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We report a patient with loss of chromosome region 2q14.3 encompassing exon 1 of the gene CNTNAP5. The deletion occurred in association with a de novo complex chromosomal rearrangement, characterized by routine G-banding, fluorescence in situ hybridization and microarray analysis. The presented patient's phenotype is dominated by severe early childhood weight gain, severe speech delay and behavioural problems. To our knowledge, a few similar patients have been reported previously. CNTNAP5 is a member of the neurexin gene family and is associated with autism spectrum disorder and potentially other behavioural and neurodevelopmental disorders. Recent data point to its possible role in obesity and/or metabolism. The phenotype of the herein presented pediatric patient corroborates CNTNAP5's pathogenic role in human disease.

Background Neurofibromatosis type 1 (NF1), which is caused by heterozygous inactivating pathogenic variants in the NF1, has poor phenotypic expressivity in the early years of life and there are numerous conditions, including many other tumor predisposition syndromes, that can mimic its appearance. These are collectively termed NF1-like syndromes and are also connected by their genetic background. Therefore, the NF1’s clinical diagnostic efficiency in childhood could be difficult and commonly should be completed with genetic testing. Methods To estimate the number of syndromes/conditions that could mimic NF1, we compiled them through an extensive search of the scientific literature. To test the utility of NF1’s National Institutes of Health (NIH) clinical diagnostic criteria, which have been in use for a long time, we analyzed the data of a 40-member pediatric cohort with symptoms of the NF1-like syndromes’ overlapping phenotype and performed NF1 genetic test, and established the average age when diagnostic suspicion arises. To facilitate timely identification, we compiled strongly suggestive phenotypic features and anamnestic data. Results In our cohort the utility of NF1’s clinical diagnostic criteria were very limited (sensitivity: 80%, specificity: 30%). Only 53% of children with clinically diagnosed NF1 had a detectable NF1 pathogenic variation, whereas 40% of patients without fulfilled clinical criteria tested positive. The average age at first genetic counseling was 9 years, and 40% of children were referred after at least one tumor had already been diagnosed. These results highlight the need to improve NF1-like syndromes’ diagnostic efficiency in childhood. We collected the most extensive spectrum of NF1-like syndromes to help the physicians in differential diagnosis. We recommend the detailed, non-invasive clinical evaluation of patients before referring them to a clinical geneticist. Conclusions Early diagnosis of NF1-like syndromes can help to prevent severe complications by appropriate monitoring and management. We propose a potential screening, diagnostic and management strategy based on our findings and recent scientific knowledge.

The specification and differentiation of eighteen intertype specific (IT) epitopes of adenovirus hexons defined by monoclonal antibodies are given by two groups of hexon types: on which they are and on which they are not present. The close specificity relationship among some groups of epitopes determined by pairwise analysis according to their presence on the hexon types indicate that they could be continuous (sequential), overlapping or discontinuous (topographic) epitopes. Based on the identification of the hydrophilic regions and the localization of beta-turns sixteen IT epitope sites were predicted on human adenovirus (HAdV) type 2 and nineteen on HAdV-41 hexon's amino acid (aa) sequences beside the type and genus specific ones. The 16 predicted IT epitopes on HAdV-2 hexon show good coincidency with the 14 IT epitopes demonstrated with monoclonal antibodies (MAbs) on this hexon type. The predicted number of common epitopes between HAdV types 2 and 41 also corresponds well with the eight IT epitopes determined by MAbs, but the 17 predicted non-common epitopes indicate the possibility of the existence of more epitopes on these hexon types. The location of the predicted epitopes of HAdV-2 were determined by alignment of their sequence numbers on the three dimensional ribbon representation of the hexon subunit. Most of the predicted IT epitopes were found between the type and genus specific epitopes i.e. in the "upper" regions of pedestal domains P1 and P2 orientated toward the virion surface and in the "lower" part of loop 1 region orientated inside the virion. Two peptides representing potential IT epitopes were synthesized corresponding to residues 309-320 from the "lower" part of loop 1 and 399-408 from the "upper" part of P1 region of HAdV-2 hexon. Antibodies raised against the peptide-carrier conjugates recognized different purified native hexon types in ELISA.

