RASopathies are a clinically heterogeneous group of conditions caused by mutations in 1 of 16 proteins in the RAS-mitogen activated protein kinase (RAS-MAPK) pathway. Recently, mutations in RIT1 were identified as a novel cause for Noonan syndrome. Here we provide additional functional evidence for a causal role of RIT1 mutations and expand the associated phenotypic spectrum. We identified two de novo missense variants p.Met90Ile and p.Ala57Gly. Both variants resulted in increased MEK-ERK signaling compared to wild-type, underscoring gain-of-function as the primary functional mechanism. Introduction of p.Met90Ile and p.Ala57Gly into zebrafish embryos reproduced not only aspects of the human phenotype but also revealed abnormalities of eye development, emphasizing the importance of RIT1 for spatial and temporal organization of the growing organism. In addition, we observed severe lymphedema of the lower extremity and genitalia in one patient. We provide additional evidence for a causal relationship between pathogenic mutations in RIT1, increased RAS-MAPK/MEK-ERK signaling and the clinical phenotype. The mutant RIT1 protein may possess reduced GTPase activity or a diminished ability to interact with cellular GTPase activating proteins; however the precise mechanism remains unknown. The phenotypic spectrum is likely to expand and includes lymphedema of the lower extremities in addition to nuchal hygroma.

American Journal of Medical GeneticsVolume 80, Issue 3 p. 300-301 Letter to the Editor Prader-Willi–like phenotype and the proximal long arm of the X chromosome Zeynep Tümer, Corresponding Author Zeynep Tümer zeynep@imbg.ku.dk Department of Medical Genetics, Panum Institute, University of Copenhagen, Copenhagen, DenmarkDepartment of Medical Genetics (24.4.32), Panum Institute, University of Copenhagen, Blegdamsvej 3, 2200 KBH N, Copenhagen, Denmark.Search for more papers by this authorNiels Tommerup, Niels Tommerup Department of Medical Genetics, Panum Institute, University of Copenhagen, Copenhagen, DenmarkSearch for more papers by this authorFranz Binkert, Franz Binkert Institute for Medical Genetics, Zurich University, Zurich, SwitzerlandSearch for more papers by this authorElke Back, Elke Back Institute for Human Genetics, Albert-Ludwig's University, Freiburg, GermanySearch for more papers by this authorKaren Brøndum-Nielsen, Karen Brøndum-Nielsen The John F. Kennedy Institute, Glostrup, DenmarkSearch for more papers by this author Zeynep Tümer, Corresponding Author Zeynep Tümer zeynep@imbg.ku.dk Department of Medical Genetics, Panum Institute, University of Copenhagen, Copenhagen, DenmarkDepartment of Medical Genetics (24.4.32), Panum Institute, University of Copenhagen, Blegdamsvej 3, 2200 KBH N, Copenhagen, Denmark.Search for more papers by this authorNiels Tommerup, Niels Tommerup Department of Medical Genetics, Panum Institute, University of Copenhagen, Copenhagen, DenmarkSearch for more papers by this authorFranz Binkert, Franz Binkert Institute for Medical Genetics, Zurich University, Zurich, SwitzerlandSearch for more papers by this authorElke Back, Elke Back Institute for Human Genetics, Albert-Ludwig's University, Freiburg, GermanySearch for more papers by this authorKaren Brøndum-Nielsen, Karen Brøndum-Nielsen The John F. Kennedy Institute, Glostrup, DenmarkSearch for more papers by this author First published: 15 December 1998 https://doi.org/10.1002/(SICI)1096-8628(19981116)80:3<300::AID-AJMG27>3.0.CO;2-OCitations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume80, Issue316 November 1998Pages 300-301 RelatedInformation

DiGeorge syndrome (DGS) is a developmental field defect, characterised by absent/hypoplastic thymus and parathyroid, and conotruncal heart defects, with haploinsufficiency loci at 22q (DGS1) and 10p (DGS2). We performed fluorescence in situ hybridisations (FISH) and polymerase chain reaction (PCR) analyses in 12 patients with 10p deletions, nine of them with features of DGS, and in a familial translocation 10p;14q associated with midline defects. The critical DGS2 region is defined by two DGS patients, and maps within a 1 cM interval including D10S547 and D10S585. The other seven DGS patients are hemizygous for both loci. The breakpoint of the reciprocal translocation 10p;14q maps at a distance of at least 12 cM distal to the critical DGS2 region. Interstitial and terminal deletions described are in the range of 10–50 cM and enable the tentative mapping of loci for ptosis and hearing loss, features which are not part of the DGS clinical spectrum.

