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Supplementary Table 1. Sensitivity analysis excluding 1 year follow-up

Background: Randomized controlled trials have demonstrated significant reductions in colorectal cancer incidence and mortality associated with polypectomy. However, little is known about whether polypectomy is effective at reducing colorectal cancer risk in routine clinical practice. The aim of this investigation was to quantify colorectal cancer risk following polypectomy in a large prospective population-based cohort study.Methods: Patients with incident colorectal polyps between 2000 and 2005 in Northern Ireland were identified via electronic pathology reports received to the Northern Ireland Cancer Registry. Patients were matched to the Northern Ireland Cancer Registry to detect colorectal cancer and deaths up to December 31, 2010. Colorectal cancer standardized incidence ratios (SIR) were calculated and Cox proportional hazards modeling applied to determine colorectal cancer risk.Results: During 44,724 person-years of follow-up, 193 colorectal cancer cases were diagnosed among 6,972 adenoma patients, representing an annual progression rate of 0.43%. Colorectal cancer risk was significantly elevated in patients who had an adenoma removed (SIR, 2.85; 95% CI, 2.61–3.25) compared with the general population. Male sex, older age, rectal site, and villous architecture were associated with an increased colorectal cancer risk in adenoma patients. Further analysis suggested that not having a full colonoscopy performed at, or following, incident polypectomy contributed to the excess colorectal cancer risk.Conclusions: Colorectal cancer risk was elevated in individuals following polypectomy for adenoma, outside of screening programs.Impact: This finding emphasizes the need for full colonoscopy and adenoma clearance, and appropriate surveillance, after endoscopic diagnosis of adenoma. Cancer Epidemiol Biomarkers Prev; 24(9); 1373–80. ©2015 AACR.

Pathogenic variants in IQ motif and SEC7 domain containing protein 2 (IQSEC2) gene cause a variety of neurodevelopmental disorders, with intellectual disability as a uniform feature. We report five cases, each with a novel missense variant in the pleckstrin homology (PH) domain of the IQSEC2 protein. Male patients all present with moderate to profound intellectual disability, significant delays or absent language and speech and variable seizures. We describe the phenotypic spectrum associated with missense variants in PH domain of IQSEC2, further delineating the genotype-phenotype correlation for this X-linked gene.

Purpose Currently, 31 patients with classical-like EDS (clEDS) due to tenascin-X deficiency have been reported in the literature. We report on the clinical and molecular characteristics of 20 additional patients with clEDS to expand knowledge and to enable improved management of this rare genetic disorder. Methods Patients diagnosed with clEDS by the national EDS service in the UK (n = 21) and abroad (n = 1) were asked for consent for publication of their clinical and molecular data. Results Of 22 patients, 20 consented. All patients had typical features of clEDS: joint hypermobility, easy bruising, and skin hyperextensibility without atrophic scars. Importantly, 3/20 patients experienced gastrointestinal complications consisting of small or large bowel ruptures and one esophageal rupture. Other notable observations included two separate occurrences of spontaneous compartment syndrome, suspicion of nonaccidental injury due to significant bruising, and significant clinical variability regarding the debilitating effect of joint dislocations. Conclusions We propose a predisposition to tissue fragility, particularly of the gastrointestinal tract in patients with clEDS. As such, clinical and molecular confirmation of this diagnosis is essential. It is recommended to follow up these patients closely to understand the natural history to develop better recommendations for management.

