Triploidy occurs in 1-2% of human conceptions and is caused by an additional haploid chromosome set from either maternal (digynic) or paternal (diandric) origin. There are three possible karyotypes: 69,XXX, 69,XXY, and rarely 69,XYY. The vast majority of triploidies results in early pregnancy failure and survival beyond the second trimester is rare. Affected fetuses typically present with structural anomalies and growth restriction. A 33-year-old woman (G2/P1) presented at 20+2 weeks of gestation with suspected fetal ventriculomegaly and multicystic kidneys. Expert ultrasound examination confirmed ventriculomegaly and additionally detected micro-lissencephaly, unilateral multicystic kidney disease, ventricular septal defect and a small omphalocele. The placenta appeared significantly enlarged with multiple large lacunae and a thickness of > 70mm. Fetal triploidy was suspected mainly due to placental features. Amniocentesis was performed confirming the karyotype 69,XXY. A fetocide was performed on parents' request and subsequently stillbirth was induced, and curettage was conducted. Placental investigation confirmed the presence of partial mole and the patient had follow-up examinations until beta-HCG levels were negative. The evaluation of placental morphology is of diagnostic value during second trimester ultrasound for differentiation of triploidy from other genetic anomalies like Trisomy 13 and 18. Supporting information can be found in the online version of this abstract Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Three Austrian patients presented with severe palmoplantar keratoderma associated with ichthyosis and sensorineural deafness. Exome sequencing revealed biallelic mutations in VPS33B, encoding VPS33B, a Sec1/Munc18 family protein which interacts with Rab11a and Rab25 proteins and is involved in trafficking of the collagen modifying enzyme LH3. Two patients showed the homozygous missense variant p.Gly131Glu, whilst one patient was compound heterozygous for p.Gly131Glu and the splice site mutation c.240-1G>C, previously reported in patients with arthrogryposis renal dysfunction and cholestasis syndrome. The pathogenicity of variant p.Gly131Glu was demonstrated by assessing the interactions of the mutant VPS33B construct and its ability to traffic LH3. Compared with wild-type, p.Gly131Glu mutant VPS33B had reduced coimmunoprecipitation and colocalization with Rab11a and Rab25 and did not rescue LH3 trafficking. Confirming the cell-based experiments, we found deficient LH3-specific collagen lysine modifications in urine and skin fibroblasts of the patients. Additionally, epidermal ultrastructure of the p.Gly131Glu patients mirrored defects in tamoxifen-inducible VPS33B deficient Vps33bfl/fl–ERT2 mice. Both patients and murine models revealed an impaired basement membrane zone and epidermal barrier structure with less prominent hemidesmosomes, a reduced number of anchoring fibrils, insufficiently fixed collagen fibers to the fibrils and aberrant secretion of lamellar bodies. Our results show that p.Gly131Glu mutant VPS33B causes Autosomal Recessive Keratoderma-Ichthyosis-Deafness (ARKID) syndrome.

Das Stüve-Wiedemann-Syndrom ist eine sehr seltene kongenitale Skelettdysplasie mit Minderwuchs, angeborener Verbiegung der langen Knochen, Deformitäten der Gelenke und Kamptodaktylie. Die Krankheit geht mit schweren Komplikationen wie respiratorischer Insuffizienz, Schluck- bzw. Ernährungsschwierigkeiten und rezidivierenden Fieberschüben, einher. Ursache sind Null-Mutationen im leukemia inhibitory factor receptor (LIFR) Gen für den Rezeptor des Leukämie-Hemmfaktors in der Chromosomenregion 5p13.

Linear nevus sebaceous syndrome (LNSS) or Schimmelpenning Syndrome is a rare disorder characterized by multiple sebaceous nevi associated with widespread pathologies of different organ systems including central nervous system, eyes and skeleton. We report the third case of discordant occurrence of LNSS in monochorionic twins. At 19 + 3 weeks of gestation a 35-year old woman was admitted due to polyhydramnios in a monochorionic twin pregnancy. Ultrasound examination revealed a twin-to-twin transfusion syndrome (Quintero stage 3) defined by severe oligohydramnios in the donor twin and polyhydramnios along with abnormal Doppler flow in the recipient twin. The next day fetoscopic laser coagulation of placental anastomoses was successfully performed. At 31 + 0 weeks preterm premature rupture of the membranes occurred and the recipient twin was born spontaneously at 31 + 3 weeks while the donor was delivered 15 minutes later by Caesarean section due to non-reassuring fetal heart rate. After delivery the donor twin showed several linear sebaceous nevi following Blaschko's lines basically at the head and additionally a defective right eyelid with mucosal duplication and epibulbar lipodermoids, which encased the eyeball and required multiple corrective surgeries. Cerebral magnetic resonance imaging revealed regional substance loss of the right cerebral hemisphere, increasing over time. Even there were no seizures within the first year of life, therapy dependent epileptic disorder developed since then. Renal ultrasounds displayed progressive cystic dysplasia in the left kidney, while the co-twin and parents had normal kidneys. Heterozygotic KRAS c.35G > A-mutation was detected confirming the diagnosis of LNSS syndrome. In otherwise genetically identic twins discordant occurrence of LNSS reassures the theory of postzygotic somatic mutation. Cystic renal dysplasia may be one newly observed pathologic organ manifestation in this syndrome.

