Structures from the Stone Age can provide unique insights into Late Glacial and Mesolithic cultures around the Baltic Sea. Such structures, however, usually did not survive within the densely populated Central European subcontinent. Here, we ...The Baltic Sea basins, some of which only submerged in the mid-Holocene, preserve Stone Age structures that did not survive on land. Yet, the discovery of these features is challenging and requires cross-disciplinary approaches between archeology and ...

FTSJ1 is a phyllogenetically conserved human 2’-O-methyltransferase (Nm-MTase) which modifies position 32 as well as the wobble position 34 in the AntiCodon Loop (ACL) of specific tRNAs: tRNA​, tRNA​ and tRNA​. FTSJ1’s loss of function has been linked to Non-Syndromic X-Linked Intellectual Disability (NSXLID), and more recently in cancers. However, the exact molecular mechanisms underlying FTSJ1-related pathogenesis are unknown and a potential extended variety of FTSJ1’s tRNA targets hasn’t been fully addressed yet. We performed unbiased and comprehensive RiboMethSeq analysis of the Nm profiles for human tRNA population extracted from cells derived from NSXLID patients’ blood bearing various characterized loss of function mutations in FTSJ1. In addition, we reported a novel FTSJ1 pathogenic variant from a NSXLID patient bearing a ​de novo mutation in the ​FTSJ1 ​gene. Some of the newly identified FTSJ1’s tRNA targets are also conserved in ​Drosophila as shown by our previous study on the fly homologues Trm7_32 and Trm7_34, whose loss affects small RNA silencing pathways. In the current study, we reveal a conserved deregulation in both the miRNA and mRNA populations when FTSJ1 function is compromised. In addition, a cross-analysing between deregulated miRNA and mRNA obtained in FTSJ1 mutants highlighted upregulation of ​miR10a-5p which has the capacity to silence the ​SPARC gene mRNA, downregulated in FTSJ1 mutant cells. This suggests that FTSJ1 loss may influence gene expression deregulation by modulation of miRNA silencing. A gene-ontology (GO) enrichment analysis of the deregulated mRNAs primarily matched to brain morphogenesis terms, followed by metabolism and translation related genes. In parallel, the deregulated miRNAs are mostly known for their implication in brain functions and cancers. Based on these results, we suggest that miRNA silencing variations may play a role in the pathological mechanisms of FTSJ1-dependent NSXLID. Finally, our results highlight ​miR-181a-5p ​as a potential companion diagnostic test in clinical settings for FTSJ1-related intellectual disability.

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

Loss-of-function mutations in the X-linked gene FLNA can lead to abnormal neuronal migration, vascular and cardiac defects, and congenital intestinal pseudo-obstruction (CIPO), the latter characterized by anomalous intestinal smooth muscle layering. Survival in male hemizygotes for such mutations is dependent on retention of residual FLNA function but it is unclear why a subgroup of males with mutations in the 5' end of the gene can present with CIPO alone. Here, we demonstrate evidence for the presence of two FLNA isoforms differing by 28 residues at the N-terminus initiated at ATG+1 and ATG+82 . A male with CIPO (c.18_19del) exclusively expressed FLNA ATG+82 , implicating the longer protein isoform (ATG+1 ) in smooth muscle development. In contrast, mutations leading to reduction of both isoforms are associated with compound phenotypes affecting the brain, heart, and intestine. RNA-seq data revealed three distinct transcription start sites, two of which produce a protein isoform utilizing ATG+1 while the third utilizes ATG+82 . Transcripts sponsoring translational initiation at ATG+1 predominate in intestinal smooth muscle, and are more abundant compared with the level measured in fibroblasts. Together these observations describe a new mechanism of tissue-specific regulation of FLNA that could reflect the differing mechanical requirements of these cell types during development.

Mosaicism for FMR1 premutation (PM: 55–199 CGG)/full mutation (FM: >200 CGG) alleles or the presence of unmethylated FM (UFM) have been associated with a less severe fragile X syndrome (FXS) phenotype and fragile X associated tremor/ataxia syndrome (FXTAS)—a late onset neurodegenerative disorder. We describe a 38 year old male carrying a 100% methylated FM detected with Southern blot (SB), which is consistent with complete silencing of FMR1 and a diagnosis of fragile X syndrome. However, his formal cognitive scores were not at the most severe end of the FXS phenotype and he displayed tremor and ataxic gait. With the association of UFM with FXTAS, we speculated that his ataxia might be related to an undetected proportion of UFM alleles. Such UFM alleles were confirmed by more sensitive PCR based methylation testing showing FM methylation between 60% and 70% in blood, buccal, and saliva samples and real-time PCR analysis showing incomplete silencing of FMR1. While he did not meet diagnostic criteria for FXTAS based on MRI findings, the underlying cause of his ataxia may be related to UFM alleles not detected by SB, and follow-up clinical and molecular assessment are justified if his symptoms worsen.

