Phenotypic spectrum of BLM- and RMI1-related Bloom syndrome

Bloom syndrome (BS) is an autosomal recessive disorder with characteristic clinical features of primary microcephaly, growth deficiency, cancer predisposition, and immunodeficiency. Here, we report the clinical and molecular findings of eight patients from six families diagnosed with BS. We identified causative pathogenic variants in all families including three different variants in BLM and one variant in RMI1. The homozygous c.581_582delTT;p.Phe194* and c.3164G>C;p.Cys1055Ser variants in BLM have already been reported in BS patients, while the c.572_573delGA;p.Arg191Lysfs*4 variant is novel. Additionally, we present the detailed clinical characteristics of two cases with BS in which we previously identified the biallelic loss-of-function variant c.1255_1259delAAGAA;p.Lys419Leufs*5 in RMI1. All BS patients had primary microcephaly, intrauterine growth delay, and short stature, presenting the phenotypic hallmarks of BS. However, skin lesions and upper airway infections were observed only in some of the patients. Overall, patients with pathogenic BLM variants had a more severe BS phenotype compared to patients carrying the pathogenic variants in RMI1, especially in terms of immunodeficiency which should be considered as one of the most important phenotypic characteristics of BS. This article is protected by copyright. All rights reserved

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Abstract The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification. This article is protected by copyright. All rights reserved.Peer reviewe

Pre-ovulatory follicular characteristics and ovulation rates in different breed crosses, carriers or non-carriers of the Booroola or Cambridge fecundity gene

Terminal follicular dynamics and ovulation rates (OR) were compared in different local breeds after introducing fecundity genes of different origin. Crossbred ewes which were carriers (F +) or non-carriers (+ +) of Booroola ((B)Fec) or Cambridge genes ((C)Fec) were included: Cambridge x Cambridge (CC), Cambridge x Suffolk (CS), Cambridge x Texel (CT), Booroola x Texel (BT) and Booroola x German Mutton Merino (BGM). The numbers of small (diameter 2-3.5 mm), medium (diameter > 3.5-5.0 mm) and large (diameter > 5.0 mm) growing follicles, the maximum diameter before ovulation and the regression and artesia rates of ovarian follicles ≥ 2 mm in diameter were studied laparoscopically and repeatedly during the last 5 days of an induced oestrous cycle. The ORs were determined one cycle before and two cycles after the repeated laparoscopy. (B)Fec and (C)Fec significantly enhanced the OR of all crossbreeds. Carriers of (B)Fec or (C)Fec did not have significantly different ORs due to any crossbreeding effect. The same observation was made for non-carriers of both Fec gene types. Whatever the crossbreed, the number of small, medium and large growing follicles were similar between carriers and non-carriers in spite of a higher number of ovulating follicles in carriers of both Fec gene types. The diameter of ovulatory follicles did not differ among crossbreds, or between carriers and non-carriers except in the BT (5.2 ± 0.2 vs. 6.5 ± 0.8 mm, respectively) and CC (6.6 ± 0.2 vs. 5.6 ± 0.3 mm) ewes. The higher OR in the presence of the Booroola gene was associated with a low atresia rate of large follicles in all crossbreeds (BT: 52 ± 8% (F +) vs. 61 ± 7% (+ +); BGM: 51 ± 6% vs. 75 ± 5%). The high OR of the carriers of the (C)Fec gene seemed to be associated with a lower number of large growing follicles with a lower (P < 0.05) atresia rate as compared with Booroola crossbreeds. In conclusion, follicular features were similar between purebred Cambridge and its crossbred CS and CT. In ewes carrying the (B)Fec or (C)Fec gene, the reduction in follicular atresia seemed to be one of the main follicular features implicated in the higher OR. (C) 2000 Elsevier Science B.V.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Somatic mosaicism in <em>STAG2</em>-associated cohesinopathies: Expansion of the genotypic and phenotypic spectrum.

STAG2 is a component of the large, evolutionarily highly conserved cohesin complex, which has been linked to various cellular processes like genome organization, DNA replication, gene expression, heterochromatin formation, sister chromatid cohesion, and DNA repair. A wide spectrum of germline variants in genes encoding subunits or regulators of the cohesin complex have previously been identified to cause distinct but phenotypically overlapping multisystem developmental disorders belonging to the group of cohesinopathies. Pathogenic variants in STAG2 have rarely been implicated in an X-linked cohesinopathy associated with undergrowth, developmental delay, and dysmorphic features. Here, we describe for the first time a mosaic STAG2 variant in an individual with developmental delay, microcephaly, and hemihypotrophy of the right side. We characterized the grade of mosaicism by deep sequencing analysis on DNA extracted from EDTA blood, urine and buccal swabs. Furthermore, we report an additional female with a novel de novo splice variant in STAG2. Interestingly, both individuals show supernumerary nipples, a feature that has not been reported associated to STAG2 before. Remarkably, additional analysis of STAG2 transcripts in both individuals showed only wildtype transcripts, even after blockage of nonsense-mediated decay using puromycin in blood lymphocytes. As the phenotype of STAG2-associated cohesinopathies is dominated by global developmental delay, severe microcephaly, and brain abnormalities, we investigated the expression of STAG2 and other related components of the cohesin complex during Bioengineered Neuronal Organoids (BENOs) generation by RNA sequencing. Interestingly, we observed a prominent expression of STAG2, especially between culture days 0 and 15, indicating an essential function of STAG2 in early brain development. In summary, we expand the genotypic and phenotypic spectrum of STAG2-associated cohesinopathies and show that BENOs represent a promising model to gain further insights into the critical role of STAG2 in the complex process of nervous system development

Mutations in the cyclin family member FAM58A cause an X-linked dominant disorder characterized by syndactyly, telecanthus and anogenital and renal malformations

We identified four girls with a consistent constellation of facial dysmorphism and malformations previously reported in a single mother-daughter pair. Toe syndactyly, telecanthus and anogenital and renal malformations were present in all affected individuals; thus, we propose the name 'STAR syndrome' for this disorder. Using array CGH, qPCR and sequence analysis, we found causative mutations in FAM58A on Xq28 in all affected individuals, suggesting an X-linked dominant inheritance pattern for this recognizable syndrome

Proceedings of the Frontiers of Retrovirology Conference 2016

The emergence of pandemic retroviral infection in small ruminant