The SRPX2 gene (Sushi-repeat-containing protein, X-linked, 2, OMIM*300642), located on Xq22.1, encodes a secreted protein that is highly expressed in neurons of cerebral cortex. SRPX2 was first implicated in neurodevelopment, learning and rolandic seizure when two patients with potentially pathogenic variants, c.980A>G (p.Asn327Ser) and c.215A>C (p.Tyr72Ser), in SRPX2 gene were identified. Subsequent experimental studies demonstrated that SRPX2 is needed for vocalization and synapse formation in mice, and that both silencing SRPX2 and injecting (p.Asn327Ser) in mouse models results in alteration in neuronal migration in cerebral cortex and epilepsy. A number of studies demonstrated that SRPX2 interacts with FOXP2 (Foxhead box protein P2), a gene responsible for speech and language disorder, and that FoxP2 controls timing and level of expression of SRPX2. Despite the supportive evidence for the role of SRPX2 in speech and language development and disorders, there are questions over its definitive association with neurodevelopmental disorders and epilepsy. In this paper, the role of SRPX2 as one in a network of many genes involved in speech and language is discussed. The goal of this paper is to examine the role of SRPX2 variants through describing two patients with potentially pathogenic variants in SRPX2, c.751G>C (p.Ala251Pro) and c.762G>T (p.Lys254Asn) presenting with language and motor delay, intellectual disability as well as congenital anomalies. We explore the contribution of SRPX2 variants to clinical phenotype in our patients and conclude that these variants at least partially explain the phenotype. Further studies are necessary to establish and confirm the association between SRPX2 and neurodevelopment particularly speech and language development.

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.

Background Irish Travellers are an endogamous, nomadic, ethnic minority population mostly resident on the island of Ireland with smaller populations in Europe and the USA. High levels of consanguinity result in many rare autosomal recessive disorders. Due to founder effects and endogamy, most recessive disorders are caused by specific homozygous mutations unique to this population. Key clinicians and scientists with experience in managing rare disorders seen in this population have developed a de facto advisory service on differential diagnoses to consider when faced with specific clinical scenarios.Objective(s) To catalogue all known inherited disorders found in the Irish Traveller population.Methods We performed detailed literature and database searches to identify relevant publications and the disease mutations of known genetic disorders found in Irish Travellers.Results We identified 104 genetic disorders: 90 inherited in an autosomal recessive manner; 13 autosomal dominant and one a recurring chromosomal duplication.Conclusion We have collated our experience of inherited disorders found in the Irish Traveller population to make it publically available through this publication to facilitate a targeted genetic approach to diagnostics in this ethnic group.

Contains fulltext : 206572.pdf (Publisher’s version ) (Open Access) We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

Background Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith–Magenis syndrome (deletion/haploinsufficiency) and Potocki–Lupski syndrome (duplication/triplosensitivity). Methods Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. Results We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. Conclusions TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith–Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective. Electronic supplementary material The online version of this article (10.1186/s13073-019-0623-0) contains supplementary material, which is available to authorized users.

© 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.

Lymphedema is characterized by chronic swelling of any body part caused by malfunctioning or obstruction in the lymphatic system. Primary lymphedema is often considered genetic in origin. VEGFC, which is a gene encoding the ligand for the vascular endothelial growth factor receptor 3 (VEGFR3/FLT4) and important for lymph vessel development during lymphangiogenesis, has been associated with a specific subtype of primary lymphedema. Through Sanger sequencing of a proband with bilateral congenital pedal edema resembling Milroy disease, we identified a novel mutation (NM_005429.2, c.361+5G&gt, A) in VEGFC. The mutation induced skipping of exon 2 of VEGFC resulting in a frameshift and the introduction of a premature stop codon (p.Ala50ValfsTer18). The mutation leads to a loss of the entire VEGF-homology domain and the C-terminus. Expression of this Vegfc variant in the zebrafish floorplate showed that the splice-site variant significantly reduces the biological activity of the protein. Our findings confirm that the splice-site variant, c.361+5G&gt, A, causes the primary lymphedema phenotype in the proband. We examine the mutations and clinical phenotypes of the previously reported cases to review the current knowledge in this area.