A case of complete trisomy 22 in live-born female child with multiple malformations is reported. The karyotype of the index patient had 46 chromosomes, with one chromosome 22 missing and one supranumerary metacentric chromosome. Different banding methods and in situ hybridization revealed that the extra chromosome consists of the long arms and a part of the short arms of two chromosomes 22. Our report supplies further proof that a fetus with complete trisomy 22 can occasionally survive to term, but the condition is not compatible with life over a long period.

A search for Y-specific DNA sequences has been performed in a sample of seven 46,XX true hermaphrodites and one 45,X mixed gonadal dysgenesis case and compared with a sample of 11 XX males. Using six Y-specific DNA probes no hybridization signal was obtained in the hermaphrodite group; in contrast, all XX males gave a positive signal with at least one probe. This difference is statistically highly significant. We conclude that the aetiology of true hermaphroditism is different from that of the XX male syndrome. As all cases of the hermaphrodite group are positive for the serological sex-specific antigen (Sxs) it is concluded that this antigen can be present even in the absence of Y-specific DNA.

A pericentric inversion in one of the chromosomes 12, found in two families living in the same region, is deseribed. This inversion was detected during routine chromosomal analysis in two separate laboratories. The breakpoints were at 12p112 and 12q13. The inverted segment represented approximately 20% of the length of chromosome 12. Twenty nine descendants of carriers of the inversion were investigated, and the inversion was present in 23 of them. The other six descendants showed a normal karyotype. After correction for sample bias with the single selection scheme, a segregation ratio of 3:1 was estimated, indicating that the inverted chromosome 12 was preferentially transmitted. All the carriers of the inversion were phenotypically normal, without noticeable fertility disturbances.

In five healthy family members of three generations a reciprocal translocation, t(6;12)(q27;q21), combined with an inverted insertion inv ins (7;8)(p14;q22q13), has been demonstrated. Neither offspring with unbalanced karyotypes nor descendants with isolated translocations or insertions were observed. Five simultaneously occurring chromosomal breaks are considered to be the reason for the new rearrangement.

A boy is reported with mild retardation and minimal dysplasias, carrying a serial duplication of 10(q11→q22). The possible origin of the aberrant chromosome is discussed in the context of similar cases from the literature.

A family is reported with a segregating t(5;10)(q15;q11) translocation resulting in a child carrying trisomy 10p. The clinical findings of the patient are compared with trisomy 10p and the Cri-du-Chat syndrome.

A girl with congenital malformations and del 4(q31), identified by QFQ- and RFA- techniques, is described. The clinical findings are compared with the four cases of 4q- of the literature. Evident variability of the clinical features and the small number of cases of 4q- does not allow the delineation of a clinical syndrome.

The association pattern of the acrocentric chromosomes shows no significant difference between a population of mothers of mongoloid children and male and female controls of the same age-group. It could only be demonstrated that the associations of the mothers were interconnected by thread-like structures in a higher percentage. However, no significance could be deduced from for this phenomenon (P ≊ 0.1).

We studied the influence of the method used in cultivating and preparing lymphocyte cultures on the quantitative and qualitative association patterns of the acrocentric chromosomes in the same individual. We compared the results obtained by macrocultures with medium TC 199 (method a), by macrocultures with McCoy’s medium 5A (method b) and by microcultures with McCoy’s medium 5A and 20% fetal calf serum (method c). These comparisons were made under two conditions: (1) fixation with glacial acetic acid/methanol 1:3 and (2) subsequent resuspension in 70% acetic acid. For cultures that were not resuspended, no marked differences could be observed in the quantitative association types {i.e., the number of associating chromosomes). As regards the qualitative association types (i.e., the relative frequency of participation of D and G chromosomes), however, an increasing deviation from the expected D-D:D-G:G-G ratio from method a to b to c, caused by an increase in G-G associations, could be demonstrated. In cultures resuspended in 70% acetic acid subsequent to the usual fixation process a significant increase in associations (primarily in associating G chromosomes) could be observed for all methods. Mechanical factors possibly responsible for these results are discussed.

Two populations of normal persons were investigated for associations of acrocentric chromosomes in lymphocyte cultures. We studied in the first series (macrocultures), 1,300 metaphase cells from five males and eight females, in the second series (microcultures), 1,550 metaphase cells from 31 males and 31 females. In the second series all the absolute values were significantly lower than in the first series. In both populations no statistically significant sex differences were observed. Differentiating between D-D, D-G and G-G associations, a relative increase of G-G associations could be shown. In a double variance analysis, performed with the results of the first series, a high stability of individual association patterns could be shown. In a single χztest of the second series significant deviations from the expected D-D, D-G and G-G associations for the individuals were observed.