Expanding the clinical spectrum of biglycan-related Meester-Loeys syndrome.

Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additional BGN variant-harboring family members (9 males and 27 females).

Homozygous variants in two unrelated patients with craniosynostosis and radioulnar synostosis.

Background: encodes an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway. Until now, rare heterozygous loss-of-function variants in were demonstrated to increase the risk of disparate clinical disorders including cardiovascular disease, craniosynostosis and radioulnar synostosis. Only two unrelated patients harbouring biallelic variants presenting a complex cardiovascular phenotype and facial dysmorphism have been described.

RUNX2-related metaphyseal dysplasia with maxillary hypoplasia: A rare skeletal disorder resembling SFRP4-related Pyle disease.

Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly (MDMHB) is an ultra-rare skeletal dysplasia caused by heterozygous intragenic RUNX2 duplications, comprising either exons 3 to 5 or exons 3 to 6 of RUNX2. In this study, we describe a 14-year-old Belgian boy with metaphyseal dysplasia with maxillary hypoplasia but without brachydactyly. Clinical and radiographic examination revealed mild facial dysmorphism, dental anomalies, enlarged clavicles, genua valga and metaphyseal flaring and thin cortices with an osteoporotic skeletal appearance.

Implementation of Exome Sequencing in Prenatal Diagnostics: Chances and Challenges.

Whole exome sequencing (WES) has become part of the postnatal diagnostic work-up of both pediatric and adult patients with a range of disorders. In the last years, WES is slowly being implemented in the prenatal setting as well, although some hurdles remain, such as quantity and quality of input material, minimizing turn-around times, and ensuring consistent interpretation and reporting of variants. We present the results of 1 year of prenatal WES in a single genetic center.

Heterozygous pathogenic variants involving cause a new skeletal disorder resembling cleidocranial dysplasia.

Background: Cleidocranial dysplasia (CCD) is a rare skeletal dysplasia with significant clinical variability. Patients with CCD typically present with delayed closure of fontanels and cranial sutures, dental anomalies, clavicular hypoplasia or aplasia and short stature. Runt-related transcription factor 2 ( is currently the only known disease-causing gene for CCD, but several studies have suggested locus heterogeneity.

Confirmation of the role of pathogenic SMAD6 variants in bicuspid aortic valve-related aortopathy.

Progressive dilatation of the thoracic aorta leads to thoracic aortic aneurysm (TAA), which is often asymptomatic but predisposes to lethal aortic dissections and ruptures. TAA is a common complication in patients with bicuspid aortic valve (BAV). Recently, rare loss-of-function SMAD6 variants were shown to contribute significantly to the genetic aetiology of BAV/TAA.

Effect of Primary Tumor Location on Second- or Later-line Treatment Outcomes in Patients With RAS Wild-type Metastatic Colorectal Cancer and All Treatment Lines in Patients With RAS Mutations in Four Randomized Panitumumab Studies.

Background: The primary tumor location has a prognostic impact in metastatic colorectal cancer (mCRC). We report the results from retrospective analyses assessing the effect of tumor location on prognosis and efficacy of second- and later-line panitumumab treatment in patients with RAS wild-type (WT) mCRC and on prognosis in all lines of treatment in patients with RAS mutant (MT) mCRC.

Patients And Methods: RAS WT data (n = 483) from 2 randomized phase III panitumumab trials (ClinicalTrials.

Mutation and Methylation Analysis of Circulating Tumor DNA Can Be Used for Follow-up of Metastatic Colorectal Cancer Patients.

Background: Targeted therapies, although contributing to survival improvement in metastatic colorectal cancer (mCRC), are expensive and may cause adverse effects. Therefore, confirming that patients are responding to these therapies is extremely important. Currently, follow-up is performed using radiographic evaluation, which has its limitations.

The predictive value of primary tumor location in patients with metastatic colorectal cancer: A systematic review.

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. It has been reported that left- and right-sided CRC harbor varying disease characteristics, which leads to a difference in prognosis and response to therapy. Recently, there have been retrospective studies about tumor location in metastatic CRC (mCRC) and its potential to predict the effect of anti-vascular endothelial growth factor and anti-epidermal growth factor receptor (anti-EGFR) therapies.

pyAmpli: an amplicon-based variant filter pipeline for targeted resequencing data.

Background: Haloplex targeted resequencing is a popular method to analyze both germline and somatic variants in gene panels. However, involved wet-lab procedures may introduce false positives that need to be considered in subsequent data-analysis. No variant filtering rationale addressing amplicon enrichment related systematic errors, in the form of an all-in-one package, exists to our knowledge.

DNA Diagnostics of Hereditary Hearing Loss: A Targeted Resequencing Approach Combined with a Mutation Classification System.

Although there are nearly 100 different causative genes identified for nonsyndromic hearing loss (NSHL), Sanger sequencing-based DNA diagnostics usually only analyses three, namely, GJB2, SLC26A4, and OTOF. As this is seen as inadequate, there is a need for high-throughput diagnostic methods to detect disease-causing variations, including single-nucleotide variations (SNVs), insertions/deletions (Indels), and copy-number variations (CNVs). In this study, a targeted resequencing panel for hearing loss was developed including 79 genes for NSHL and selected forms of syndromic hearing loss.

Prognostic and Predictive Value of RAS Gene Mutations in Colorectal Cancer: Moving Beyond KRAS Exon 2.

The advent of anti-EGFR (epidermal growth factor receptor) therapy resulted in significant progress in the treatment of metastatic colorectal cancer patients. However, many patients do not respond to this therapy or develop acquired resistance within a few months after the start of treatment. Since 2008, anti-EGFR therapy is restricted to KRAS wild-type patients as it has been shown that KRAS exon 2-mutated patients do not respond to this therapy.