Staging and managing patients with acromegaly in clinical practice: baseline data from the SAGIT® validation study

Pituitary - The SAGIT® instrument, designed to assist clinicians to stage acromegaly, assess treatment response and adapt patient management, was well received by endocrinologists in a pilot...     

Novel NOBOX loss-of-function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort

Primary ovarian insufficiency (POI) is a disorder associated with female infertility, which affects approximately 1% of women under 40 years of age. A genetic component has been suggested as one possible cause of the majority of cases of nonsyndromic forms. Newborn Ovary Homeobox (NOBOX) is an ovary-specific gene, playing a critical role in ovary in mice, as its absence leads to sterility mimicking a POI. In this study, we sequenced NOBOX in a cohort of 178 women with idiopathic POI. Among 19 identified variations, we described one nonsense (c.907C>T/p.R303X) and four missense (c.271G>T/p.G91W, c.349C>T/p.R117W, c.1025G>C/p.S342T, and c.1048G>T/p.V350L) NOBOX heterozygous mutations in 12 patients. We reproduced each of the five mutations and tested their effects on the signaling activity in transfected cells. We demonstrated that these mutations compromised the ability of the proteins to bind to and transactivate the well-known growth differentiation factor 9 (GDF9) promoter. The pattern of our findings suggests that the genetic mechanism in humans responsible for POI in women involves haploinsufficiency rather than dominant negative gene action. The identification, characterization, and the very high 6.2% prevalence of these new mutations in POI patients suggest considering NOBOX as the first autosomal candidate gene involved in this syndrome.     

Parental mosaicism in Marfan and Ehlers–Danlos syndromes and related disorders

Marfan syndrome (MFS) is a heritable connective tissue disorder (HCTD) caused by pathogenic variants in FBN1 that frequently occur de novo. Although individuals with somatogonadal mosaicisms have been reported with respect to MFS and other HCTD, the overall frequency of parental mosaicism in this pathology is unknown. In an attempt to estimate this frequency, we reviewed all the 333 patients with a disease-causing variant in FBN1. We then used direct sequencing, combined with High Resolution Melting Analysis, to detect mosaicism in their parents, complemented by NGS when a mosaicism was objectivized. We found that (1) the number of apparently de novo events is much higher than the classically admitted number (around 50% of patients and not 25% as expected for FBN1) and (2) around 5% of the FBN1 disease-causing variants were not actually de novo as anticipated, but inherited in a context of somatogonadal mosaicisms revealed in parents from three families. High Resolution Melting Analysis and NGS were more efficient at detecting and evaluating the level of mosaicism compared to direct Sanger sequencing. We also investigated individuals with a causal variant in another gene identified through our “aortic diseases genes” NGS panel and report, for the first time, on an individual with a somatogonadal mosaicism in COL5A1. Our study shows that parental mosaicism is not that rare in Marfan syndrome and should be investigated with appropriate methods given its implications in patient’s management.Subject terms: Aortic diseases, Medical genetics, Disease genetics, Genetic counselling     

IL‐33‐expanded human Vγ9Vδ2 T cells have anti‐lymphoma effect in a mouse tumor model

From several years, the anticancer effects of Vγ9 T lymphocytes make these cells good candidates for cancer immunotherapies. However, the proved efficacy of γδ Τ cell‐based cancer immunotherapies in some clinical trials was minimized due to the inherent toxicity of IL‐2, which is essential for the combination therapy with Phosphoantigen (PAg). Recently, we showed that IL‐33, a γ chain receptor‐independent cytokine, was able to induce the in vitro proliferation of PAg‐activated Vγ9 T cells, which were fully functional expressing IFN‐γ and TNF‐α and showing in vitro anti‐tumor cytotoxicity. We proposed IL‐33 as an alternative to IL‐2 for Vγ9 T cell‐based cancer immunotherapies, and have therefore evaluated the efficacy of this cytokine in preclinical investigations. This study shows that human Vγ9 T cells are able to proliferate in a mouse model with the combination of PAg and rhIL‐33, and that IL‐33‐expanded Vγ9 T cells can prevent tumor growth in a mouse lymphoma model.     

Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders

Background

Autism spectrum disorders (ASD) refer to a broader group of neurobiological conditions, pervasive developmental disorders. They are characterised by a symptomatic triad associated with qualitative changes in social interactions, defect in communication abilities, and repetitive and stereotyped interests and activities. ASD is prevalent in 1 to 3 per 1000 people. Despite several arguments for a strong genetic contribution, the molecular basis of a most cases remains unexplained. About 5% of patients with autism have a chromosome abnormality visible with cytogenetic methods. The most frequent are 15q11–q13 duplication, 2q37 and 22q13.3 deletions. Many other chromosomal imbalances have been described. However, most of them remain undetectable using routine karyotype analysis, thus impeding diagnosis and genetic counselling.

Methods and results

29 patients presenting with syndromic ASD were investigated using a DNA microarray constructed from large insert clones spaced at approximately 1 Mb intervals across the genome. Eight clinically relevant rearrangements were identified in 8 (27.5%) patients: six deletions and two duplications. Altered segments ranged in size from 1.4 to 16 Mb (2–19 clones). No recurrent abnormality was identified.

Conclusion

These results clearly show that array comparative genomic hybridisation should be considered to be an essential aspect of the genetic analysis of patients with syndromic ASD. Moreover, besides their importance for diagnosis and genetic counselling, they may allow the delineation of new contiguous gene syndromes associated with ASD. Finally, the detailed molecular analysis of the rearranged regions may pave the way for the identification of new ASD genes.Autism spectrum disorders (ASD) belong to the group of pervasive developmental disorders (PDD). According to the Diagnostic statistical manual for mental disorders—fourth edition (DSM IV) classification,¹ ASD are characterised by impairments in communication, social skills and restricted or stereotyped pattern of behaviours and interests. A diagnosis within the autism spectrum requires one or more symptoms in each of the three areas of impairment. The prevalence of ASD is estimated at about 1/1000 to 3/1000.^2,3 ASD are heterogeneous conditions which can be either isolated or syndromic—that is, associated with other clinical features such as facial dysmorphism, limb or visceral malformations, and growth abnormalities.A total of 10–20% of ASD cases are due to known medical conditions involving chromosomal imbalances, genetic disorders (X fragile syndrome and tuberous sclerosis)⁴ or environmental factors (valproate⁵ and rubella). The other cases remain unexplained. Twin and familial studies have documented a higher concordance rate in monozygotic twins (90%) than in dizygotic twins (4.5%),^6,7,8 and a 75‐fold greater risk to siblings in idiopathic patients than in the general population.^9,10 Collectively, these studies support the involvement of numerous genes in autistic disorders.About 1.7–4.8% of people with ASD have chromosome abnormalities. Almost all chromosomes have been involved, including unbalanced translocations, inversions, rings, and interstitial or terminal deletions and duplications.^11,12,13,14 The rare chromosome abnormalities that have been reported on more than one occasion are duplication of 15q,¹⁵ deletions of 18q,^16,17 Xp,^18,19 2q37,²⁰ 22q13^21,22 and the sex chromosome aneuploidies 47,XYY^23,24 and 45,X/46,XY.^25,26 This diversity of loci suggests that studying chromosomal aberrations in relationship to autism will require efficient and highly sensitive tools. In addition to the importance for diagnosis, identification of chromosomal imbalances in patients with ASD may also be instrumental for cloning disease‐causing genes. Analysis of Xp22.3 deletion has indeed allowed the identification of the NLGN4 gene.²⁷Recent technological developments, such as array‐based comparative genomic hybridisation (array‐CGH),^28,29,30 allow the investigation of the human genome at a resolution that is 5–10 times higher than that of routine chromosome analysis by karyotyping.^29,31,32,33 Array‐CGH has been used successfully for analysis of tumour samples and cell lines, and for high‐resolution analysis of patients with mental retardation and congenital anomalies.^{34,35,36,37,38}Here, we report the application of genomewide array‐CGH, at 1 Mb resolution, to the study of 29 patients with syndromic ASD. In addition to their clinical relevance, our results emphasise the importance of chromosomal imbalance in the aetiology of syndromic ASD and may help the identification of new genes involved in autistic disorders.