Nine out of 19 genes encoding GABAA receptor subunits have been linked to monogenic syndromes characterized by seizures and developmental disorders. Previously, we reported the de novo variant p.(Thr300Ile) in GABRA4 in a patient with epilepsy and neurodevelopmental abnormalities. However, no new cases have been reported since then. Through an international collaboration, we collected molecular and phenotype data of individuals carrying de novo variants in GABRA4. Patients and their parents were investigated either by exome or genome sequencing, followed by targeted Sanger sequencing in some cases. All variants within the transmembrane domain, including the previously reported p.(Thr300Ile) variant, were characterized in silico and analyzed by molecular dynamics (MD) simulation studies. We identified three novel de novo missense variants in GABRA4 (NM_000809.4): c.797 C > T, p.(Pro266Leu), c.899 C > A, p.(Thr300Asn), and c.634 G > A, p.(Val212Ile). The p.(Thr300Asn) variant impacts the same codon as the previously reported variant p.(Thr300Ile) and likely arose post-zygotically as evidenced by sequencing oral mucosal cells. Overlapping phenotypes among affected individuals included developmental delay (4/4), epileptiform EEG abnormalities (3/4), attention deficits (3/4), seizures (2/4), autistic features (2/4) and structural brain abnormalities (2/4). MD simulations of the three variants within the transmembrane domain of the receptor indicate that sub-microsecond scale dynamics differ between wild-type and mutated subunits. Taken together, our findings further corroborate an association between GABRA4 and a neurological phenotype including variable neurodevelopmental, behavioral and epileptic abnormalities.

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1 +/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1 +/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1 +/ − mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1 +/ − brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.

Pränatalsonographische Auffälligkeiten im Zweittrimester mit familiärer Diagnostik in zwei Schwangerschaften, einer rental tubulären Dysgenesie und eines Cornelia de Lange Syndroms.

X-linked intellectual disability (XLID) is a genetically heterogeneous disorder with more than 100 genes known to date. Most genes are responsible for a small proportion of patients only, which has hitherto hampered the systematic screening of large patient cohorts. We performed targeted enrichment and next-generation sequencing of 107 XLID genes in a cohort of 150 male patients. Hundred patients had sporadic intellectual disability, and 50 patients had a family history suggestive of XLID. We also analysed a sporadic female patient with severe ID and epilepsy because she had strongly skewed X-inactivation. Target enrichment and high parallel sequencing allowed a diagnostic coverage of >10 reads for ~96% of all coding bases of the XLID genes at a mean coverage of 124 reads. We found 18 pathogenic variants in 13 XLID genes ( AP1S2 , ATRX, CUL4B, DLG3 , IQSEC2 , KDM5C , MED12 , OPHN1 , SLC9A6 , SMC1A, UBE2A, UPF3B and ZDHHC9 ) among the 150 male patients. Thirteen pathogenic variants were present in the group of 50 familial patients (26%), and 5 pathogenic variants among the 100 sporadic patients (5%). Systematic gene dosage analysis for low coverage exons detected one pathogenic hemizygous deletion. An IQSEC2 nonsense variant was detected in the female ID patient, providing further evidence for a role of this gene in encephalopathy in females. Skewed X-inactivation was more frequently observed in mothers with pathogenic variants compared with those without known X-linked defects. The mutation rate in the cohort of sporadic patients corroborates previous estimates of 5–10% for X-chromosomal defects in male ID patients.

A double-bubble sign was detected by ultrasonography in a GII, PII, who suffers from Ehlers-Danlos syndrome type II. The delivery was done by Caesarean section based on the suspicion of premature placental separation. Postnatally, the child was found to have duodenal atresia caused by an annular pancreas. These features have not been described in EDS so far. Molecular genetic analysis showed a novel COL5A1 splice mutation in the mother, which is responsible for the EDS phenotype. The mutation is absent in the male newborn. Therefore, we assume that maternal EDS and the malformation of the child are not related.

Purpose: The aim of this study was to compare the perinatal and maternal outcome of our own cohort of twin pregnancies after IVF/ICSI and spontaneous conception to the respective available standards and findings in the current literature.Material and Methods: Perinatal and maternal data of 305 twin pregnancies conceived spontaneously and 74 pregnancies conceived by IVF/ICSI were compared. The following parameters were examined: maternal age, first parity, gestational age, Caesarean section rate, birth weight, sex constellation, umbilical arterial blood pH of the first and second child, maternal complications, fetal malformations, perinatal and neonatal mortality. These data were tested by retrospective statistical analysis (Fisher exact test, Wilcoxon Rank Sum Test). In addition, these parameters were also evaluated separately in dichorionic/diamniotic twins and monochorionic/diamniotic twins.Results: We found significant differences with higher maternal age, higher rate of first parity, an increased incidence of pre-eclampsia and a lower rate of SGA (VLBW) in the ART group and ART subgroup (di/di) compared to the SC group. Caesarean section rate, birth weight, arterial pH of the first and second twin, prematurity, rate of malformations, perinatal and neonate mortality, respectively, were not significantly different between the two groups. For prematurity < 37 weeks of gestation, a significantly higher frequency of the male/male sex constellation was observed.Conclusion: Actually, we are now able to more specifically counsel women conceiving by IVF/ICSI concerning maternal and perinatal outcome.

