Duplication of the EFNB1 Gene in Familial Hypertelorism: Imbalance in Ephrin-B1 Expression and Abnormal Phenotypes in Humans and Mice

Familial hypertelorism, characterized by widely spaced eyes, classically shows autosomal dominant inheritance (Teebi type), but some pedigrees are compatible with X-linkage. No mechanism has been described previously, but clinical similarity has been noted to craniofrontonasal syndrome (CFNS), which is caused by mutations in the X-linked EFNB1 gene. Here we report a family in which females in three generations presented with hypertelorism, but lacked either craniosynostosis or a grooved nasal tip, excluding CFNS. DNA sequencing of EFNB1 was normal, but further analysis revealed a duplication of 937 kb including EFNB1 and two flanking genes: PJA1 and STARD8. We found that the X chromosome bearing the duplication produces ∼1.6-fold more EFNB1 transcript than the normal X chromosome and propose that, in the context of X-inactivation, this difference in expression level of EFNB1 results in abnormal cell sorting leading to hypertelorism. To support this hypothesis, we provide evidence from a mouse model carrying a targeted human EFNB1 cDNA, that abnormal cell sorting occurs in the cranial region. Hence, we propose that X-linked cases resembling Teebi hypertelorism may have a similar mechanism to CFNS, and that cellular mosaicism for different levels of ephrin-B1 (as well as simple presence/absence) leads to craniofacial abnormalities. Hum Mutat 32:1–9, 2011. © 2011 Wiley-Liss, Inc

Pathogenic variants in the paired-related homeobox 1 gene (PRRX1) cause craniosynostosis with incomplete penetrance

Purpose Studies previously implicated PRRX1 in craniofacial development, including demonstration of murine Prrx1 expression in the pre-osteogenic cells of the cranial sutures. We investigated the role of heterozygous missense and loss-of-function variants in PRRX1 associated with craniosynostosis. Methods Trio-based genome, exome or targeted sequencing were used to screen PRRX1 in patients with craniosynostosis; immunofluorescence analyses were used to assess nuclear localization of wild-type and mutant proteins. Results Genome sequencing identified 2 of 9 sporadically affected individuals with syndromic/multisuture craniosynostosis who were heterozygous for rare/undescribed variants in PRRX1. Exome or targeted sequencing of PRRX1 revealed a further 9/1449 patients with craniosynostosis harboring deletions or rare heterozygous variants within the homeodomain. By collaboration, seven additional individuals (four families) were identified with putatively pathogenic PRRX1 variants. Immunofluorescence analyses showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localization. Of patients with variants considered likely pathogenic, bicoronal or other multi-suture synostosis was present in 11/17 (65% of the cases). Pathogenic variants were inherited from unaffected relatives in many instances, yielding a 12.5% penetrance estimate for craniosynostosis. Conclusion This work supports a key role for PRRX1 in cranial suture development and shows that haploinsufficiency of PRRX1 is a relatively frequent cause of craniosynostosis

Gastrointestinal disorders in Curry-Jones syndrome: Clinical and molecular insights from an affected newborn.

Curry-Jones syndrome (CJS) is a pattern of malformation that includes craniosynostosis, pre-axial polysyndactyly, agenesis of the corpus callosum, cutaneous and gastrointestinal abnormalities. A recurrent, mosaic mutation of SMO (c.1234 C>T; p.Leu412Phe) causes CJS. This report describes the gastrointestinal and surgical findings in a baby with CJS who presented with abdominal obstruction and reviews the spectrum of gastrointestinal malformations in this rare disorder. A 41-week, 4,165 g, female presented with craniosynostosis, pre-axial polysyndactyly, and cutaneous findings consistent with a clinical diagnosis of CJS. The infant developed abdominal distension beginning on the second day of life. Surgical exploration revealed an intestinal malrotation for which she underwent a Ladd procedure. Multiple small nodules were found on the surface of the small and large bowel in addition to an apparent intestinal duplication that seemed to originate posterior to the pancreas. Histopathology of serosal nodules revealed bundles of smooth muscle with associated ganglion cells. Molecular analysis demonstrated the SMO c.1234 C>T mutation in varying amounts in affected skin (up to 35%) and intestinal hamartoma (26%). Gastrointestinal features including structural malformations, motility disorders, and upper GI bleeding are major causes of morbidity in CJS. Smooth muscle hamartomas are a recognized feature of children with CJS typically presenting with abdominal obstruction requiring surgical intervention. A somatic mutation in SMO likely accounts for the structural malformations and predisposition to form bowel hamartomas and myofibromas. The mutation burden in the involved tissues likely accounts for the variable manifestations

New locus underlying auriculocondylar syndrome (ARCND): 430 kb duplication involving TWIST1 regulatory elements.