Introduction: Monochorionic twins are by definition monozygotic. Schimmelpenning-Feuerstein-Mims syndrome (SFM) is a rare disorder characterized by sebaceous nevi associated with abnormalities of the central nervous system, eyes and skeleton. We report the third case of discordant occurrence of SFM in monochorionic twins.

Introduction: Despite a growing number of syndromes and inborn errors of metabolism associated with impaired development, the aetiology of mental retardation remains unclear in a considerable proportion of cases. Deletion syndromes help to identify new genes associated with mental retardation.

Prader–Willi syndrome (PWS) is a complex genetic syndrome involving imprinted genes on chromosome 15. It is usually sporadic, and very few affected siblings have been described. Here, we report the clinical and molecular findings in two families with a microdeletion affecting the chromosome 15 imprinting centre (IC). Carrier males have a 50% risk of having children with an imprinting defect leading to PWS, and in one of the two families, a father has two affected daughters. In the other family, diagnostic testing was confounded by the presence of a neutral microdeletion close to the IC. The silent transmission of PWS IC deletions through the female germline and the occurrence of neutral microdeletions close to the IC can impose considerable problems on diagnostic testing and genetic counselling in affected families.

Kuang et al. (1998) isolated 29 gene fragments that were coexpressed with ER (estrogen receptor) in breast carcinoma cell lines using the technique of suppression subtractive hybridization. One of these gene fragments, DEME-2 (GenBank EST accession AA506763), could be identified as a part of the human Anterior Gradient-2 (AGR2) gene, the human homologue of the Xenopus laevis cement gland gene Xenopus Anterior Gradient-2 (XAG-2, GenBank accession AF025474; Aberger et al., 1998; Thompson et al., 1998). The 1,702 nucleotide cDNA sequence of AGR2 was obtained by combination of sequence data derived from three individual mRNA transcripts differing in their 3)-untranslated regions (GenBank accession No. AF007791 for AGR2/C, AF038452 for AGR2/I and AF038451 for AGR2/R; Thompson et al., 1998). Detailed chromosome mapping of this gene will be important to explore its genomic organization, its regulation and therefore its function in hormone-responsive breast carcinomas. Materials and methods

In the search for genetic causes of mental retardation, we have studied a five-generation family that includes 10 individuals in generations IV and V who are affected with mild-to-moderate mental retardation and mild, nonspecific dysmorphic features. The disease is inherited in a seemingly autosomal dominant fashion with reduced penetrance. The pedigree is unusual because of (1) its size and (2) the fact that individuals with the disease appear only in the last two generations, which is suggestive of anticipation. Standard clinical and laboratory screening protocols and extended cytogenetic analysis, including the use of high-resolution karyotyping and multiplex FISH (M-FISH), could not reveal the cause of the mental retardation. Therefore, a whole-genome scan was performed, by linkage analysis, with microsatellite markers. The phenotype was linked to chromosome 16p13.3, and, unexpectedly, a deletion of a part of 16pter was demonstrated in patients, similar to the deletion observed in patients with ATR-16 syndrome. Subsequent FISH analysis demonstrated that patients inherited a duplication of terminal 3q in addition to the deletion of 16p. FISH analysis of obligate carriers revealed that a balanced translocation between the terminal parts of 16p and 3q segregated in this family. This case reinforces the role of cryptic (cytogenetically invisible) subtelomeric translocations in mental retardation, which is estimated by others to be implicated in 5%-10% of cases.

Suzuki et al. (1996) recently isolated mouse and human cDNAs encoding the novel neuron-specific protein STAC. The protein has two functional domains, a cysteine-rich domain and an SH3 domain. Although the exact function of STAC is unknown so far, it is, because of it’s predominant expression in brain tissues, likely involved in a signal transduction pathway in neurons. Kawai et al. (1998) determined the chromosome location of the STAC gene in mouse to chromosome 9 and by radiation hybrid mapping in human to 3p24→p22. In another study we investigated a de novo complex chromosome rearrangement involving two breakpoints on 3p in a patient with spastic paraplegia (Emberger et al., in preparation). Since STAC is thought to contribute to several hereditary neurological diseases, we wanted to determine the location of this gene in order to evaluate its potential as a candidate gene for spastic paraplegia.

We report the results of a prospective study using quantitative fluorescent polymerase chain reaction (QF-PCR) and small tandem repeat markers (STR) for the rapid prenatal detection of aneuploidies in a group of pregnant women at increased risk of having fetuses with numerical chromosome disorders. Amniotic fluid samples (n = 52) were collected from mothers undergoing prenatal invasive testing for fetal abnormalities on ultrasonographic examination or abnormal maternal serum aneuploidy screening results. All samples were tested by cytogenetic analysis, but rapid diagnoses of aneuploidies were offered and performed using QF-PCR analysis with several STRs specific for chromosomes 21, 18, 13 and X. All cases with numerical chromosome aberrations involving chromosomes 21, 18 and 13 (n = 8) were correctly diagnosed. Three gonosomal aneuplodies (one 47,XXY and two 45,X) were not detected because they were uninformative for the X markers. Another sample with a deletion (46,XX,7q-), that the present assay was not designed to detect, was not identified. One sample was heavily contaminated with maternal blood and the results of the QF-PCR assays were uninformative. The remaining samples from normal fetuses provided QF-PCR patterns disomic for chromosomes 21, 18, 13 and X. Our study demonstrates that QF-PCR is a rapid method for the detection of common numerical chromosome disorders and it may play an important role in prenatal diagnosis for women at high risk for fetal aneuploidy.