Hansjörg Plendl

Evaluating the performance of the breast cancer genetic risk models BOADICEA, IBIS, BRCAPRO and Claus for predicting BRCA1/2 mutation carrier probabilities: a study based on 7352 families from the German Hereditary Breast and Ovarian Cancer Consortium

Background Risk prediction models are widely used in clinical genetic counselling. Despite their frequent use, the genetic risk models BOADICEA, BRCAPRO, IBIS and extended Claus model (eCLAUS), used to estimate BRCA1/2 mutation carrier probabilities, have never been comparatively evaluated in a large sample from central Europe. Additionally, a novel version of BOADICEA that incorporates tumour pathology information has not yet been validated. Patients and methods Using data from 7352 German families we estimated BRCA1/2 carrier probabilities under each model and compared their discrimination and calibration. The incremental value of using pathology information in BOADICEA was assessed in a subsample of 4928 pedigrees with available data on breast tumour molecular markers oestrogen receptor, progesterone receptor and human epidermal growth factor 2. Results BRCAPRO (area under receiver operating characteristic curve (AUC)=0.80 (95% CI 0.78 to 0.81)) and BOADICEA (AUC=0.79 (0.78–0.80)), had significantly higher diagnostic accuracy than IBIS and eCLAUS (p<0.001). The AUC increased when pathology information was used in BOADICEA: AUC=0.81 (95% CI 0.80 to 0.83, p<0.001). At carrier thresholds of 10% and 15%, the net reclassification index was +3.9% and +5.4%, respectively, when pathology was included in the model. Overall, calibration was best for BOADICEA and worst for eCLAUS. With eCLAUS, twice as many mutation carriers were predicted than observed. Conclusions Our results support the use of BRCAPRO and BOADICEA for decision making regarding genetic testing for BRCA1/2 mutations. However, model calibration has to be improved for this population. eCLAUS should not be used for estimating mutation carrier probabilities in clinical settings. Whenever possible, breast tumour molecular marker information should be taken into account.

Lp(a) Lipoprotein and Plasminogen Activity in Patients with Different Etiology of Ischemic Stroke

Background and Purpose: Lp(a) lipoprotein plays an important part in atherothrombogenesis and is considered an independent risk factor for coronary heart disease. However, its role in cerebrovascular disease remains unclear, in particular because of the heterogeneous nature of strokes. We investigated whether elevated Lp(a) is more frequent in ischemic stroke related to atherothrombosis than in other etiologies of stroke. Because of the close structural homology between Lp(a) and plasminogen, we also studied the role of plasminogen in different stroke subtypes and whether there is a dependency on Lp(a) plasma levels. Methods: Lp(a) levels and plasminogen activity were measured in 253 consecutive patients with acute ischemic stroke and in 63 controls (CS). Subtypes of stroke were established according to the TOAST criteria. Results: Median Lp(a) levels were found to be higher in the total cerebral infarction group and in patients with large artery atherosclerosis (LAA) when compared with CS (20.9 and 22.0 mg/dl, respectively, vs. 16.0 mg/dl; p < 0.05). In addition, elevated Lp(a) levels >30 mg/dl were more frequent among the LAA subgroup than among CS (39.4 vs. 11.1%; p < 0.001). Mean plasminogen activity was lower in the total cerebral infarction group (110.8 vs. 120.3%; p < 0.001) and in patients with cardioembolic stroke (109.8 vs. 120.3%; p < 0.05) when compared with CS. There was no correlation between Lp(a) levels and plasminogen activity. Conclusions: Our results support the hypothesis that elevated Lp(a) is a risk factor for ischemic stroke and especially for strokes caused by LAA. Low plasminogen activity may play a role in the pathogenesis of cerebrovascular disease, especially for the development of cardioembolic stroke.

Revealing a subclinical salt-losing phenotype in heterozygous carriers of the novel S562P mutation in the α subunit of the epithelial sodium channel

Objective  Pseudohypoaldosteronism type I (PHA1) is a rare inborn disease causing severe salt loss. Mutations in the three coding genes of the epithelial sodium channel (ENaC) are responsible for the systemic autosomal recessive form. So far, no phenotype has been reported in heterozygous carriers.

Characterization of two supernumerary marker chromosomes in a patient with signs of Klinefelter syndrome, mild facial anomalies, and severe speech delay*

A boy with signs of Klinefelter syndrome, mild facial dysmorphic features, and severely retarded speech development displayed a female karyotype with mosaicism for two marker chromosomes 48,XX,+mar1,+mar2[68]/47,XX,+mar1[19]/47,XX,+mar2[6]/46,XX[8]. Using chromosomal microdissection, locus‐specific fluorescence in situ hybridization (FISH), and PCR with several Y‐chromosome markers, the larger supernumerary marker chromosome (SMC) was characterized as a ring Y‐chromosome. Detection of the SRY‐region explained the male phenotype. The smaller second marker chromosome contained the pericentromeric region of chromosome 8. We suggest that the co‐occurrence of a partial Y‐chromosome and partial trisomy 8 explain the severe speech delay and the facial dysmorphic features.

Maternal uniparental disomy 15 in a fetus resulting from a balanced familial translocation t(2;15)(p11;q11.2).

Prader-Willi syndrome (PWS) is caused by loss of function of the paternal region q12 of chromosome 15 containing among others the SNRPN gene. In approximately 70% of PWS patients SNRPN is lost due to deletions. In approximately 28% of cases, the function of the paternal SNRPN allele is lost due to uniparental, maternal disomy of the whole or of parts of chromosome 15 (UPD15mat). One to three percent of cases show imprinting center defects with or without IC mutations, whereas disruption of the SNRPN gene has been observed only in few PWS patients (for review see Horsthemke and Buiting, 2006). The phenotype of PWS is characterized by obesity, muscular hypotonia, mental retardation, short stature, small hands and feet, facial dysmorphism, behavioral problems and hypogonadotropic hypogonadism. During embryonal development, some of these typical features such as facial dysmorphism, hypoplasia of the corpus callosum and hypoplasic genitalia are frequently present, other anomalies such as short femoral length, polyhydramnios and abnormal fetal heart rhythm are rarely seen on ultrasound (L’Hermine et al., 2003). We report here on a fetus of 19th week of gestation with maternal uniparental disomy (UPD) 15 without any obvious internal or external malformations, peculiarities in pregnancy or family history. Solely a balanced translocation t(2;15)(p11;q11.2) indicated a possible risk of a syndrome related to UPD 15. The 36-year-old III gravida (I para) was referred to prenatal testing at 15th week of gestation due to advanced maternal age. The woman had one healthy child. Except for one spontaneous abortion the family history was unremarkable. The pregnancy had been uneventful. Alpha feto protein concentration in the amniotic fluid was within the normal range (0.9 MoM). Chromosome analyses were performed using standard GTGand fluorescent R-banding techniques. Chromosome analysis on cultivated amniocytic fluid

Isoelektrische Fokussierung von Fruchtwasser-AFP zur Diagnose offener Neuralrohrdefekte

AFP von uber 500 Fruchtwasserproben aus der 11. bis 32. SSW wurde mittels isoelektrischer Fokussierung und anschliesendem Immunoblot untersucht. Die praktische Relevanz dieser qualitativen AFP-Bestimmung bei Fruhschwangerschaften wird noch weiter gepruft. Ab der 15. SSW erlaubt unser Verfahren die sichere Unterscheidung normaler Schwangerschaften von solchen mit offenem Neuralrohrdefekt bzw. intrauterinem Fruchttod.