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Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Genetics: MOPD types 1 and 3 were originally described as two separate disorders, mainly on the basis of radiological criteria, and were subsequently identified as a single entity. Inheritance is autosomal recessive. A candidate region has been mapped on 2q14.2-q14.3. Biallelic mutations have been identified in the RNU4ATAC gene, which encodes U4atac, a small nuclear RNA that is a crucial component of the minor spliceosome. This is the first disorder known to be associated with a defect in small nuclear RNA mutations in the RNU4ATAC gene.
First-trimester detection of micrognathia as a presentation of mandibulofacial dysostosis with microcephaly
Published in Journal of Obstetrics and Gynaecology, 2021
Bi-Qiu Xu, Li Zhen, Dong-Zhi Li
EFTUD2 encodes a small GTPase that is one of several subunits belonging to the U5 small nuclear ribonucleoprotein particle (snRNP) (Fabrizio et al. 1997). The U5 snRNP is a component of the major and minor spliceosome, two large macromolecular machines that mediate intron splicing. Therefore, a shortage of this enzyme impairs mRNA processing. This condition is inherited in an autosomal dominant pattern, and almost all cases result from new variants in the gene and occur in patients with no history of the disorder in their family. A range of gene deletions and rearrangements, as well as pathogenic point mutations of EFTUD2, have been reported. According to ACMG 2015 guidelines (Richards et al. 2015), the c.1058 + 1G > A variant is classified as likely pathogenic. A similar donor splice site variant, c.1058 + 2dup, has been reported in a MFDM patient (Yu et al. 2018). In total, splice site variants account for 29% of cases of MFDM. These arguments support the hypothesis that c.1058 + 1G > A is the causative variant in the present case. Although WES discloses the EFTUD2 variant in many sporadic cases, this approach is not recommended as a first-tier testing due to its technology limitations in the detection of gene deletions, which makes up approximately 16% of all reported MFDM-associated EFTUD2 defects (Gandomi et al. 2015; Zarate et al. 2015). WES is an excellent second-tier/reflex testing option in prenatal cases with structural anomalies when pathogenic copy number variations have been ruled out.
Cancer risk in systemic sclerosis: identifying risk and managing high-risk patients
Published in Expert Review of Clinical Immunology, 2020
George E. Fragoulis, Dimitris Daoussis, Eleni Pagkopoulou, Alexandros Garyfallos, George D. Kitas, Theodoros Dimitroulas
Although the association of malignancy with SSc-specific autoantibodies was the subject of some controversy in the past, recent studies have demonstrated a robust association between cancer and immunological profile, predominantly anti-RNAPol III) and antibodies against and topoisomerase-1 (Anti-Scl70) [9,46,69,70]. Patients with positive anti-RNAPol III have a > 5-fold increased risk of cancer within twoyears of scleroderma onset [71–75] independent of age at that time point. These patients have genetic alterations (somatic mutations and/or loss of heterozygosity) in the POLR3A locus that encodes for RNA polymerase III in their tumors that elicit a specific CD4 + T-cell response that ultimately triggers cross-reactive autoantibodies and appear to initiate the immune response in these individuals [74]. SSc patients with autoantibodies to RNA Binding Region Containing three (anti-RNPC3) have a short cancer-scleroderma interval (median 0.9 years), although their presence does not signify an increased risk of cancer overall [76]. RNPC3 is a member of the minor spliceosome complex that participates in the removal of U12-type introns from pre-mRNA and the mechanistic role of the autoantibodies against RNPC3 in the pathogenesis of scleroderma remains unclear. Regarding Anti-Scl70 antibodies, in a retrospective study of 318 patients, these antibodies were a risk factor for the occurrence of lung cancer (95% CI 1.7–24.1) [69]. Moreover, SSc Anti-Scl70-positive patients show a shortening of cancer–scleroderma interval with increased age at scleroderma onset [72]. SSc ‘triple-negative’ patients, meaning those who are lacking anticentromere antibodies (ACA), Anti-Scl70 and anti-RNAPol III antibodies (CentromereTopoisomerasePol [CTP]-negative), may also be at high risk of cancer-associated scleroderma [72,76,77], suggesting the possibility of other serologic subsets in the development of cancer-associated scleroderma. In contrast, patients with SSc and ACA antibodies appear to have a decreased risk of cancer compared with the general population [78]. Some studies in small cohorts of SSc patients with breast cancer have demonstrated that ACA antibodies may be associated with improved disease-free and overall survival [79–81]. Apart from anti-RNAPol III, it is likely that certain other more recently discovered autoantibodies such as PM/Scl seem to be associated with a higher risk of neoplasia [72,82].