Further evidence that imbalance of WT1 isoforms may be involved in Denys-Drash syndrome

No abstract availabl

Novel associations in disorders of sex development: findings from the I-DSD registry

Context: The focus of care in disorders of sex development (DSD) is often directed to issues related to sex and gender development. In addition, the molecular etiology remains unclear in the majority of cases.<p></p> Objective: To report the range of associated conditions identified in the international DSD (I-DSD) Registry.<p></p> Design, Setting, and Patients: Anonymized data were extracted from the I-DSD Registry for diagnosis, karyotype, sex of rearing, genetic investigations, and associated anomalies. If necessary, clarification was sought from the reporting clinician.<p></p> Results: Of 649 accessible cases, associated conditions occurred in 168 (26%); 103 (61%) cases had one condition, 31 (18%) had two conditions, 20 (12%) had three conditions, and 14 (8%) had four or more conditions. Karyotypes with most frequently reported associations included 45,X with 6 of 8 affected cases (75%), 45,X/46,XY with 19 of 42 cases (45%), 46,XY with 112 of 460 cases (24%), and 46,XX with 27 of 121 cases (22%). In the 112 cases of 46,XY DSD, the commonest conditions included small for gestational age in 26 (23%), cardiac anomalies in 22 (20%), and central nervous system disorders in 22 (20%), whereas in the 27 cases of 46,XX DSD, skeletal and renal anomalies were commonest at 12 (44%) and 8 (30%), respectively. Of 170 cases of suspected androgen insensitivity syndrome, 19 (11%) had reported anomalies and 9 of these had confirmed androgen receptor mutations.<p></p> Conclusions: Over a quarter of the cases in the I-DSD Registry have an additional condition. These associations can direct investigators toward novel genetic etiology and also highlight the need for more holistic care of the affected person.<p></p&gt

Novel associations in disorders of sex development: findings from the I-DSD registry

Context: The focus of care in disorders of sex development (DSD) is often directed to issues related to sex and gender development. In addition, the molecular etiology remains unclear in the majority of cases.<p></p> Objective: To report the range of associated conditions identified in the international DSD (I-DSD) Registry.<p></p> Design, Setting, and Patients: Anonymized data were extracted from the I-DSD Registry for diagnosis, karyotype, sex of rearing, genetic investigations, and associated anomalies. If necessary, clarification was sought from the reporting clinician.<p></p> Results: Of 649 accessible cases, associated conditions occurred in 168 (26%); 103 (61%) cases had one condition, 31 (18%) had two conditions, 20 (12%) had three conditions, and 14 (8%) had four or more conditions. Karyotypes with most frequently reported associations included 45,X with 6 of 8 affected cases (75%), 45,X/46,XY with 19 of 42 cases (45%), 46,XY with 112 of 460 cases (24%), and 46,XX with 27 of 121 cases (22%). In the 112 cases of 46,XY DSD, the commonest conditions included small for gestational age in 26 (23%), cardiac anomalies in 22 (20%), and central nervous system disorders in 22 (20%), whereas in the 27 cases of 46,XX DSD, skeletal and renal anomalies were commonest at 12 (44%) and 8 (30%), respectively. Of 170 cases of suspected androgen insensitivity syndrome, 19 (11%) had reported anomalies and 9 of these had confirmed androgen receptor mutations.<p></p> Conclusions: Over a quarter of the cases in the I-DSD Registry have an additional condition. These associations can direct investigators toward novel genetic etiology and also highlight the need for more holistic care of the affected person.<p></p&gt

Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history

Background: There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. Methods: The study comprised 802 women (median age 40 years, range 19–76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. Results: A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20–29 years compared to 6.9% in the age group 60–69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50–2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years. Conclusions: Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation

MÖGLICHKEITEN UND GRENZEN DER GENDIAGNOSTIK

Forschungsgegenstand der Humangenetik ist die genetisch bedingte Variabilität zwischen den Menschen. Die klinische Genetik als medizinisches Anwendungsgebiet der Humangenetik beschäftigt sich mit den genetischen Grundlagen von Erkrankungen. Erblich bedingte Erkrankungen sind häufiger als meistens angenommen. Ungefähr 5 % aller Neugeborenen weisen genetisch bedingte Erkrankungen oder Fehlbildungen auf. Viele genetisch bedingte Erkrankungen werden allerdings erst im Laufe des Lebens manifest. Unter Berücksichtigung dieser spät manifestierenden Erkrankungen dürften ca. zwei Drittel aller Menschen im Laufe ihres Lebens von einer oder mehreren erblich (mit)bedingten Erkrankungen betroffen sein. Auch wenn die klinische Genetik zu den jüngsten medizinischen Disziplinen gehört, sind Beobachtungen über erbliche Zusammenhänge und Versuche, Konsequenzen daraus abzuleiten, recht alt. Zum Beispiel wird im babylonischen Talmud erwähnt, daß man von der Beschneidung eines Knaben absehen sollte, wenn bei einem Bruder oder Onkel mütterlicherseits schwere Blutungen im Rahmen dieses Eingriffs aufgetreten sind. Hinter dieser „genetischen Beratung“ steckt die Beobachtung, daß Frauen Überträgerinnen der Hämophilie sein können, von der aufgrund des X-chromosomal-rezessiven Erbgangs männliche Personen mehrfach in einer Familie betroffen sein können. Die Erkenntnis formalgenetischer Aspekte beim Menschen nach der Wiederentdeckung der Mendelschen Regeln im letzten Jahrhundert hat erstmals wissenschaftlich begründete Aussagen zur Wahrscheinlichkeit für das Auftreten erblich bedingter Erkrankungen erlaubt. Die Fortschritte der Humangenetik, vor allem der molekularen Humangenetik, machen es zunehmend möglich, aus solchen Wahrscheinlichkeiten Gewißheiten zu machen. Damit werden einerseits Hoffnungen geknüpft, daß Erkrankungen immer sicherer diagnostiziert werden und sich in wachsendem Maße therapeutische Konsequenzen daraus ableiten lassen. Andererseits ruft die Vorstellung, daß immer mehr erbliche Merkmale identifizierbar und voraussehbar werden, bei den meisten Unbehagen hervor. In diesem Zusammenhang sollen Möglichkeiten, Grenzen und einige ethische Aspekte der gegenwärtigen Gendiagnostik diskutiert werden

Summaries

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