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Objective Our objective was to improve molecular diagnostics in patients with hereditary pheochromocytoma and paraganglioma (PPGL) by using next-generation sequencing (NGS) multi-gene panel analysis. Derived from this study, we here present three cases that were diagnosed with NF1 germline mutations but did not have a prior clinical diagnosis of neurofibromatosis type 1 (NF1). Design We performed genetic analysis of known tumor predisposition genes, including NF1, using a multi-gene NGS enrichment-based panel applied to a total of 1029 PPGL patients. We did not exclude genes known to cause clinically defined syndromes such as NF1 based on missing phenotypic expression as is commonly practiced. Methods Genetic analysis was performed using NGS (TruSight Cancer Panel/customized panel by Illumina) for analyzing patients’ blood and tumor samples. Validation was carried out by Sanger sequencing. Results Within our cohort, three patients, who were identified to carry pathogenic NF1 germline mutations, attracted attention, since none of the patients had a clinical suspicion of NF1 and one of them was initially suspected to have MEN2A syndrome due to co-occurrence of a medullary thyroid carcinoma. In these cases, one splice site, one stop and one frameshift mutation in NF1 were identified. Conclusions Since phenotypical presentation of NF1 is highly variable, we suggest analysis of the NF1 gene also in PPGL patients who do not meet diagnostic NF1 criteria. Co-occurrence of medullary thyroid carcinoma and PPGL was found to be a clinical decoy in NF1 diagnostics. These observations underline the value of multi-gene panel NGS for PPGL patients.

Pierpont syndrome (OMIM #602342) is a rare disorder characterized by developmental delay, characteristic facial gestalt, hearing loss, and abnormal fat distribution in the distal limbs. A specific mutation in TBL1XR1 [c.1337A>G; p.(Tyr446Cys)] has been described recently in six unrelated patients with Pierpont syndrome. We report on a male child with developmental delay, distinctive facial dysmorphic features, dystrophy, and abnormal fat distribution in the feet, in whom we identified the identical TBL1XR1 mutation. This patient also had additional clinical features including microphthalmia, pendular nystagmus, cryptorchidism, dermal sinus, and peripheral joint laxity, which had not been reported previously in association with Pierpont syndrome. This patient corroborates the assumption that Pierpont syndrome is exclusively caused by the specific TBL1XR1 missense mutation p.(Tyr446Cys) and the additional features broaden the phenotypic spectrum of this rare disorder.

Background Mutations in the STXBP1 gene (MUNC18-1) were first described to cause Ohtahara syndrome (Early infantile epileptic encephalopathy, EIEE)12–14 characterized by very early infantile epileptic encephalopathy with frequent tonic spasms and a suppression-burst pattern on electroencephalogram. In the following years a wider phenotype was recognized having milder forms of epilepsies. All patients showed also intellectual disability and movement disorders. Methods Here, we present three female patients with an ataxia-tremor-retardation syndrome caused by a de novo STXBP1 mutation. Two of the girls were diagnosed through next-generation-sequencing as mutations in STXBP1 were not suspected. The third patient was diagnosed by targeted genetic testing due to its clinical features strikingly similar to the first two girls. Results The characteristic feature of our three patients is the lack of epilepsy which is in contrast to the majority of the patients with STXBP1 mutation. Conclusion Hence, epilepsy is not a mandatory feature of patients with a STXBP1 mutation.

Expression of the fusion genes is considered to be an important mechanism of tumorigenesis. However it is hardly ever discussed in relation to the neurodevelopmental disorders. Here we report on an 18-years-old female patient with 13.1 kb deletion of 8q24.3 fusing the 5′-portion of SCRIB with the 3′-portion of PUF60 and presenting with borderline intellectual disability, eye coloboma, short stature, scoliosis, heart defects and interestingly postnatal megalencephaly, in contrast to microcephaly, which is usually associated with 8q24.3 deletion (Verheij syndrome). Using next generation sequencing we mapped the breakpoints at nucleotide resolution and showed that the deletion preserved the reading frame. In contrast to the laborious techniques previously used for the precise mapping of deletion breakpoints, our approach identified an accurate interval very rapidly. We demonstrated the expression of the PUF60-SCRIB fusion gene in patient's cells and suggest that the fusion transcript might be a cause of the atypical clinical presentation.