Summary Background Germline pathogenic variants in the E-cadherin gene ( CDH1 ) are strongly associated with the development of hereditary diffuse gastric cancer. There is a paucity of data to guide risk assessment and management of families with hereditary diffuse gastric cancer that do not carry a CDH1 pathogenic variant, making it difficult to make informed decisions about surveillance and risk-reducing surgery. We aimed to identify new candidate genes associated with predisposition to hereditary diffuse gastric cancer in affected families without pathogenic CDH1 variants. Methods We did whole-exome sequencing on DNA extracted from the blood of 39 individuals (28 individuals diagnosed with hereditary diffuse gastric cancer and 11 unaffected first-degree relatives) in 22 families without pathogenic CDH1 variants. Genes with loss-of-function variants were prioritised using gene-interaction analysis to identify clusters of genes that could be involved in predisposition to hereditary diffuse gastric cancer. Findings Protein-affecting germline variants were identified in probands from six families with hereditary diffuse gastric cancer; variants were found in genes known to predispose to cancer and in lesser-studied DNA repair genes. A frameshift deletion in PALB2 was found in one member of a family with a history of gastric and breast cancer. Two different MSH2 variants were identified in two unrelated affected individuals, including one frameshift insertion and one previously described start-codon loss. One family had a unique combination of variants in the DNA repair genes ATR and NBN . Two variants in the DNA repair gene RECQL5 were identified in two unrelated families: one missense variant and a splice-acceptor variant. Interpretation The results of this study suggest a role for the known cancer predisposition gene PALB2 in families with hereditary diffuse gastric cancer and no detected pathogenic CDH1 variants. We also identified new candidate genes associated with disease risk in these families. Funding UK Medical Research Council (Sackler programme), European Research Council under the European Union's Seventh Framework Programme (2007–13), National Institute for Health Research Cambridge Biomedical Research Centre, Experimental Cancer Medicine Centres, and Cancer Research UK.

Mutations which perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7,833 probands with developmental disorders (DD) and their unaffected parents, as well as >60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice site, and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. Using mutational burden analyses in this large cohort of proband-parent trios, we could estimate in an unbiased manner the relative contributions of mutations at canonical dinucleotides (73%) and flanking non-canonical positions (27%), and calculated the positive predictive value of pathogenicity for different classes of mutations. We identified 18 patients with likely diagnostic de novo mutations in dominant DD-associated genes at non-canonical positions in splice sites. We estimate 35-40% of pathogenic variants in non-canonical splice site positions are missing from public databases.

It was highlighted that the original article [1] contained a typographical error in the Results section. Subject 17 was incorrectly cited as Subject 1. This Correction article shows the revised statement. The original article has been updated.

Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.

Early B cell factor 3 (EBF3) is an atypical transcription factor that is thought to influence the laminar formation of the cerebral cortex. Here, we report that de novo mutations in EBF3 cause a complex neurodevelopmental syndrome. The mutations were identified in two large-scale sequencing projects: the UK Deciphering Developmental Disorders (DDD) study and the Canadian Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) study. The core phenotype includes moderate to severe intellectual disability, and many individuals exhibit cerebellar ataxia, subtle facial dysmorphism, strabismus, and vesicoureteric reflux, suggesting that EBF3 has a widespread developmental role. Pathogenic de novo variants identified in EBF3 include multiple loss-of-function and missense mutations. Structural modeling suggested that the missense mutations affect DNA binding. Functional analysis of mutant proteins with missense substitutions revealed reduced transcriptional activities and abilities to form heterodimers with wild-type EBF3. We conclude that EBF3, a transcription factor previously unknown to be associated with human disease, is important for brain and other organ development and warrants further investigation.

Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve.

MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients. © 2012 Macmillan Publishers Limited All rights reserved.

The biological processes controlling human growth are diverse, complex and poorly understood. Genetic factors are important and human height has been shown to be a highly polygenic trait to which common and rare genetic variation contributes. Weaver syndrome is a human overgrowth condition characterised by tall stature, dysmorphic facial features, learning disability and variable additional features. We performed exome sequencing in four individuals with Weaver syndrome, identifying a mutation in the histone methyltransferase, EZH2, in each case. Sequencing of EZH2 in additional individuals with overgrowth identified a further 15 mutations. The EZH2 mutation spectrum in Weaver syndrome shows considerable overlap with the inactivating somatic EZH2 mutations recently reported in myeloid malignancies. Our data establish EZH2 mutations as the cause of Weaver syndrome and provide further links between histone modifications and regulation of human growth.

