Framing the potential of public frameshift peptides as immunotherapy targets in colon cancer.

Approximately 15% of Colon Cancers are Microsatellite Instable (MSI). Frameshift Peptides (FPs) formed in MSI Colon Cancer are potential targets for immunotherapeutic strategies. Here we comprehensively characterize the mutational landscape of 71 MSI Colon Cancer patients from the cancer genome atlas (TCGA).

Stüve-Wiedemann syndrome: recurrent neonatal infections caused by impairment of JAK/STAT 3 pathway.

Stüve-Wiedemann syndrome (OMIM #601559) is a rare, autosomal recessive disorder characterized by skeletal dysplasia, consecutive infections, feeding difficulties and autonomic dysregulation. We present an Afro-Caribbean family with two siblings diagnosed with Stüve-Wiedemann syndrome. The underlying loss-of-function mutation in the leukemia inhibitory factor receptor gene is thought to impair proper functioning of the JAK/STAT 3 pathway.

Cancer Risks for PMS2-Associated Lynch Syndrome.

Purpose: Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants.

Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement.

Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide.

Mitochondrial Encephalopathy and Transient 3-Methylglutaconic Aciduria in ECHS1 Deficiency: Long-Term Follow-Up.

We report the major diagnostic challenge in a female patient with signs and symptoms suggestive of an early-onset mitochondrial encephalopathy. Motor and cognitive development was severely delayed and brain MRI showed signal abnormalities in the putamen and caudate nuclei. Metabolic abnormalities included 3-methylglutaconic aciduria and elevated lactate levels in plasma and cerebrospinal fluid, but were transient.

With expanded carrier screening, founder populations run the risk of being overlooked.

Genetically isolated populations exist worldwide. Specific genetic disorders, including rare autosomal recessive disorders may have high prevalences in these populations. We searched for Dutch genetically isolated populations and their autosomal recessive founder mutations.

Phenotypes and genotypes in individuals with SMC1A variants.

SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS.

Uptake of prenatal diagnostic testing for retinoblastoma compared to other hereditary cancer syndromes in the Netherlands.

Since the 1980s the genetic cause of many hereditary tumor syndromes has been elucidated. As a consequence, carriers of a deleterious mutation in these genes may opt for prenatal diagnoses (PND). We studied the uptake of prenatal diagnosis for five hereditary cancer syndromes in the Netherlands.

Targeted carrier screening for four recessive disorders: high detection rate within a founder population.

In a genetically isolated community in the Netherlands four severe recessive genetic disorders occur at relatively high frequency (pontocerebellar hypoplasia type 2 (PCH2), fetal akinesia deformation sequence (FADS), rhizomelic chondrodysplasia punctata type 1 (RCDP1), and osteogenesis imperfecta (OI) type IIB/III. Over the past decades multiple patients with these disorders have been identified. This warranted the start of a preconception outpatient clinic, in 2012, aimed at couples planning a pregnancy.

Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism.

Background: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS.

High rate of mosaicism in individuals with Cornelia de Lange syndrome.

Background: Cornelia de Lange syndrome (CdLS) is a well known malformation syndrome for which five causative genes are known, accounting for ∼55-65% of cases. In this study, we hypothesised that mosaicism might explain some of the ∼35-45% of cases without detectable mutation in DNA derived from lymphocytes; we investigated the frequency of NIPBL mutations in buccal cells in individuals negative for mutations in any of the five genes in lymphocytes; and we evaluated the efficiency of obtaining DNA from buccal swabs and the best strategy for optimal mutation detection in CdLS.

Methods: Buccal swabs were obtained from eight mutation positive and 13 mutation negative individuals with clinically diagnosed CdLS, following informed consent.

Microfluidic amplification as a tool for massive parallel sequencing of the familial hypercholesterolemia genes.

Background: Familial hypercholesterolemia (FH) is an autosomal dominant disorder that affects cholesterol metabolism and is an important risk factor for heart disease. Three different genes were causally linked to this disorder: LDLR (low density lipoprotein receptor), APOB [apolipoprotein B (including Ag(x) antigen)], and PCSK9 (proprotein convertase subtilisin/kexin type 9). We evaluated a new amplicon preparation tool for resequencing these genes on next generation sequencing (NGS) platforms.

Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study.

Background: Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch-repair genes and leads to a high risk of colorectal and endometrial cancer. We previously showed that constitutional 3' end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM-expressing tissues, resulting in tissue-specific MSH2 deficiency. We aim to establish the risk of cancer associated with such EPCAM deletions.

Development of NIPBL locus-specific database using LOVD: from novel mutations to further genotype-phenotype correlations in Cornelia de Lange Syndrome.

The establishment of Locus Specific Databases (LSDB) is a crucial aspect for the Human Genetics field and one of the aims of the Human Variation Project. We report the development of a publicly accessible LSDB for the NIPBL gene (http://www.lovd.

Leiden Open Variation Database of the MUTYH gene.

The MUTYH gene encodes a DNA glycosylase involved in base excision repair (BER). Biallelic pathogenic MUTYH variants have been associated with colorectal polyposis and cancer. The pathogenicity of a few variants is beyond doubt, including c.

Multiplex ligation-dependent probe amplification (MLPA) enhances the molecular diagnosis of aniridia and related disorders.

Mutations in the PAX6 gene have been implicated in aniridia, a congenital malformation of the eye with severe hypoplasia of the iris. However, not all aniridia cases can be explained by mutations in the PAX6 gene. The purpose of this study was to enhance the molecular diagnosis of aniridia using multiplex ligation-dependent probe amplification (MLPA).

Increased DNA damage sensitivity of Cornelia de Lange syndrome cells: evidence for impaired recombinational repair.

Cornelia de Lange syndrome (CdLS) is a rare dominantly inherited multisystem disorder affecting both physical and mental development. Heterozygous mutations in the NIPBL gene were found in about half of CdLS cases. Scc2, the fungal ortholog of the NIPBL gene product, is essential for establishing sister chromatid cohesion.

Large genomic rearrangements in NIPBL are infrequent in Cornelia de Lange syndrome.

Cornelia de Lange Syndrome (CdLS) is a multiple congenital anomaly syndrome characterized by a distinctive facial appearance, malformations of the upper limbs, and delay in growth and development. Mutations in NIPBL are associated with CdLS in 27-56% of cases and have been reported as point mutations, small insertions and deletions in coding regions, regulatory regions and at splice junctions. All previous studies used PCR-based exon-scanning methodologies that do not allow detection of large genomic rearrangements.

DNA analysis of the SH3BP2 gene in patients with aggressive central giant cell granuloma.

A mutation of the SH3BP2 gene is known to cause cherubism. As there are clinical and histopathological similarities between central giant cell granuloma and cherubism, we made a constitutional DNA analysis of the SH3BP2 gene in four patients with aggressive giant cell granuloma (having one or more of the following features pain, paraesthesia, rapid growth, or root resorption). We found no mutations in the SH3BP2 gene, which indicates that cherubism is a separate entity.