CHARGE syndrome is an autosomal dominant malformation disorder caused by heterozygous loss of function mutations in the chromatin remodeler CHD7. Chd7 regulates the expression of Sema3a, which also contributes to the pathogenesis of Kallmann syndrome, a heterogeneous condition with the typical features hypogonadotropic hypogonadism and an impaired sense of smell. Both features are common in CHARGE syndrome suggesting that SEMA3A may provide a genetic link between these syndromes. Indeed, we find evidence that SEMA3A plays a role in the pathogenesis of CHARGE syndrome. First, Chd7 is enriched at the Sema3a promotor in neural crest cells and loss of function of Chd7 inhibits Sema3a expression. Second, using a Xenopus CHARGE model, we show that human SEMA3A rescues Chd7 loss of function. Third, to elucidate if SEMA3A mutations in addition to CHD7 mutations also contribute to the severity of the CHARGE phenotype, we screened 31 CHD7-positive patients and identified one patient with a heterozygous non-synonymous SEMA3A variant, c. 2002A> G (p. I668V). By analyzing protein expression and processing, we did not observe any differences of the p. I668V variant compared with wild-type SEMA3A, while a pathogenic SEMA3A variant p. R66W recently described in a patient with Kallmann syndrome did affect protein secretion. Furthermore, the p. I668V variant, but not the pathogenic p. R66W variant, rescues Chd7 loss of function in Xenopus, indicating that the p. I668V variant is likely benign. Thus, SEMA3A is part of an epigenetic loop that plays a role in the pathogenesis of CHARGE syndrome, however, it seems not to act as a common direct modifier.

Truncating mutations in the last and penultimate exons of the PPM1D gene were recently described as a cause for mild to severe intellectual disability in fourteen patients. Feeding difficulties, periods of fever and vomiting as well as a high pain threshold were described as additional characteristic features and the disorder was subsequently termed "intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (IDDGIP)" in the OMIM database (MIM # 617450). Here we report on an additional patient carrying a novel de novo truncating mutation NM_003620.3: c.1535del, p.(Asn512Ilefs*2) in the last exon of PPM1D. While the patient showed features overlapping with the reported phenotype, such as a short stature and small hands and feet, he also presented with additional features like cleft lip and palate and an aberrant right subclavian artery. Notably, the patient did not have any gastrointestinal difficulties or periods of fever, indicating variability of the phenotype of patients with PPM1D mutations.

Aicardi-Goutieres syndrome (AGS) is a hereditary inflammatory encephalopathy resulting in severe neurological damage in the majority of cases. We report on two siblings with AGS6 due to compound heterozygosity for a known and a novel mutation in the ADAR gene and a strikingly variable phenotype. The first sibling presented at 12 months of age with a subacute encephalopathy following a mild respiratory infection. The child developed a spastic tetraparesis, generalized dystonia and dysarthria. In contrast, the younger sibling presented with an acute episode of neurological impairment in his third year of life, from which he recovered without sequelae within a few weeks. These findings illustrate a striking intrafamilial phenotypic variability in patients with AGS6 and describe the first case of a full recovery from an acute encephalopathy in an AGS patient. Our findings also suggest that AGS should be considered as an important differential diagnosis of an infection-triggered encephalopathy in infancy despite the absence of typical neuroimaging findings.

Histamine (HA) acts as a neurotransmitter in the brain, which participates in the regulation of many biological processes including inflammation, gastric acid secretion and neuromodulation. The enzyme histamine N-methyltransferase (HNMT) inactivates HA by transferring a methyl group from S-adenosyl-l-methionine to HA, and is the only well-known pathway for termination of neurotransmission actions of HA in mammalian central nervous system. We performed autozygosity mapping followed by targeted exome sequencing and identified two homozygous HNMT alterations, p.Gly60Asp and p.Leu208Pro, in patients affected with nonsyndromic autosomal recessive intellectual disability from two unrelated consanguineous families of Turkish and Kurdish ancestry, respectively. We verified the complete absence of a functional HNMT in patients using in vitro toxicology assay. Using mutant and wild-type DNA constructs as well as in silico protein modeling, we confirmed that p.Gly60Asp disrupts the enzymatic activity of the protein, and that p.Leu208Pro results in reduced protein stability, resulting in decreased HA inactivation. Our results highlight the importance of inclusion of HNMT for genetic testing of individuals presenting with intellectual disability.