Summary Patients with chronic mucocutaneous candidiasis (CMC) suffer persistent infections with the yeast Candida. CMC includes patients with autoimmune regulator (AIRE) gene mutations who have autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), and patients without known mutations. CMC patients have dysregulated cytokine production, and dendritic cells (DCs), as central orchestrators, may underlie pathogenic disease mechanisms. In 29 patients with CMC (13 with APECED) and controls, we generated monocyte-derived DCs, stimulated them with Candida albicans, Toll-like receptor-2/6 ligand and lipopolysaccharide to assess cytokine production [interleukin (IL)-12p70, IL-23, interferon (IFN)-γ, IL-2, tumour necrosis factor (TNF)-α, IL-6, transforming growth factor-β, IL-10, IL-5, IL-13] and cell-surface maturation marker expression (CD83, CD86, human leucocyte antigen D-related). In both APECED and non-APECED CMC patients, we demonstrate impairment of DC function as evidenced by altered cytokine expression profiles and DC maturation/activation: (1) both groups over-produce IL-2, IFN-γ, TNF-α and IL-13 and demonstrate impaired DC maturation. (2) Only non-APECED patients showed markedly decreased Candida-stimulated production of IL-23 and markedly increased production of IL-6, suggesting impairment of the IL-6/IL-23/T helper type 17 axis. (3) In contrast, only APECED patients showed DC hyperactivation, which may underlie altered T cell responsiveness, autoimmunity and impaired response to Candida. We demonstrate different pathogenic mechanisms on the same immune response pathway underlying increased susceptibility to Candida infection in these patients.

The major function of vascular smooth muscle cells (SMCs) is contraction to regulate blood pressure and flow. SMC contractile force requires cyclic interactions between SMC alpha-actin (encoded by ACTA2) and the beta-myosin heavy chain (encoded by MYH11). Here we show that missense mutations in ACTA2 are responsible for 14% of inherited ascending thoracic aortic aneurysms and dissections (TAAD). Structural analyses and immunofluorescence of actin filaments in SMCs derived from individuals heterozygous for ACTA2 mutations illustrate that these mutations interfere with actin filament assembly and are predicted to decrease SMC contraction. Aortic tissues from affected individuals showed aortic medial degeneration, focal areas of medial SMC hyperplasia and disarray, and stenotic arteries in the vasa vasorum due to medial SMC proliferation. These data, along with the previously reported MYH11 mutations causing familial TAAD, indicate the importance of SMC contraction in maintaining the structural integrity of the ascending aorta.

Background: Randomized controlled trials have demonstrated significant reductions in colorectal cancer incidence and mortality associated with polypectomy. However, little is known about whether polypectomy is effective at reducing colorectal cancer risk in routine clinical practice. The aim of this investigation was to quantify colorectal cancer risk following polypectomy in a large prospective population-based cohort study. Methods: Patients with incident colorectal polyps between 2000 and 2005 in Northern Ireland were identified via electronic pathology reports received to the Northern Ireland Cancer Registry. Patients were matched to the Northern Ireland Cancer Registry to detect colorectal cancer and deaths up to December 31, 2010. Colorectal cancer standardized incidence ratios (SIR) were calculated and Cox proportional hazards modeling applied to determine colorectal cancer risk. Results: During 44,724 person-years of follow-up, 193 colorectal cancer cases were diagnosed among 6,972 adenoma patients, representing an annual progression rate of 0.43%. Colorectal cancer risk was significantly elevated in patients who had an adenoma removed (SIR, 2.85; 95% CI, 2.61–3.25) compared with the general population. Male sex, older age, rectal site, and villous architecture were associated with an increased colorectal cancer risk in adenoma patients. Further analysis suggested that not having a full colonoscopy performed at, or following, incident polypectomy contributed to the excess colorectal cancer risk. Conclusions: Colorectal cancer risk was elevated in individuals following polypectomy for adenoma, outside of screening programs. Impact: This finding emphasizes the need for full colonoscopy and adenoma clearance, and appropriate surveillance, after endoscopic diagnosis of adenoma. Cancer Epidemiol Biomarkers Prev; 24(9); 1373–80. ©2015 AACR.

