Mutations in the ERCC2 (XPD) gene associated with severe fetal ichthyosis and dysmorphic features

International audienceCongenital ichthyosis is a condition that includes several distinct subtypes with significant genetic heterogeneity. Defects in the ERCC2 [xeroderma pigmentosum (XP) complementation group D] gene lead to one of several clinical diseases, including XP, trichothiodystrophy, cerebrooculofacioskeletal syndrome, XP/Cockayne syndrome, and XP/trichothiodystrophy

A Central Role of Telomere Dysfunction in the Formation of a Unique Translocation within the Sub-Telomere Region Resulting in Duplication and Partial Trisomy

Telomeres play a major role in maintaining genome stability and integrity. Putative involvement of telomere dysfunction in the formation of various types of chromosomal aberrations is an area of active research. Here, we report a case of a six-month-old boy with a chromosomal gain encompassing the 11q22.3q25 region identified by SNP array analysis. The size of the duplication is 26.7 Mb and contains 170 genes (OMIM). The duplication results in partial trisomy of the region in question with clinical consequences, including bilateral renal dysplasia, delayed development, and a heart defect. Moreover, the karyotype determined by R-banding and chromosome painting as well as by hybridization with specific sub-telomere probes revealed the presence of an unbalanced t(9;11)(p24;q22.3) translocation with a unique breakpoint involving the sub-telomere region of the short arm of chromosome 9. The karyotypes of the parents were normal. Telomere integrity in circulating lymphocytes from the child and from his parents was assessed using an automated high-throughput method based on fluorescence in situ hybridization (FISH) with telomere- and centromere-specific PNA probes followed by M-FISH multicolor karyotyping. Very short telomeres, as well as an increased frequency of telomere loss and formation of telomere doublets, were detected in the child’s cells. Interestingly, similar telomere profiles were found in the circulating lymphocytes of the father. Moreover, an assessment of clonal telomere aberrations identified chromosomes 9 and 11 with particularly high frequencies of such aberrations. These findings strongly suggest that telomere dysfunction plays a central role in the formation of this specific unbalanced chromosome rearrangement via chromosome end-to-end fusion and breakage–fusion–bridge cycles

Telomere aberrations, including telomere loss, doublets, and extreme shortening, are increased in patients with infertility

International audienc

Bi-allelic variants in WNT7B disrupt the development of multiple organs in humans

International audienceBackground Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia and Cardiac defects delineate the PDAC syndrome. We aim to identify the cause of PDAC syndrome in patients who do not carry pathogenic variants in RARB and STRA6 , which have been previously associated with this disorder. Methods We sequenced the exome of patients with unexplained PDAC syndrome and performed functional validation of candidate variants. Results We identified bi-allelic variants in WNT7B in fetuses with PDAC syndrome from two unrelated families. In one family, the fetus was homozygous for the c.292C>T (p.(Arg98*)) variant whereas the fetuses from the other family were compound heterozygous for the variants c.225C>G (p.(Tyr75*)) and c.562G>A (p.(Gly188Ser)). Finally, a molecular autopsy by proxy in a consanguineous couple that lost two babies due to lung hypoplasia revealed that both parents carry the p.(Arg98*) variant. Using a WNT signalling canonical luciferase assay, we demonstrated that the identified variants are deleterious. In addition, we found that wnt7bb mutant zebrafish display a defect of the swimbladder, an air-filled organ that is a structural homolog of the mammalian lung, suggesting that the function of WNT7B has been conserved during evolution for the development of these structures. Conclusion Our findings indicate that defective WNT7B function underlies a form of lung hypoplasia that is associated with the PDAC syndrome, and provide evidence for involvement of the WNT–β-catenin pathway in human lung, tracheal, ocular, cardiac, and renal development

Biallelic variants in the transcription factor PAX7 are a new genetic cause of myopathy

Skeletal muscle growth and regeneration rely on muscle stem cells, called satellite cells. Specific transcription factors, particularly PAX7, are key regulators of the function of these cells. Knockout of this factor in mice leads to poor postnatal survival; however, the consequences of a lack of PAX7 in humans have not been established. Purpose Skeletal muscle growth and regeneration rely on muscle stem cells, called satellite cells. Specific transcription factors, particularly PAX7, are key regulators of the function of these cells. Knockout of this factor in mice leads to poor postnatal survival; however, the consequences of a lack of PAX7 in humans have not been established. Methods Here, we study five individuals with myopathy of variable severity from four unrelated consanguineous couples. Exome sequencing identified pathogenic variants in the PAX7 gene. Clinical examination, laboratory tests, and muscle biopsies were performed to characterize the disease. Results The disease was characterized by hypotonia, ptosis, muscular atrophy, scoliosis, and mildly dysmorphic facial features. The disease spectrum ranged from mild to severe and appears to be progressive. Muscle biopsies showed the presence of atrophic fibers and fibroadipose tissue replacement, with the absence of myofiber necrosis. A lack of PAX7 expression was associated with satellite cell pool exhaustion; however, the presence of residual myoblasts together with regenerating myofibers suggest that a population of PAX7-independent myogenic cells partially contributes to muscle regeneration. Conclusion These findings show that biallelic variants in the master transcription factor PAX7 cause a new type of myopathy that specifically affects satellite cell survival.German Bundesministerium für Bildung und Forschung through the Juniorverbund in der Systemmedizin “mitOmics” (FKZ01ZX1405C to T.B.H.) and Horizon2020 through the E-Rare project GENOMIT (01GM1603 and 01GM1207 for H.P. and FWFI2741B26 for J.A.M.) and the Deutsche Forschungsgemeinschaft (SCHO754/52 to L.S. and BA2427/22 to P.B.) as well as the Vereinigung zur Förderung Pädiatrischer Forschung und Fortbildung Salzburg, the EU FP7 Mitochondrial European Educational Training Project (317433 to H.P. and J.A.M.), and the EU Horizon2020 Collaborative Research Project SOUND (633974 to H.P.). N.A.D. is supported by grants from the Fonds de recherche du Québec–Santé (35015), Canadian Institutes of Health Research (388296), Rare Disease Foundation (2301), and CHU Sainte-Justine Foundation. N.A.D. acknowledges the support of ThéCell and Stem Cell Netwo