American Journal of Medical Genetics Part AVolume 170, Issue 12 p. 3360-3362 Research Letter Somatic-gonadal mosaicism causing Sotos syndrome Benjamin Kamien, Corresponding Author Benjamin Kamien benkamien@yahoo.com.au Hunter Genetics, Newcastle, New South Wales, Australia School of Medicine and Public Health, The University of Newcastle, Newcastle, New South Wales, Australia School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, New South Wales, Australia Correspondence to: Benjamin Kamien, Hunter Genetics, PO Box 84, Waratah, Newcastle 2298, New South Wales, Australia. E-mail: benkamien@yahoo.com.auSearch for more papers by this authorTessa Dadd, Tessa Dadd Department of Diagnostic Genomics, PathWest Laboratory Medicine Western Australia, Perth, Western Australia, AustraliaSearch for more papers by this authorMelissa Buckman, Melissa Buckman Tamworth Community Health Centre, Genetic Counselling Service, Tamworth, New South Wales, AustraliaSearch for more papers by this authorAnne Ronan, Anne Ronan Hunter Genetics, Newcastle, New South Wales, Australia School of Medicine and Public Health, The University of Newcastle, Newcastle, New South Wales, AustraliaSearch for more papers by this authorTracy Dudding, Tracy Dudding Hunter Genetics, Newcastle, New South Wales, Australia School of Medicine and Public Health, The University of Newcastle, Newcastle, New South Wales, AustraliaSearch for more papers by this authorCliff Meldrum, Cliff Meldrum Molecular Medicine, Pathology North, Newcastle, New South Wales, AustraliaSearch for more papers by this authorRodney Scott, Rodney Scott School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, New South Wales, Australia Molecular Medicine, Pathology North, Newcastle, New South Wales, AustraliaSearch for more papers by this authorKym Mina, Kym Mina Department of Diagnostic Genomics, PathWest Laboratory Medicine Western Australia, Perth, Western Australia, Australia School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, Western Australia, AustraliaSearch for more papers by this author Benjamin Kamien, Corresponding Author Benjamin Kamien benkamien@yahoo.com.au Hunter Genetics, Newcastle, New South Wales, Australia School of Medicine and Public Health, The University of Newcastle, Newcastle, New South Wales, Australia School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, New South Wales, Australia Correspondence to: Benjamin Kamien, Hunter Genetics, PO Box 84, Waratah, Newcastle 2298, New South Wales, Australia. E-mail: benkamien@yahoo.com.auSearch for more papers by this authorTessa Dadd, Tessa Dadd Department of Diagnostic Genomics, PathWest Laboratory Medicine Western Australia, Perth, Western Australia, AustraliaSearch for more papers by this authorMelissa Buckman, Melissa Buckman Tamworth Community Health Centre, Genetic Counselling Service, Tamworth, New South Wales, AustraliaSearch for more papers by this authorAnne Ronan, Anne Ronan Hunter Genetics, Newcastle, New South Wales, Australia School of Medicine and Public Health, The University of Newcastle, Newcastle, New South Wales, AustraliaSearch for more papers by this authorTracy Dudding, Tracy Dudding Hunter Genetics, Newcastle, New South Wales, Australia School of Medicine and Public Health, The University of Newcastle, Newcastle, New South Wales, AustraliaSearch for more papers by this authorCliff Meldrum, Cliff Meldrum Molecular Medicine, Pathology North, Newcastle, New South Wales, AustraliaSearch for more papers by this authorRodney Scott, Rodney Scott School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, New South Wales, Australia Molecular Medicine, Pathology North, Newcastle, New South Wales, AustraliaSearch for more papers by this authorKym Mina, Kym Mina Department of Diagnostic Genomics, PathWest Laboratory Medicine Western Australia, Perth, Western Australia, Australia School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, Western Australia, AustraliaSearch for more papers by this author First published: 08 September 2016 https://doi.org/10.1002/ajmg.a.37867Citations: 3 Conflict of interest: None. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume170, Issue12December 2016Pages 3360-3362 RelatedInformation