Non-syndromic familial thoracic aortic aneurysms and dissections (TAAD) are inherited in an autosomal dominant manner. We report a missense mutation in the smooth muscle α-actin (ACTA2; MIM*102620) gene in a 3 generational family from Northern Ireland in which iris flocculi were an ocular marker of the disease.

PURPOSE Stiff skin syndrome (SSS; MIM#184900) is a rare autosomal dominantly inherited Mendelian disorder characterised by thickened and stone-hard indurations of the skin, mild hypertrichosis, and limitation of joint mobility with flexion contractures. It is autosomal dominant with high penetrance and results from mutations in the fibrillin 1 (FBN1; MIM*134797) gene. Here we present the associated ocular phenotype in a two generation nonconsanguineous Northern Irish family.METHODS The affected patients underwent complete ophthalmic and orthoptic assessment and genetic testing.RESULTS All three patients had ophthalmoplegia of varying degrees. Direct sequencing of the FBN1 gene detected a heterozygous pathogenic mutation (c.4710G>C; p.Trp1570Cys) in all affected patients.CONCLUSIONS This is the first report of ophthalmoplegia in association with SSS.

Background COL11A1 is a large complex gene around 250 kb in length and consisting of 68 exons. Pathogenic mutations in the gene can result in Stickler syndrome, Marshall syndrome or Fibrochondrogenesis. Many of the mutations resulting in either Stickler or Marshall syndrome alter splice sites and result in exon skipping, which because of the exon structure of collagen genes usually leaves the message in-frame. The mutant protein then exerts a dominant negative effect as it co-assembles with other collagen gene products. To date only one large deletion of 40 kb in the COL11A1, which was detected by RT-PCR, has been characterized. However, commonly used screening protocols, utilizing genomic amplification and exon sequencing, are unlikely to detect such large deletions. Consequently the frequency of this type of mutation is unknown. Case presentations We have used Multiplex Ligation-Dependent Probe Amplification (MLPA) in conjunction with exon amplification and sequencing, to analyze patients with clinical features of Stickler syndrome, and have detected six novel deletions that were not found by exon sequencing alone. Conclusion Exon deletions appear to represent a significant proportion of type 2 Stickler syndrome. This observation was previously unknown and so diagnostic screening of COL11A1 should include assays capable of detecting both large and small deletions, in addition to exon sequencing.

Sotos syndrome is an overgrowth disorder with autosomal dominant inheritance caused by mutations and deletions in the nuclear receptor Set domain-containing protein 1 gene. In general, affected individuals have an advanced bone age, macrocephaly, characteristic facial gestalt and learning difficulties. Genotype-phenotype correlations are unclear. Full penetrance is seen and 95% of cases are de novo. Here, we report a three-generation pedigree, with at least eight affected individuals, shown to harbour the nuclear receptor Set domain-containing protein 1 missense mutation c. 6115C>T. To our knowledge, this is the largest Sotos family reported. The observed phenotype is extremely variable, thus highlighting the clinical heterogeneity that may occur.

Most patients with autoimmune polyendocrine syndrome type I (APS-I) display chronic mucocutaneous candidiasis (CMC). We hypothesized that this CMC might result from autoimmunity to interleukin (IL)-17 cytokines. We found high titers of autoantibodies (auto-Abs) against IL-17A, IL-17F, and/or IL-22 in the sera of all 33 patients tested, as detected by multiplex particle-based flow cytometry. The auto-Abs against IL-17A, IL-17F, and IL-22 were specific in the five patients tested, as shown by Western blotting. The auto-Abs against IL-17A were neutralizing in the only patient tested, as shown by bioassays of IL-17A activity. None of the 37 healthy controls and none of the 103 patients with other autoimmune disorders tested had such auto-Abs. None of the patients with APS-I had auto-Abs against cytokines previously shown to cause other well-defined clinical syndromes in other patients (IL-6, interferon [IFN]-γ, or granulocyte/macrophage colony-stimulating factor) or against other cytokines (IL-1β, IL-10, IL-12, IL-18, IL-21, IL-23, IL-26, IFN-β, tumor necrosis factor [α], or transforming growth factor β). These findings suggest that auto-Abs against IL-17A, IL-17F, and IL-22 may cause CMC in patients with APS-I.

