Zentrum für Pränataldiagnostik

Unter Labor 4.0 wird in Anlehnung an die Industrie 4.0 ein komplett digitalisiertes und vernetztes Labor verstanden: Aufträge werden elektronisch ans Labor gesandt, anhand der eintreffenden Probe wird der Auftrag aktiviert, die Proben werden automatisch aliquotiert, auf die entsprechenden Analyzer verteilt, die Tests werden durchgeführt, und die Ergebnisse werden ins Laborinformationssystem zurückgespielt. Es erfolgt die (Auto-)Validation der Messergebnisse, ein elektronischer Befund wird erstellt und auch elektronisch an die Arztpraxis oder die einsendende Abteilung übermittelt. Die Grundlage für eine effiziente Kommunikation zwischen verschiedenen Software- und Hardwaresystemen sind so genannte Schnittstellen. Doch was ist eine Schnittstelle überhaupt? Was sollte man beachten?

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. 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. 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. 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.

SMPD4 loss is a rare neurodevelopmental disorder that leads to severe mental and physical disability and early death in infancy. Most cases of this genetic condition have been diagnosed postnatally. This article focuses on the prenatal findings of affected fetuses. The phenotypes can include growth restriction, arthrogryposis (clenched hands, foot deformity), as well as cerebral abnormalities (simplified gyral pattern/lissencephaly, cerebellar hypoplasia, corpus callosum deformity). SMPD4 loss is detectable via exome sequencing. Here, two fetuses displayed a homozygotic pathogen variant in the SMPD4 gene, encoding for the enzyme Sphingomyelinase-4. Both parents were heterozygous carriers of the pathogenic variant. On detection of the above mentioned signs exome sequencing is indicated, with focus on the SMPD4 gene.

Ultrasound has become an essential diagnostic tool in gynecology, and every practicing gynecologist must be able to differentiate normal from pathologic findings, such as benign or malignant pelvic masses, adnexal torsion, pelvic inflammation disease, endometriosis, ectopic pregnancies, and congenital uterine malformations at least on a basic level. A standardized approach to the correct settings of the ultrasound system, the indications for gynecologic ultrasound investigations, and the sonographic appearance of normal anatomy and common pathologic findings in the standard planes are important prerequisites for safe and confident clinical management of gynecologic patients. Based on current publications and different national and international guidelines, updated DEGUM, ÖGUM, and SGUM recommendations for the performance of basic gynecologic ultrasound examinations were established.

ABSTRACTPURPOSEBi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus.METHODSThrough an international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms.RESULTSA cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections and central/nocturnal hypopnea as core manifestations. A review of brain MRI scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing β-propeller repeats. Despite constituting nearly half of disease associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1,221 in the general and 1/155 in the Jewish Ashkenazi populations.CONCLUSIONBased on clinical, neuroimaging and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2-associated disorder. This sets the stage for future prospective natural history studies.CONFLICTS OF INTERESTAll authors involved in the study declare no conflicts of interest relevant to this study.

Die sonografische Beurteilung der inneren Genitalorgane ist eine der Basisuntersuchungen im Rahmen der Infertilitatsdiagnostik. Neben der Feststellung des individuellen Hormonstatus ist eine detaillierte B-Bilddiagnostik zum Ausschluss von Uterusanomalien, Adnextumoren und anderen Auffalligkeiten des kleinen Beckens obligat. Daruber hinaus bietet die Beurteilung der Endometriumstarke und -textur, die Follikulometrie und die Dopplersonografie der uterinen und ovariellen Perfusion die Moglichkeit dar, anatomische Veranderungen der uterinen Feinstruktur erkennen bzw. Aussagen zur ovariellen Reserve treffen zu konnen – noch vor der Veranlassung weiterfuhrender interventioneller (Hysterosalpingographie) und invasiver diagnostischer Masnahmen (Laparoskopie mit Chromopertubation).