Neuronal ceroid lipofuscinoses (NCL) is characterized by a combination of retinopathy, dementia, and epilepsy. As a group, they encompass ten distinct biological and clinical entities and are the most common type of childhood neurodegenerative disease. Case reports. We demonstrate the clinical course of two neonates (brother and sister) with infantile neuronal ceroid lipofuscinoses (NCL) (CLN 10 disease) presenting with intractable seizures and respiratory insufficiency immediately after birth. Characteristic clinical, radiological and pathological findings of this form of NCL are presented. We conclude that the diagnosis of CLN10 should be kept in mind as a differential diagnosis in newborns presenting with respiratory insufficiency and severe epilepsy that is largely refractory to anti-epileptic drugs (AED) treatment. Because of the severity of CLN10 disease and futility of treatment, important ethical issues arise when caring for children with this clinical entity.

Angelman syndrome is a neurodevelopmental disorder characterized by mental retardation, severe speech disorder, facial dysmorphism, secondary microcephaly, ataxia, seizures, and abnormal behaviors such as easily provoked laughter. It is most frequently caused by a de novo maternal deletion of chromosome 15q11-q13 (about 70-90%), but can also be caused by paternal uniparental disomy of chromosome 15q11-q13 (3-7%), an imprinting defect (2-4%) or in mutations in the ubiquitin protein ligase E3A gene UBE3A mostly leading to frame shift mutation. In addition, for patients with overlapping clinical features (Angelman-like syndrome), mutations in methyl-CpG binding protein 2 gene MECP2 and cyclin-dependent kinase-like 5 gene CDKL5 as well as a microdeletion of 2q23.1 including the methyl-CpG binding domain protein 5 gene MBD5 have been described. Here, we describe a patient who carries a de novo 5Mb-deletion of chromosome 15q11.2-q13.1 known to be associated with Angelman syndrome and a further, maternally inherited deletion 2q21.3 (~364kb) of unknown significance. In addition to classic features of Angelman syndrome, she presented with severe infections in the first year of life, a symptom that has not been described in patients with Angelman syndrome. The 15q11.2-q13.1 deletion contains genes critical for Prader-Willi syndrome, the Angelman syndrome causing genes UBE3A and ATP10A/C, and several non-imprinted genes: GABRB3 and GABRA5 (both encoding subunits of GABA A receptor), GOLGA6L2, HERC2 and OCA2 (associated with oculocutaneous albinism II). The deletion 2q21.3 includes exons of the genes RAB3GAP1 (associated with Warburg Micro syndrome) and ZRANB3 (not disease-associated). Despite the normal phenotype of the mother, the relevance of the 2q21.3 microdeletion for the phenotype of the patient cannot be excluded, and further case reports will need to address this point.