Summary Patients with chronic mucocutaneous candidiasis (CMC) have an unknown primary immune defect and are unable to clear infections with the yeast Candida. CMC includes patients with AIRE gene mutations who have autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), and patients without known mutations. CMC patients have dysregulated cytokine production, suggesting that defective expression of pattern recognition receptors (PRRs) may underlie disease pathogenesis. In 29 patients with CMC (13 with APECED) and controls, we assessed dendritic cell (DC) subsets and monocyte Toll-like receptor (TLR) expression in blood. We generated and stimulated monocyte-derived (mo)DCs with Candida albicans, TLR-2/6 ligand and lipopolysaccharide and assessed PRR mRNA expression by polymerase chain reaction [TLR-1–10, Dectin-1 and -2, spleen tyrosine kinase (Syk) and caspase recruitment domain (CARD) 9] in immature and mature moDCs. We demonstrate for the first time that CMC patients, with or without APECED, have normal blood levels of plasmocytoid and myeloid DCs and monocyte TLR-2/TLR-6 expression. We showed that in immature moDCs, expression levels of all PRRs involved in anti-Candida responses (TLR-1, -2, -4, -6, Dectin-1, Syk, CARD9) were comparable to controls, implying that defects in PRR expression are not responsible for the increased susceptibility to Candida infections seen in CMC patients. However, as opposed to healthy controls, both groups of CMC patients failed to down-regulate PRR mRNA expression in response to Candida, consistent with defective DC maturation, as we reported recently. Thus, impaired DC maturation and consequent altered regulation of PRR signalling pathways rather than defects in PRR expression may be responsible for inadequate Candida handling in CMC patients.

Context: In autoimmune polyendocrinopathy syndrome type I (APS-I), mutations in the autoimmune regulator gene (AIRE) impair thymic self-tolerance induction in developing T cells. The ensuing autoimmunity particularly targets ectodermal and endocrine tissues, but chronic candidiasis usually comes first. We recently reported apparently APS-I-specific high-titer neutralizing autoantibodies against type I interferons in 100% of Finnish and Norwegian patients, mainly with two prevalent AIRE truncations. Objectives: Because variability in clinical features and age at onset in APS-I frequently results in unusual presentations, we prospectively checked the diagnostic potential of anti-interferon antibodies in additional APS-I panels with other truncations or rare missense mutations and in disease controls with chronic mucocutaneous candidiasis (CMC) but without either common AIRE mutation. Design: The study was designed to detect autoantibodies against interferon-α2 and interferon-ω in antiviral neutralization assays. Setting and Patients: Patients included 14 British/Irish, 15 Sardinian, and 10 Southern Italian AIRE-mutant patients with APS-I; also 19 other patients with CMC, including four families with cosegregating thyroid autoimmunity. Outcome: The diagnostic value of anti-interferon autoantibodies was assessed. Results: We found antibodies against interferon-α2 and/or interferon-ω in all 39 APS-I patients vs. zero of 48 unaffected relatives and zero of 19 British/Irish CMC patients. Especially against interferon-ω, titers were nearly always high, regardless of the exact APS-I phenotype/duration or AIRE genotype, including 12 different AIRE length variants or 10 point substitutions overall (n = 174 total). Strikingly, in one family with few typical APS-I features, these antibodies cosegregated over three generations with autoimmune hypothyroidism plus a dominant-negative G228W AIRE substitution. Conclusions: Otherwise restricted to patients with thymoma and/or myasthenia gravis, these precocious persistent antibodies show 98% or higher sensitivity and APS-I specificity and are thus a simpler diagnostic option than detecting AIRE mutations.