Surveillance on classical swine fever virus persistently infected farms and phenotypic alterations of peripheral blood mononuclear cells of swine after virus infection

中 文 摘 要豬瘟為豬之急性病毒性疾病，經常造成 嚴重的經濟損失。豬瘟病毒之持續性感染現象為豬瘟防疫及清除工作上所 需克服之難題。為配合政府豬瘟清除計畫之執行及了解豬瘟病毒在豬瘟污 染場中持續感染狀況，以病理學配合RT-PCR檢查，長期監控三場豬瘟污染 之一貫作業養豬場之病弱保育豬隻潛在感染豬瘟狀況，並配合豬瘟抗體 ELISA檢測，以了解豬場之群體免疫力。結果顯示，在持續一年的監控期 間，豬場內雖沒有典型豬瘟病例發生，但仍能持續從病弱豬隻中發現疑似 豬瘟病變及可檢測出豬瘟病毒RNA存在，證明豬瘟病毒確能在病弱豬群間 長期潛伏感染。由血清ELISA檢測結果，亦顯示在正常豬瘟活毒疫苗免疫 計畫下，仍有少數豬隻未呈現抗體反應，而易暴露於豬瘟病毒感染之威脅 下。進一步延續田間監控之試驗，在實驗室條件下，觀察免疫豬隻遭受野 外強毒攻毒後之細胞性免疫反應與淋巴次族群之變化情形，並探討豬瘟病 毒在免疫後耐過豬隻中持續性感染情形。結果指出，免疫過的豬隻在經豬 瘟病毒攻擊後，淋巴細胞對 concanvalin A 刺激引起的增殖反應，在大 部分豬隻皆不受到影響，但在少部份免疫反應不良之個體，呈現輕微抑制 的現象。在淋巴細胞次族群的變化方面，經免疫過的豬隻IgM+、CD4-CD8+ 、CD4+CD8-及CD4+CD8+淋巴細胞有暫時性抑制後上升的現象，但在不同免 疫方式下其改變有些許不同。其中以哺乳前免疫加六週齡免疫組在豬瘟病 毒攻擊後，血液中淋巴次族群的變化較小。免疫過的豬隻在攻毒後一個月 ，仍可以RT-PCR檢測出豬瘟病毒存在於淋巴臟器中，顯示免疫豬隻仍有帶 野外毒之可能。綜合各實驗結果，豬瘟病毒在豬場病弱保育豬隻及正常免 疫豬群中可長期持續感染。因此，加強豬瘟污染場之監控，完整的免疫計 畫，並配合病弱豬淘汰，有助於將豬瘟病毒由豬場中清除。AbstractClassical swine fever ( CSF ) is a highly contagious disease of swine and leads to severe economic losses. The persistence of CSF virus (CSFV) infection is the major problem in the control and eradication of the disease. In corresponding to the CSFV eradication program in Taiwan and the investigation of CSFV persistence in pig farms, a monitoring system of pathological examination and reverse transcriptase - polymerase chain reaction ( RT-PCR ) method focused on weak nursing pigs were undertaken on three CSFV contaminated farms. Over one-year monitoring, there was no typical clinical CSF case, however, presumable pathological lesions and positive reaction of RT-PCR for CSFV could be persistently detected in those random samples from all three pig farms. Moreover, a serological survey on these pig farms with routine LPC vaccination programs also indicated that there were still some portions of pigs lack of CSF ELISA antibody response, which might be susceptible for CSFV infection. Following monitoring study of CSF virus persistence, the alteration of subpopulations of peripheral blood mononuclear cells, lymphoproliferative responses, and virus persistence were carried on pigs with three different CSF vaccination programs and control pigs, which were challenged with virulent CSFV ( 2*10^7 pfu). The results indicated that the lymphoproliferative function of most vaccinated pigs was not significantly affected, however, the function in a few vaccinated pigs with poor immune response was partially impaired. The alterations of lymphocyte subpopulations, including, IgM+, CD4-CD8+, CD4+CD8-, and CD4+ CD8+ lymphocytes showed slight decrease during early phase of infection and then returned to normal level later. Pigs vaccinated before consumption of colostrum and booosted at 6-week-old showed the less effect on these alterations and less clinical signs after CSFV challenge. However, virulent virus RNA from recovered pigs could be detected by RT-PCR method over 1 month after CSFV challenged (2*107 pfu). Conclusively, CSFV could long term persistence in weak nursing pigs in CSFV contaminated pig farms. Therefore, to eradicate CSFV from contaminated pig farms, an intensive CSF vaccination program and a monitoring system on CSF persistence by RT-PCR combined with a strict culling strategy might be required

Additional file 5: of Uncommon nucleotide excision repair phenotypes revealed by targeted high-throughput sequencing

Clinical pictures of patients #8 (A) and #9 (B) (mutated in ERCC8(CSA)). (PPTX 403 kb

Further delineation of theduplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features

The Xq28 duplication involving thegene (duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitialduplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype ofduplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life.status: accepte

Further delineation of the MECP2 duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features

IF 5.751International audienceThe Xq28 duplication involving the MECP2 gene (MECP2 duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitial MECP2 duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype of MECP2 duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life