Identification of people with Lynch syndrome from those presenting with colorectal cancer in England: baseline analysis of the diagnostic pathway.

It is believed that >95% of people with Lynch syndrome (LS) remain undiagnosed. Within the National Health Service (NHS) in England, formal guidelines issued in 2017 state that all colorectal cancers (CRC) should be tested for DNA Mismatch Repair deficiency (dMMR). We used a comprehensive population-level national dataset to analyse implementation of the agreed diagnostic pathway at a baseline point 2 years post-publication of official guidelines. Using real-world data collected and curated by the National Cancer Registration and Analysis Service (NCRAS), we retrospectively followed up all people diagnosed with CRC in England in 2019. Nationwide laboratory diagnostic data incorporated somatic (tumour) testing for dMMR (via immunohistochemistry or microsatellite instability), somatic testing for MLH1 promoter methylation and BRAF status, and constitutional (germline) testing of MMR genes. Only 44% of CRCs were screened for dMMR; these figures varied over four-fold with respect to geography. Of those CRCs identified as dMMR, only 51% underwent subsequent diagnostic testing. Overall, only 1.3% of patients with colorectal cancer had a germline MMR genetic test performed; up to 37% of these tests occurred outside of NICE guidelines. The low rates of molecular diagnostic testing in CRC support the premise that Lynch syndrome is underdiagnosed, with significant attrition at all stages of the testing pathway. Applying our methodology to subsequent years' data will allow ongoing monitoring and analysis of the impact of recent investment. If the diagnostic guidelines were fully implemented, we estimate that up to 700 additional people with LS could be identified each year.

Deletions in the 3' part of the NFIX gene including a recurrent Alu-mediated deletion of exon 6 and 7 account for previously unexplained cases of Marshall-Smith syndrome.

Marshall-Smith syndrome (MSS) is a very rare malformation syndrome characterized by typical craniofacial anomalies, abnormal osseous maturation, developmental delay, failure to thrive, and respiratory difficulties. Mutations in the nuclear factor 1/X gene (NFIX) were recently identified as the cause of MSS. In our study cohort of 17 patients with a clinical diagnosis of MSS, conventional sequencing of NFIX revealed frameshift and splice-site mutations in 10 individuals. Using multiplex ligation-dependent probe amplification analysis, we identified a recurrent deletion of NFIX exon 6 and 7 in five individuals. We demonstrate this recurrent deletion is the product of a recombination between AluY elements located in intron 5 and 7. Two other patients had smaller deletions affecting exon 6. These findings show that MSS is a genetically homogeneous Mendelian disorder. RT-PCR experiments with newly identified NFIX mutations including the recurrent exon 6 and 7 deletion confirmed previous findings indicating that MSS-associated mutant mRNAs are not cleared by nonsense-mediated mRNA decay. Predicted MSS-associated mutant NFIX proteins consistently have a preserved DNA binding and dimerization domain, whereas they grossly vary in their C-terminal portion. This is in line with the hypothesis that MSS-associated mutations encode dysfunctional proteins that act in a dominant negative manner.

The face in congenital melanocytic nevus syndrome.

Congenital melanocytic nevi (CMN) are known to be associated with neurological abnormalities and melanoma, but have not been considered to be part of a developmental syndrome. The objective of this study was to test our clinical observation that children with CMN show more facial similarities than might be expected by coincidence. We selected facial photographs of 95 white Caucasian children with CMN from our database only on the basis of good neutral views, allowing careful evaluation of facial morphology. These were scored independently by two clinical geneticists using standardized categories and definitions for facial morphology. Prevalence of age-independent features was compared to established norms in a large population, and associations with cutaneous phenotype were investigated. CMN were found to be associated with characteristic facies, and 74% of children in this series had at least three typical features. The characteristic features were: wide or prominent forehead, apparent hypertelorism, eyebrow variants, periorbital fullness, small/short nose, narrow nasal ridge, broad nasal tip, broad or round face, full cheeks, prominent pre-maxilla, prominent/long philtrum, and everted lower lip. No association was found with the severity of cutaneous phenotype. We conclude that children with CMN often have a characteristic face. We propose the term "congenital melanocytic nevus syndrome" to describe this association.

Phenotype and natural history in Marshall-Smith syndrome.

Marshall-Smith syndrome (MSS) is a distinctive entity of unknown etiology with fewer than 50 patients described in the medical literature to date. Through an International collaboration and use of an online wiki to facilitate data collection and sharing, we further delineate the phenotype and natural history of this syndrome. We present 15 new patients, the oldest being 30 years, provide an update on four previously published cases, and compare all patients with other patients reported in literature. Main clinical features are moderate to severe developmental delay with absent or limited speech, unusual behavior, dysharmonic bone maturation, respiratory compromise secondary to upper airway obstruction, short stature, and kyphoscoliosis. Facial features are characteristic with high forehead, underdeveloped midface, proptosis, anteverted nares, and everted lips. Minor abnormalities of brain morphology such as hypoplasia of the corpus callosum are common. Mortality from respiratory complications is high, but airway support increasingly allows survival into adulthood. Array-CGH was performed on 12 of the cohort and no copy number variants of clear clinical relevance were identified. The present study is the first reported use of an online wiki to aid delineation of a genetic syndrome, and illustrates its value in collecting detailed data in rare conditions.