Background Age-related macular degeneration (AMD) is the major cause of blindness in the elderly. Those with the neovascular end-stage of disease have irreversible loss of central vision. AMD is a complex disorder in which genetic and environmental factors play a role. Polymorphisms in the complement factor H (CFH) gene, LOC387715, and the HTRA1 promoter are strongly associated with AMD. Smoking also contributes to the etiology. We aimed to provide a model of disease risk based on these factors. Methods and Findings We genotyped polymorphisms in CFH and LOC387715/HTRA1 in a case–control study of 401 patients with neovascular AMD and 266 controls without signs of disease, and used the data to produce genetic risk scores for the European-descent population based on haplotypes at these loci and smoking history. CFH and LOC387715/HTRA1 haplotypes and smoking status exerted large effects on AMD susceptibility, enabling risk scores to be generated with appropriate weighting of these three factors. Five common haplotypes of CFH conferred a range of odds ratios (ORs) per copy from 1 to 4.17. Most of the effect of LOC387715/HTRA1 was mediated through one detrimental haplotype (carriage of one copy: OR 2.83; 95% confidence interval [CI] 1.91–4.20), with homozygotes being at particularly high risk (OR 32.83; 95% CI 12.53–86.07). Patients with neovascular macular degeneration had considerably higher scores than those without disease, and risk of blinding AMD rose to 15.5% in the tenth of the population with highest predicted risk. Conclusions An individual's risk of developing AMD in old age can be predicted by combining haplotype data with smoking status. Until there is effective treatment for AMD, encouragement to avoid smoking in those at high genetic risk may be the best option. We estimate that total absence of smoking would have reduced the prevalence of severe AMD by 33%. Unless smoking habits change or preventative treatment becomes available, the prevalence of AMD will rise as a consequence of the increasing longevity of the population., Anne Hughes and colleagues show that an individual's risk of developing age-related macular degeneration in old age can be predicted by combining haplotype data with smoking status., Editors' Summary Background. Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly. The macula is the central region of the retina, the tissue at the back of the eye that converts light into electrical messages and sends them to the brain. In the commonest form of AMD—“dry” AMD—the light-sensitive cells in the macula gradually die. In “wet” or “neovascular” AMD (one in 10 cases of AMD, but responsible for 90% of severe AMD-related blindness), abnormal blood vessels grow below the macula. Fluid leaking out of these vessels dislodges and damages the macula, after which loss of vision occurs rapidly. Both forms of AMD destroy the sharp central vision that is needed for reading and driving, leaving only dim, blurred images or a black hole at the center of vision. Neither form can be cured but with wet AMD the loss of vision can sometimes be slowed or halted if caught early by destroying the new blood vessels with laser surgery or a technique called photodynamic therapy or by blocking their formation by injecting special drugs into the eye. Why Was This Study Done? No-one knows what causes AMD but factors that increase a person's risk of developing the disease include increasing age, smoking, being white, and a family history of AMD. Recently, researchers have identified several “polymorphisms” (inherited DNA sequence variations that are common within populations) that are associated with AMD. These polymorphisms are in the complement factor H gene (the scientific symbol for this gene is CFH) and in a gene region called LOC387715/HTRA1. It would be useful to be able to use these risk factors to identify those people at the highest risk of developing neovascular AMD before the disease damages their vision. In this study, the researchers have investigated the association between AMD and polymorphisms in CFH and LOC387715/HTRA1 in more depth. They have then used this new information to build a model of AMD risk that should allow physicians to identify individuals at high risk of developing neovascular AMD. What Did the Researchers Do and Find? The researchers catalogued polymorphisms in CFH and LOC387715/HTRA1 in several hundred people with and without neovascular AMD. From these data, they identified three haplotypes (sets of polymorphisms that are inherited as a unit; everyone inherits two copies of each haplotype, one from each parent) in CFH that were more common in people with AMD than in those without and two that were associated with a decreased risk of developing AMD. In LOC387715/HTRA1 they identified one particularly detrimental haplotype. Compared to people without this haplotype, people with one copy of the deleterious haplotype were three times as likely to develop neovascular AMD; people with two copies were thirty times as likely to develop AMD. Smoking history also had a large effect on susceptibility to AMD. The researchers then developed a simple AMD risk scoring system based on CFH and LOC387715/HTRA1haplotypes and smoking status. From this, they calculated that people with the lowest risk scores have a minimal risk of developing AMD whereas about 15% of people with the highest risk scores are likely to develop AMD. What Do These Findings Mean? These findings indicate that it is possible to predict an individual's risk of developing AMD in old age by examining a small number of haplotypes and asking about their smoking status. The model developed by the researchers needs to be validated in other groups of people and may have to be modified if other gene variants that affect the risk of AMD are identified. For now, the results of this research provide physicians with a way to identify those individuals at the highest genetic risk of developing AMD so that they can step up their efforts to persuade these people to avoid smoking. In the future, when effective long-term treatments for AMD become available, the scoring system could also help doctors decide which of their elderly patients should be monitored most intensively for the early signs of AMD so that they can be treated before their vision is irreversibly damaged. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040355. MedlinePlus provides links to information on macular degeneration and an encyclopedia page on macular degeneration (in English and Spanish) Pages on the US National Institutes of Health NIH SeniorHealth site provides text and speech information about AMD The US National Eye Institute and the UK Royal National Institute of Blind People also provide information about AMD