For the investigation of epitope composition of different adenovirus hexon types sixty-one mouse ascitic fluids containing monoclonal antibodies (MAbs) developed in three different panels were used. The distinction and marking of the different epitopes recognized by the MAbs were carried out by the determination of the composite cross-reactivity pattern, the titer and the correlation coefficient of all the 61 MAbs with 21 different hexon types representing all the six human subgenera, as well as different bovine and simian adenoviruses. The distinct epitopes were marked by two numbers referring the homologous hexon type to which the MAbs were directed and the serial number of the epitope specified by the different members of the given panel of the MAbs. The three panels of MAbs recognized 22 epitopes on the 21 hexon types among them a genus and three type specific ones and 18 different bi- and multilateral intertype (IT) specific epitopes that grouped adenoviruses within the genus, independently from the subgenus they belong to. Considering that the type specific epitope could be present only on the homologous hexon type, the largest number of the different epitopes distinguishable by the MAbs used could be 20 on the homologous hexon and 19 on the heterologous ones. It was found that the total number of IT specific epitopes on the hexons varied between 2 and 18. The distribution of the distinct specific epitopes on the different hexon types was different, as expected. The antigenic structure of the individual hexon types were characterized by the determination of their IT specific epitope spectrum. By pairwise analysis ten human hexon types formed three epitope clusters (types 4 and 19; types 8, 9, 9/13 and 10; as well as all types of subgenus C) showing identical epitope spectra. No clustering was found with human type 7, 12, 13, 18, 26, 27, 35 and 41, as well as with bovine and simian adenovirus hexons studied. However, they displayed a closer or looser antigenic relationship among each other and to members of the epitope clusters. The degree of antigenic relationship could be expressed by the similarity/dissimilarity percentage calculated from the number of the identical and different epitopes present on any two given hexon types.

Antigenic relationships of hexons of human adenovirus (Ad h) types 1, 2, 5 and 6 of subgenus C were studied with 61 monoclonal antibodies (MAbs) raised against human Ad h1, Ad h35 and bovine adenovirus 2. The reactivity pattern (RP) and the titers of the MAbs were determined in indirect ELISA. In previous experiments with hexons of different subgenera 49 MAbs displayed numerous different intertype specificities besides genus specific and type specific ones. With the four hexon types of subgenus C all MAbs gave identical RPs except the type specific ones. Data reveal the existence of a remarkable homogeneity in the antigenic structure among the hexon types of subgenus C defined by the presence of identical or closely related intertype specific epitopes on the surface of the hexons. The possible significance of the results in the experimental gene therapy is discussed.

Summary Eighteen mouse ascitic fluids containing monoclonal antibodies (MAbs) directed against crystallized hexon of adenovirus (AV) type I were used to map the antigenic structure of the capsomer in reciprocal competitive binding ELISA. With the help of peroxidase-labelled MAbs at least nine epitopes (epitope clusters) located on three distinct antigenic sites were identified on the hexon. Epitope on antigenic site I recognized by two MAbs could be the genus specific antigenic determinant based on the broad reactivity patterns of the MAbs. Epitopes on the antigenic site II recognized by fifteen MAbs could be divided into seven epitope clusters according to the competition patterns. Antigenic site III recognized by one MAb completely differs from the antigenic site I and on the basis of one-way blocking with all the MAbs specific for antigenic site II, should be also different from the latter one. The data suggest that the seven epitope clusters of antigenic site II contain partially overlapping epitopes and may be a part of a large single immunodominant antigenic region on AV1 hexon as well as on hexons of heterologous types.

Thirty two mouse ascitic fluids containing monoclonal antibodies (MAbs) directed against the hexon of human adenovirus type 1 were examined. The type and degree of cross-reactivity (CR) of the MAbs were determined by ELISA and hemagglutination methods with 10 heterologous hexon types. The similarity and the dissimilarity of the MAbs was also characterized by the correlation coefficient calculated from their reactivity values. On the basis of these, the 32 MAbs could be divided into five groups and fourteen individual MAbs, which altogether recognized 19 distinct epitopes. One of the recognized epitopes is the genus specific epitope of adenovirus hexons; the others are interspecies specific ones which can be found on the surface of the different hexon types in characteristic, mosaic-like combinations. The type and degree of CR of the MAbs lead to the conclusion that there exists a close antigenic relationship among the members of subgenus C of human adenoviruses and there is also a definite antigenic relationship between subgenera C and D. Hexons belonging to the oncogenic subgenera A and B display a much looser antigenic relationship with subgenus C.

In der Zonenelektrophorese wurde das Verhalten der Komponenten von sechs Adenovirusstammen untersucht. Das Hamagglutinin von drei, das Virion von vier und das Hexon-Antigen von allen Stammen besas die gleiche elektrophoretische Beweglichkeit. Die Komponenten der Prototypstamme 9 und 23 liesen sich nicht voneinander trennen. Hamagglutinin und Virion konnten bei einem Typ 9 und dem Typ 9–15-Stamm, sowie bei den Prototypen 15 und 19 getrennt gewonnen werden. Eine Beziehung zwischen der elektrophoretischen Beweglichkeit des Hamagglutinins und dem serologischen Typ scheint nicht zu bestehen.