Exome Sequencing and Rare Variant Analysis Reveals Multiple Filaggrin Mutations in Bangladeshi Families with Atopic Eczema and Additional Risk Genes

M.P was supported by a Fellowship from the German Research Foundation (DFG). This work received infrastructure support through the DFG Cluster of Excellence “Inflammation at Interfaces” (grants EXC306 and EXC306/2), and was supported by grants (WE2678/6-1, WE2678/6-2, WE2678/9) from the DFG and the e:Med sysINFLAME grant no. 01ZX1306A from the German Federal Ministry of Education and Research (BMBF). J.E.A.C. and X.F.C.C.W. are funded by A*STAR SPF funding for translational skin research and genetic orphan disease

Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A

Funder: Agency for Innovation by Science and Technology, IWTFunder: U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)Funder: BOF-University of Antwerp (FFB180053) and FWO (1861419N).Abstract: The developmental and epileptic encephalopathies (DEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60–65% of patients without a molecular diagnosis. Here, we explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for a lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 putative transcript models. Our annotations increase the transcriptional ‘footprint’ of these genes by over 674 kb. Using SCN1A as a case study, due to its close phenotype/genotype correlation with Dravet syndrome, we screened 122 people with Dravet syndrome or a similar phenotype with a panel of exon sequences representing eight established genes and identified two de novo SCN1A variants that now - through improved gene annotation - are ascribed to residing among our exons. These two (from 122 screened people, 1.6%) molecular diagnoses carry significant clinical implications. Furthermore, we identified a previously classified SCN1A intronic Dravet syndrome-associated variant that now lies within a deeply conserved exon. Our findings illustrate the potential gains of thorough gene annotation in improving diagnostic yields for genetic disorders

The clinical implementation of non-invasive prenatal diagnosis for single gene disorders: Challenges and progress made

Recently we have witnessed the rapid translation into clinical practice of noninvasive prenatal testing for the common aneuploidies, most notably within USA and China. This represents a lucrative market with testing being driven by companies developing and offering their services. These tests are currently aimed at women with high/medium risk pregnancies identified by serum screening and/or ultrasoundscanning. Uptake has been impressive, albeit limited to the commercial sector. However, non-invasive prenatal diagnosis (NIPD) for single gene disorders has attracted less interest, no doubt because this represents a much smaller market opportunity and in the majority of cases has to be provided on a bespoke, patient or disease-specific basis. The methods and workflows are labour intensive and not readily scalable. Nonetheless, there exists a significant need for NIPD of single gene disorders and the continuing advances in technology and data analysis should facilitate the expansion of the NIPD test repertoire. Here we review the progress that has been made to date, the different methods and platform technologies, the technical challenges, and assess how new developments may be applied to extend testing to a wider range of genetic disorders

The future role of genetic screening to detect newborns at risk of childhood-onset hearing loss

OBJECTIVE: To explore the future potential of genetic screening to detect newborns at risk of childhood-onset hearing loss. DESIGN: An expert led discussion of current and future developments in genetic technology and the knowledge base of genetic hearing loss to determine the viability of genetic screening and the implications for screening policy. RESULTS AND DISCUSSION: Despite increasing pressure to adopt genetic technologies, a major barrier for genetic screening in hearing loss is the uncertain clinical significance of the identified mutations and their interactions. Only when a reliable estimate of the future risk of hearing loss can be made at a reasonable cost, will genetic screening become viable. Given the speed of technological advancement this may be within the next 10 years. Decision-makers should start to consider how genetic screening could augment current screening programmes as well as the associated data processing and storage requirements. CONCLUSION: In the interim, we suggest that decision makers consider the benefits of (1) genetically testing all newborns and children with hearing loss, to determine aetiology and to increase knowledge of the genetic causes of hearing loss, and (2) consider screening pregnant women for the m.1555A> G mutation to reduce the risk of aminoglycoside antibiotic-associated hearing loss

A Third Novel Locus for Primary Autosomal Recessive Microcephaly Maps to Chromosome 9q34

Primary autosomal recessive microcephaly is a clinical diagnosis of exclusion in an individual with a head circumference ⩾4 SDs below the expected age-and-sex mean. There is associated moderate mental retardation, and neuroimaging shows a small but structurally normal cerebral cortex. The inheritance pattern in the majority of cases is considered to be autosomal recessive. Although genetic heterogeneity for this clinical phenotype had been expected, this has only recently been demonstrated, with the mapping of two loci for autosomal recessive primary microcephaly: MCPH1 at 8p and MCPH2 at 19q. We have studied a large multiaffected consanguineous pedigree, using a whole-genome search, and have identified a third locus, MCPH3 at 9q34. The minimal critical region is ∼12 cM, being defined by the markers cen-D9S1872-D9S159-tel, with a maximum two-point LOD score of 3.76 (recombination fraction 0) observed for the marker D9S290