Mutations in alpha- and beta-tubulins are increasingly recognized as a major cause of malformations of cortical development (MCD), typically lissencephaly, pachygyria and polymicrogyria; however, sequencing tubulin genes in large cohorts of MCD patients has detected tubulin mutations in only 1-13%. We identified patients with a highly characteristic cerebellar dysplasia but without lissencephaly, pachygyria and polymicrogyria typically associated with tubulin mutations. Remarkably, in seven of nine patients (78%), targeted sequencing revealed mutations in three different tubulin genes (TUBA1A, TUBB2B and TUBB3), occurring de novo or inherited from a mosaic parent. Careful re-review of the cortical phenotype on brain imaging revealed only an irregular pattern of gyri and sulci, for which we propose the term tubulinopathy-related dysgyria. Basal ganglia (100%) and brainstem dysplasia (80%) were common features. On the basis of in silico structural predictions, the mutations affect amino acids in diverse regions of the alpha-/beta-tubulin heterodimer, including the nucleotide binding pocket. Cell-based assays of tubulin dynamics reveal various effects of the mutations on incorporation into microtubules: TUBB3 p.Glu288Lys and p.Pro357Leu do not incorporate into microtubules at all, whereas TUBB2B p.Gly13Ala shows reduced incorporation and TUBA1A p.Arg214His incorporates fully, but at a slower rate than wild-type. The broad range of effects on microtubule incorporation is at odds with the highly stereotypical clinical phenotype, supporting differential roles for the three tubulin genes involved. Identifying this highly characteristic phenotype is important due to the low recurrence risk compared with the other (recessive) cerebellar dysplasias and the apparent lack of non-neurological medical issues.

Filamin A, the filamentous protein encoded by the X-linked gene FLNA, cross-links cytoskeletal actin into three-dimensional networks, facilitating its role as a signalling scaffold and a mechanosensor of extrinsic shear forces. Central to these functions is the ability of FLNA to form V-shaped homodimers through its C-terminal located filamin repeat 24. Additionally, many proteins that interact with FLNA have a binding site that includes the C-terminus of the protein. Here, a cohort of patients with mutations affecting this region of the protein is studied, with particular emphasis on the phenotype of male hemizygotes. Seven unrelated families are reported, with five exhibiting a typical female presentation of periventricular heterotopia (PH), a neuronal migration disorder typically caused by loss-of-function mutations in FLNA. One male presents with widespread PH consistent with previous male phenotypes attributable to hypomorphic mutations in FLNA. In stark contrast, two brothers are described with a mild PH presentation, due to a missense mutation (p.Gly2593Glu) inserting a large negatively charged amino acid into the hydrophobic dimerisation interface of FLNA. Co-immunoprecipitation, in vitro cross-linking studies and gel filtration chromatography all demonstrated that homodimerisation of isolated FLNA repeat 24 is abolished by this p.Gly2593Glu substitution but that extended FLNAGly2593Glu repeat 16–24 constructs exhibit dimerisation. These observations imply that other interactions apart from those mediated by the canonical repeat 24 dimerisation interface contribute to FLNA homodimerisation and that mutations affecting this region of the protein can have broad phenotypic effects.

Smith-Magenis syndrome (SMS) is a complex syndrome involving intellectual disabilities, sleep disturbance, behavioural problems, and a variety of craniofacial, skeletal, and visceral anomalies. While the majority of SMS cases harbor an ~3.5 Mb common deletion on 17p11.2 that encompasses the retinoic acid induced-1 (RAI1) gene, some patients carry small intragenic deletions or point mutations in RAI1. We present data on two cases of Smith-Magenis syndrome with mutation of RAI1. Both cases are phenotypically consistent with SMS and RAI1 mutation but also have other anomalies not previously reported in SMS, including spontaneous pneumothoraces. These cases also illustrate variability in the SMS phenotype not previously shown for RAI1 mutation cases, including hearing loss, absence of self-abusive behaviours, and mild global delays. Sequencing of RAI1 revealed mutation of the same heptameric C-tract (CCCCCCC) in exon 3 in both cases (c.3103delC one case and and c.3103insC in the other), resulting in frameshift mutations. Of the seven reported frameshift mutations occurring in poly C-tracts in RAI1, four cases (~57%) occur at this heptameric C-tract. Collectively, these results indicate that this heptameric C-tract is a preferential hotspot for single nucleotide insertion/deletions (SNindels) and therefore, should be considered a primary target for analysis in patients suspected for mutations in RAI1. We expect that as more patients are sequenced for mutations in RAI1, the incidence of frameshift mutations in this hotspot will become more evident.