Item does not contain fulltext BACKGROUND: The genetic cause of intellectual disability in most patients is unclear because of the absence of morphological clues, information about the position of such genes, and suitable screening methods. Our aim was to identify de-novo variants in individuals with sporadic non-syndromic intellectual disability. METHODS: In this study, we enrolled children with intellectual disability and their parents from ten centres in Germany and Switzerland. We compared exome sequences between patients and their parents to identify de-novo variants. 20 children and their parents from the KORA Augsburg Diabetes Family Study were investigated as controls. FINDINGS: We enrolled 51 participants from the German Mental Retardation Network. 45 (88%) participants in the case group and 14 (70%) in the control group had de-novo variants. We identified 87 de-novo variants in the case group, with an exomic mutation rate of 1.71 per individual per generation. In the control group we identified 24 de-novo variants, which is 1.2 events per individual per generation. More participants in the case group had loss-of-function variants than in the control group (20/51 vs 2/20; p=0.022), suggesting their contribution to disease development. 16 patients carried de-novo variants in known intellectual disability genes with three recurrently mutated genes (STXBP1, SYNGAP1, and SCN2A). We deemed at least six loss-of-function mutations in six novel genes to be disease causing. We also identified several missense alterations with potential pathogenicity. INTERPRETATION: After exclusion of copy-number variants, de-novo point mutations and small indels are associated with severe, sporadic non-syndromic intellectual disability, accounting for 45-55% of patients with high locus heterogeneity. Autosomal recessive inheritance seems to contribute little in the outbred population investigated. The large number of de-novo variants in known intellectual disability genes is only partially attributable to known non-specific phenotypes. Several patients did not meet the expected syndromic manifestation, suggesting a strong bias in present clinical syndrome descriptions. FUNDING: German Ministry of Education and Research, European Commission 7th Framework Program, and Swiss National Science Foundation.

Background Oral-facial-digital type 1 syndrome (OFD1; OMIM 311200) belongs to the expanding group of disorders ascribed to ciliary dysfunction. With the aim of contributing to the understanding of the role of primary cilia in the central nervous system (CNS), we performed a thorough characterization of CNS involvement observed in this disorder. Methods A cohort of 117 molecularly diagnosed OFD type I patients was screened for the presence of neurological symptoms and/or cognitive/behavioral abnormalities on the basis of the available information supplied by the collaborating clinicians. Seventy-one cases showing CNS involvement were further investigated through neuroimaging studies and neuropsychological testing. Results Seventeen patients were molecularly diagnosed in the course of this study and five of these represent new mutations never reported before. Among patients displaying neurological symptoms and/or cognitive/behavioral abnormalities, we identified brain structural anomalies in 88.7%, cognitive impairment in 68%, and associated neurological disorders and signs in 53% of cases. The most frequently observed brain structural anomalies included agenesis of the corpus callosum and neuronal migration/organisation disorders as well as intracerebral cysts, porencephaly and cerebellar malformations. Conclusions Our results support recent published findings indicating that CNS involvement in this condition is found in more than 60% of cases. Our findings correlate well with the kind of brain developmental anomalies described in other ciliopathies. Interestingly, we also described specific neuropsychological aspects such as reduced ability in processing verbal information, slow thought process, difficulties in attention and concentration, and notably, long-term memory deficits which may indicate a specific role of OFD1 and/or primary cilia in higher brain functions.

The title compounds show low reactivity towards electrophiles. Under forced conditions, however, the As[dbnd]C derivative 1a is attacked by methyl iodide and CCl4 to give λ5- and (δ3-dihydro)benzoxarsoles, respectively. Nucleophilic additions take place with “soft” bases while “hard” bases fail to react, thus indicating some aromaticity of the heterocycles. Me3SnH is smoothly added by a radical way. Die Titelverbindungen sind gegenuber Elektrophilen wenig reaktiv. Unter encrgischen Bedingungen setzt sich das As[dbnd]C-Derivat 1a jedoch mit Methyliodid und CCl4 zu δ5- bzw. (δ3-Dihydro)benzoxarsolen um. Nucleophile Additionen gelingen mit “weichen” Basen, wahrend “harte” Basen nicht reagieren. Dies verweist auf gewisse aromatische Stabilisierung der Heterocyclen. Me3SnH wird leicht radikalisch addiert.

Phenylacetylen und Isopropenylacetylen addieren sekundare 2-Aminoathylarsine bzw. o-Aminophenylarsine. Dabei entstehen Gemische der cis- und trans-Styrylarsine bzw. trans-4,3- (etwa 90%) und 4,1-Addukte (etwa 10%) des Enins. Die 1H-NMR-Daten der Verbindungen werden angegeben.

Die elektro- r chemische Reduktion von (I) fuhrt zum Grundkorper (IIa) der o-Aminophenylarsine (II), die als olige und stark luftempfindliche Flussigkeiten anfallen.