Age related macular degeneration (AMD) is a common cause of severe vision loss. Identification of genes involved in AMD will facilitate early detection and ultimately help to identify pathways for treatment for this disorder. The A16,263G mutation in the HEMICENTIN-1 gene produces a non-conservative substitution of arginine for glutamine at codon 5345 which has been implicated in familial AMD. The aim of this study is to develop a rapid diagnostic assay for the detection of this mutation and to evaluate its frequency in a sample of AMD patients.A primer probe set was designed from exon 104 of the HEMICENTIN-1 gene to differentiate between mutant and wild type alleles. A region spanning the mutation was amplified by PCR using a LightCycler (Roche Diagnostic). The mutation was then detected by melt curve analysis of the hybrid formed between the PCR product and a specific fluorescent probe. The frequency of the mutation within the Northern Ireland population was evaluated by assaying 508 affected AMD patients, 25 possibly affected and 163 controls.This assay clearly discriminates between the A16,263G mutant and wild type HEMICENTIN-1 alleles. The wild type sequence has a single base mismatch with the probe which decreases the stability of the hybrid, resulting in a lower TM (TM=51.27 degrees C) than that observed for the perfectly matched mutant allele (TM=59.9 degrees C). The mutant allele was detected in only one of the 696 subjects, an affected AMD patient.We describe a rapid assay for the genotyping of the Gln5345Arg mutation using real-time fluorescence PCR to facilitate rapid processing of samples through combined amplification and detection steps. These characteristics are suitable for a clinical setting where high throughput diagnostic procedures are required. The frequency of this mutation within the Northern Ireland population has been estimated at 0.2%, concurring with previous findings that this mutation is a rare variant associated with AMD. A rapid diagnostic assay will facilitate a reliable and convenient evaluation of the frequency of the Gln5345Arg mutation and its association with AMD within other populations.

The existence of familial de Lange syndrome has been documented in sibs and in parent-child families, but the inheritance pattern continues to be the cause of much debate. We describe a classically affected neonate with de Lange syndrome, an affected mother and probably affected maternal grandmother. These cases show evidence for a dominantly inherited syndrome with a de Lange phenotype.

Nature Genetics 39, 1488–1493 (2007); published online 11 November 2007; corrected after print 23 January 2008 In the version of this article initially published, the affiliation for C S Raman was incorrect. Dr. Raman is affiliated with the Department of Biochemistry and Molecular Biology at the University of Texas Health Science Center, and not with the Structural Biology Center.

The biological processes controlling human growth are diverse, complex and poorly understood. Genetic factors are important and human height has been shown to be a highly polygenic trait to which common and rare genetic variation contributes. Weaver syndrome is a human overgrowth condition characterised by tall stature, dysmorphic facial features, learning disability and variable additional features. We performed exome sequencing in four individuals with Weaver syndrome, identifying a mutation in the histone methyltransferase, EZH2, in each case. Sequencing of EZH2 in additional individuals with overgrowth identified a further 15 mutations. The EZH2 mutation spectrum in Weaver syndrome shows considerable overlap with the inactivating somatic EZH2 mutations recently reported in myeloid malignancies. Our data establish EZH2 mutations as the cause of Weaver syndrome and provide further links between histone modifications and regulation of human growth.