On prenatal ultrasonography, polyhydramnion, internal hydrocephalus, hypoplasia of the corpus callosum, and dysmorphic features were detected in a fetus of a 22-year-old mother. Subsequent karyotyping of amniocytes revealed supernumerary material in distal 7q. The baby was delivered after 38+4 weeks of gestation, and postnatal array CGH analysis showed a triplication of 7q35→q36, resulting in partial tetrasomy. The triplication was not distinguishable from a duplication by conventional and molecular cytogenetic methods, but was clearly identified by array CGH analysis. The phenotype was rather severe with limited cardiac contractility and subsequent respiratory problems, as well as progressive neurologic deterioration and several dysmorphic features. Triplications in general are rare, and this case is the first report of a microscopically visible triplication in 7q. Duplication patients of the same chromosomal segment also showed a severe phenotype, however, in our opinion there are no common features suggesting a clinically recognizable distal 7q duplication/triplication syndrome.

Ehlers-Danlos Typ II (OMIM 130010) autosomal dominant vererbt. Inzidenz: 1: 2500 bis 1: 10000. Single gene disorder. Ursächlich handelt es sich um eine Mutation in COL 5A1 oder COL 5A2.

Editor—Partial loss of chromosome 18q (MIM 601808) results in characteristic clinical features including mental retardation, short stature, developmental delay, CNS defects, dysmorphic facies, and hearing loss. By phenotype mapping in 26 patients, Strathdee et al 1showed that a region critical for many of the 18q− features lies in 18q22-23. Later, they were able to refine this region to an approximate 6 Mb segment within 18q23.2 However, the clinical picture of 18q− patients is extremely variable, rendering a precise prediction of the clinical outcome impossible, even when the extent of the deletion is determined.1 3 4 Among the factors contributing to this phenotypic variability, the genetic background of affected patients, environmental factors, and possibly genomic imprinting of genes in 18q may play a role. The selective expression of the paternal or maternal allele of a gene responsible for a phenotypic feature5-7 might influence the phenotype of 18q− patients, depending on whether the mutation arose in the maternal or paternal germline. Most of the 18q− patients have a paternal deletion.8 Assuming deletions originate with the same frequency in the maternal and paternal germline, imprinting of maternal genes could explain a more severe phenotype in patients with a paternal deletion, leading to a higher detection rate. Evidence for imprinting in 18q came from linkage studies of bipolar affective disorder (BPAD). While several reports have shown linkage to 18q,9-15 in some studies most of the linkage evidence derived from families with affected phenotypes in only the paternal lineage and from marker alleles in 18q11 and 18q21 transmitted on the paternal chromosome.9 10 13 16 Genomic imprinting might explain the uniparental linkage, if critical maternal genes are imprinted (inactivated) and thus inheritance of a BPAD gene predisposes to the illness only if it is inherited from …

We describe a simple method for expanding CAG trinucleotides in CAG-repeat containing genes which, in contrast to other techniques, leaves the original gene sequence intact. Here, we expanded the CAG stretches of a plasmid clone containing the cDNA of the SCA3/MJD gene from 22 CAG up to > 130 CAG repeats using polymerase chain reaction (PCR)-mediated mutagenesis. The method reported in this article requires minimal resources, is very fast, and enables to construct recombinant plasmids carrying large CAG expansions.

A rapid molecular screening programme has been established for the long arm of the human Y chromosome in Yq11 in order to quickly detect small interstitial deletions in this chromosome region. They have been observed in idiopathic sterile males with azoospermia and a severe oligozoospermia and are therefore indicative for deletion of AZF gene sequences. AZF (i.e. azoospermia factor) is a genetic factor located in Yq11 which controls human spermatogenesis. The screening programme is based mainly on a multiplex PCR approach using a series of Y-specific primers amplifying single DNA loci in Yq11. The order of all Y-DNA loci can be unequivocally arranged along the whole long Y arm. Therefore, any detected deletion can be quickly mapped in relation to the proposed position of AZF. Benefits and pitfalls of this new diagnostic Y screening method will be discussed.

AbstractUntersuchungen im Labor‐ und halbtechnischen Maßstab zeigten, daß sich Spurenmetalle vor der Verhüttung der Erze vom Hauptmetall durch Wirbelschichtverfahren abtrennen und gewinnen lassen. So kann man Rhenium aus Zink‐Klinkern, Selen aus Bleisulfat‐Schlämmen oder den Anoden‐Schlämmen der Kupfer‐Elektrolyse und Indium aus Flugstäuben der Blei/Zink‐Metallurgie abscheiden.