Funder: VTCT Foundation FellowshipBACKGROUND: Auriculocondylar syndrome (ARCND) is a rare genetic disease that affects structures derived from the first and second pharyngeal arches, mainly resulting in micrognathia and auricular malformations. To date, pathogenic variants have been identified in three genes involved in the EDN1-DLX5/6 pathway (PLCB4, GNAI3 and EDN1) and some cases remain unsolved. Here we studied a large unsolved four-generation family. METHODS: We performed linkage analysis, resequencing and Capture-C to investigate the causative variant of this family. To test the pathogenicity of the CNV found, we modelled the disease in patient craniofacial progenitor cells, including induced pluripotent cell (iPSC)-derived neural crest and mesenchymal cells. RESULTS: This study highlights a fourth locus causative of ARCND, represented by a tandem duplication of 430 kb in a candidate region on chromosome 7 defined by linkage analysis. This duplication segregates with the disease in the family (LOD score=2.88) and includes HDAC9, which is located over 200 kb telomeric to the top candidate gene TWIST1. Notably, Capture-C analysis revealed multiple cis interactions between the TWIST1 promoter and possible regulatory elements within the duplicated region. Modelling of the disease revealed an increased expression of HDAC9 and its neighbouring gene, TWIST1, in neural crest cells. We also identified decreased migration of iPSC-derived neural crest cells together with dysregulation of osteogenic differentiation in iPSC-affected mesenchymal stem cells. CONCLUSION: Our findings support the hypothesis that the 430 kb duplication is causative of the ARCND phenotype in this family and that deregulation of TWIST1 expression during craniofacial development can contribute to the phenotype

Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans

Remodeling of the cytoskeleton is central to the modulation of cell shape and migration. Filamin A, encoded by the gene FLNA, is a widely expressed protein that regulates re-organization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes and second messengers. We identified localized mutations in FLNA that conserve the reading frame and lead to a broad range of congenital malformations, affecting craniofacial structures, skeleton, brain, viscera and urogenital tract, in four X-linked human disorders: otopalatodigital syndrome types 1 (OPD1; OMIM 311300) and 2 (OPD2; OMIM 304120), frontometaphyseal dysplasia (FMD; OMIM 305620) and Melnick-Needles syndrome (MNS; OMIM 309350). Several mutations are recurrent, and all are clustered into four regions of the gene: the actin-binding domain and rod domain repeats 3, 10 and 14/15. Our findings contrast with previous observations that loss of function of FLNA is embryonic lethal in males but manifests in females as a localized neuronal migration disorder, called periventricular nodular heterotopia (PVNH; refs. 3-6). The patterns of mutation, X-chromosome inactivation and phenotypic manifestations in the newly described mutations indicate that they have gain-of-function effects, implicating filamin A in signaling pathways that mediate organogenesis in multiple systems during embryonic development.status: publishe

A Recurrent Mosaic Mutation in SMO, Encoding the Hedgehog Signal Transducer Smoothened, Is the Major Cause of Curry-Jones Syndrome

Curry-Jones syndrome (CJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. Cerebellar medulloblastoma has been described in a single affected individual; in another, biopsy of skin lesions showed features of trichoblastoma. The combination of asymmetric clinical features, patchy skin manifestations, and neoplastic association previously led to the suggestion that this could be a mosaic condition, possibly involving hedgehog (Hh) signaling. Here, we show that CJS is caused by recurrent somatic mosaicism for a nonsynonymous variant in SMO (c.1234C>T [p.Leu412Phe]), encoding smoothened (SMO), a G-protein-coupled receptor that transduces Hh signaling. We identified eight mutation-positive individuals (two of whom had not been reported previously) with highly similar phenotypes and demonstrated varying amounts of the mutant allele in different tissues. We present detailed findings from brain MRI in three mutation-positive individuals. Somatic SMO mutations that result in constitutive activation have been described in several tumors, including medulloblastoma, ameloblastoma, and basal cell carcinoma. Strikingly, the most common of these mutations is the identical nonsynonymous variant encoding p.Leu412Phe. Furthermore, this substitution has been shown to activate SMO in the absence of Hh signaling, providing an explanation for tumor development in CJS. This raises therapeutic possibilities for using recently generated Hh-pathway inhibitors. In summary, our work uncovers the major genetic cause of CJS and illustrates strategies for gene discovery in the context of low-level tissue-specific somatic mosaicism

The elite athlete´s mental recovery

Att vila fysiskt är för många en självklarhet, däremot pratas det sällan om den mentala återhämtningen. Båda är viktiga och har stor påverkan på prestation och hälsa. I den här studien är syftet att undersöka elitidrottares upplevelser och erfarenheter av mental återhämtning. För att ta reda på detta har vi genomfört kvalitativa intervjuer. På vilket sätt respondenterna får återhämtning, hur de påverkas av frånvaro av mental återhämtning och om dessa idrottare upplever ett samband mellan frånvaron av mental återhämtning och psykisk ohälsa presenteras i resultatet. När vi analyserade resultaten av intervjuerna gjorde vi innehållsanalyser. Vi kom fram till att samtliga får återhämtning genom att tänka på annat än idrotten och genom att utöva aktiviteter som är roliga. Vid frånvaro av mental återhämtning upplevde majoriteten en försämrad prestation och att hälsan påverkades negativt. Respondenterna beskrev ett samband mellan psykisk ohälsa och frånvaro av mental återhämtning. Det finns relativt lite forskning inom detta område, däremot stämde resultaten med tidigare forskning som idag finns tillgänglig.To many people, resting physically is a matter of course, however, mental recovery is rarely talked about. Both are important and have major impact on performance and health. In this study, the aim is to investigate athletes experiences of mental recovery. In order to find out, we have conducted qualitative interviews. In what way the respondents receive recovery, how they are affected by the absence of mental recovery and if these athletes experience a connection between the absence of mental recovery and mental illness is presented in the results. When we analyzed the results of the interviews, we used content analyses. We concluded that all respondents receive recovery by thinking about other things than sport and by doing activities that are fun. In the absence of mental recovery, the majority experienced a deterioration in performance and a negative impact on health. The respondents described a link between mental illness and the absence of mental recovery. There is limited research in this area, but the results were consistent with previous research available today