PURPOSE:To measure the effectiveness of a tailored decision aid (DA) designed to help women make informed decisions about genetic testing for breast/ovarian cancer risk.METHODS:A total of 145 women were randomized to receive the DA or a control pamphlet at the end of their first genetic counseling consultation. Of these, 120 (82.8%) completed two questionnaires, 1 week and 6 months post-consultation.RESULTS:While the DA had no effect on informed choice, post-decisional regret or actual genetic testing decision, the trial showed that women who received the DA had higher knowledge levels and felt more informed about genetic testing than women who received the control pamphlet (chi(2)(2) = 6.82; P = 0.033; chi(2)(1) = 4.86; P = 0.028 respectively). The DA also helped women who did not have blood drawn at their first consultation to clarify their values with regards to genetic testing (chi(2)(1) = 5.27; P = 0.022). Women who received the DA were less likely to share the information with other family members than women in the control condition (chi(2)(1) = 8.78; P = 0.003).CONCLUSIONS:Decision aids are an effective decision-support strategy for women considering genetic testing for breast/ovarian cancer risk, and are most effective before the patient has made a decision, which is generally at the point of having blood drawn.

Two elderly brothers with severe intellectual disability were diagnosed with Angelman syndrome after a once‐removed, 15‐year‐old cousin was found to have the syndrome due to a deletion of the imprinting center. For many years it was believed the brothers, who both have macrocephaly, were affected by nonsyndromic X‐linked mental retardation. This was because, apart from absent speech and intellectual disability, the phenotype of the two men was not characteristic of Angelman syndrome. Conversely, the cousin, in addition to severe intellectual disability, language impairment, and ataxic gait, has microcephaly. None of the three have seizures, and so in the presence of the brothers' macrocephaly, Angelman syndrome was not considered until a diagnosis was made in the younger distant cousin. We report on a familial imprinting center deletion and the importance of considering the mild and atypical Angelman syndrome phenotypes within the differential diagnosis of intellectual handicap, particularly in clarifying the genetic risk to other family members. © 2007 Wiley‐Liss, Inc.

This multicentre study examined uptake of bilateral risk-reducing mastectomy (BRRM) and bilateral risk-reducing oophorectomy (BRRO) in women at increased risk for breast and/or ovarian cancer who had attended a familial cancer clinic (FCC) between January 1999 and June 2000. Eligible women (N=396), were mailed a questionnaire assessing: BRRM and BRRO details; risk perception; and anxiety. Family history, genetic testing and risk assessment were abstracted from medical records. Surgery was cross-tabulated with demographics, risk perception and anxiety with either Fisher’s exact test or the exact form of the Mantel–Haenszel test (for ordinal factors) used to investigate for associations. Ordinal logistic regression was used with continuous-scale covariates. In total, 130 women were lost to follow-up leaving 266; of these 182 (68.4%) responded. Mean follow-up time was 3.73 years. The BRRM rate was 4.4%; with no difference found between moderate and high-risk groups. BRRM was associated with increasing numbers of affected relatives (P=0.025). BRRO was undertaken by 17.3%, more commonly in women older than 40 years of age (P=0.023) and with a BRCA1/2 mutation (P=0.017). Women who underwent BRRM (P=0.052) or BRRO (P<0.001) had a lower post-procedure risk perception than those who did not. During the timeframe of this study, risk-reducing surgery was undertaken by a small percentage of Australian women at increased risk for breast and/or ovarian cancer who attended FCCs. Family cancer history and mutation status were associated with uptake.

This multicenter study examined the adherence of high-risk women to screening recommendations for breast and ovarian cancer following consultation at a familial cancer clinic (FCC). Self-report questionnaires assessing recall of screening advice, tests undertaken, risk perception, anxiety (Impact of Events Scale) and demographics were mailed to 396 consecutive eligible women who had attended one of six FCCs a median of 3.6 years prior. Family history, genetic test results and screening recommendations were abstracted from medical records. 182/266 (68.4%) women responded with 130 lost to follow-up. The proportions of women undertaking at least the recommended frequency of screening tests were: breast self examination (BSE) 50.4%, clinical breast examination (CBE) 66.0%, mammography 82.2%, transvaginal ultrasound (TVUS) 70.0%, CA125 84.0%. Factors associated with adherence to screening were: higher anxiety for BSE and CBE, being BRCA1/2 positive for CBE, older age, method of arrangement and having at least one affected first degree relative for mammography. Factors significantly associated with over-adherence were higher scores for anxiety for BSE and CBE and younger age (< 40 years) for TVUS. Between 41.3% (BSE) and 57.6% (CBE) of women incorrectly recalled their screening recommendations. A substantial minority of high-risk women do not adhere to screening advice. Strategies to improve the accuracy of recall of recommendations and the uptake of recommended screening are required.

Four cases with multiple patches of nevoid hypertrichosis have been reported. This fifth patient had multiple patches of nevoid hypertrichosis that underwent almost complete spontaneous resolution. Areas of unaffected skin showed depigmentation that followed the lines of Blaschko.