927C < T/p.Gln643*, and c.857&#95;858delinsT/p.Gly286Val fs *65, were novel, whereas the variant c.1018C > T/ p.Arg340* had been previously reported in a patient with schwannomatosis. Similar to what is known from other LZTR1 -associated conditions, penetrance of the skin manifestations was reduced in two carriers of the familial variants. Our study expands the LZTR1 phenotype to the presence of isolated café au lait macules with or without freckling. Thus, variants in the LZTR1 gene should be considered in patients with multiple café au lait macules., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Horn, Neuhann, Hennig, Abad-Perez, Prott, Cardellini, Potratz, Leubner, Eichhorn, Merkel, Abicht and Kaindl.)

Timely identification of fetal conditions enables comprehensive evaluation, counseling, postnatal planning, and prenatal treatments. This study assessed the existing evidence on how social determinants of health (SDOH) influence diagnosis timing of fetal conditions appropriate for care in fetal care centers (FCCs). Eligible studies were conducted in the U.S. and published in English after 1999. We employed the Healthy People 2020 SDOH framework to categorize and analyze data from 16 studies, where 86% focused solely on congenital heart disease (CHD). Studies primarily focused on individual-level SDOH, with only 36% addressing structural-level factors. A total of 31 distinct indicators of SDOH were identified, with 68% being unique to individual studies. Indicators often varied in definition and specificity. Three studies covered all five SDOH categories in the Healthy People 2020 Framework. Studies revealed varying and often conflicting associations with SDOH indicators, with race and ethnicity being the most explored (100%), followed by socioeconomic status (69%), maternal age (57%), residence (43%), and structural factors (29%). Our findings highlight the need for more comprehensive research, including conditions beyond CHD, and the establishment of consensus on indicators of SDOH. Such efforts are necessary to gain a deeper understanding of the underlying factors driving disparities in fetal diagnosis and treatment.

Background: Epilepsy is one of the most common and disabling neurological disorders. It is highly prevalent in children with neurodevelopmental delay and syndromic diseases. However, epilepsy can also be the only disease-determining symptom. The exact molecular diagnosis is essential to determine prognosis, comorbidity, and probability of recurrence, and to inform therapeutic decisions., Methods and Materials: Here, we describe a prospective cohort study of patients with epilepsy evaluated in seven diagnostic outpatient centers in Germany. Over a period of 2 months, 07/2022 through 08/2022, 304 patients (317 returned result) with seizure-related human phenotype ontology (HPO) were analyzed. Evaluated data included molecular results, phenotype (syndromic and non-syndromic), and sequencing methods., Results: Single exome sequencing (SE) was applied in half of all patients, followed by panel (P) testing (36%) and trio exome sequencing (TE) (14%). Overall, a pathogenic variant (PV) (ACMG cl. 4/5) was identified in 22%; furthermore, a significant number of patients (12%) carried a reported clinically meaningful variant of unknown significance (VUS). The average diagnostic yield in patients ≤ 12 y was higher compared to patients >12 y cf. Figure 2B vs. Figure 3B . This effect was more pronounced in cases, where TE was applied in patients ≤ 12 vs. >12 y [PV (PV + VUS): patients ≤ 12 y: 35% (47%), patients > 12 y: 20% (40%)]. The highest diagnostic yield was achieved by TE in syndromic patients within the age group ≤ 12 y (ACMG classes 4/5 40%). In addition, TE vs. SE had a tendency to result in less VUS in patients ≤ 12 y [SE: 19% (22/117) VUS; TE: 17% (6/36) VUS] but not in patients >12 y [SE: 19% (8/42) VUS; TE: 20% (2/10) VUS]. Finally, diagnostic findings in patients with syndromic vs. non-syndromic symptoms revealed a significant overlap of frequent causes of monogenic epilepsies, including SCN1A, CACNA1A , and SETD1B , confirming the heterogeneity of the associated conditions., Conclusion: In patients with seizures-regardless of the detailed phenotype-a monogenic cause can be frequently identified, often implying a possible change in therapeutic action (36.7% (37/109) of PV/VUS variants); this justifies early and broad application of genetic testing. Our data suggest that the diagnostic yield is highest in exome or trio-exome-based testing, resulting in a molecular diagnosis within 3 weeks, with profound implications for therapeutic strategies and for counseling families and patients regarding prognosis and recurrence risk., Competing Interests: MW, CG, AA, and TN were employed by MGZ Medizinisch Genetisches Zentrum. SW and SKl were employed by Gemeinschaftspraxis für Humangenetik and Genetische Labore Hamburg. BE and PL were employed by MVZ Mitteldeutscher Praxisverbund Humangenetik GmbH. LH, MK, and ML were employed by MVZ Genetikum GmbH. MD, JJ, and BS were employed by Zentrum für Humangenetik. KH was employed by Zentrum für Humangenetik und Laboratoriumsdiagnostik (MVZ). RG, SKn, and AT were employed by Amedes Genetics., (Copyright © 2023 Witzel, Gebhard, Wenzel, Kleier, Eichhorn, Lorenz, Heyden, Kuhn, Luedeke, Döcker, Jüngling, Schulte, Hörtnagel, Glaubitz, Knippenberger, Teubert, Abicht and Neuhann.)

With the rapid growth of specialized fetal care centers (FCCs) across the United States, a new area of nursing practice has emerged. Fetal care nurses provide care in FCCs to pregnant persons experiencing complex fetal conditions. This article describes the unique practice of fetal care nurses necessitated by the complexity of perinatal care and the provision of maternal-fetal surgery in FCCs. The Fetal Therapy Nurse Network has played a significant role in the evolution of this nursing practice and will serve as a platform for the generation of core competencies and the development of a potential specialty certification for fetal care nurses., (Copyright © 2023 AWHONN. Published by Elsevier Inc. All rights reserved.)

Background: A diet high in parent's own milk (parental milk) is a lifesaving intervention for critically ill infants. Lactating parents whose infants are born with birth defects that require surgical repair (surgical infants) shortly after birth often struggle to initiate and maintain a milk supply that meets their infant's nutritional needs. Antenatal milk expression has been identified as a safe, feasible, and potentially effective strategy that promotes parents' direct chest/breastfeeding or milk expression (lactation) confidence and helps parents attain their lactation goals. Two cases are presented to illustrate the potential for using antenatal milk expression as a lactation support intervention for parents of surgical infants., Case Presentation: Cases were drawn from a pilot study exploring the feasibility of implementing antenatal milk expression among pregnant parents of surgical infants. Participants were healthy women recruited after 30 weeks of gestation who received a fetal diagnosis of a complex congenital heart defect. Despite variability in clinical course and length of stay, parental milk was provided for the duration of each infant's hospitalization. Participant perceptions of antenatal milk expression varied., Conclusion: More research is needed to evaluate the feasibility, efficacy, and parent or provider perceptions of antenatal milk expression as a lactation support intervention for parents of surgical infants., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)