Wales Infants' and childreN's Genome Service (WINGS): providing rapid genetic diagnoses for unwell children.

INTRODUCTION: This study reviews the first 3 years of delivery of the first National Health Service (NHS)-commissioned trio rapid whole genome sequencing (rWGS) service for acutely unwell infants and children in Wales. METHODS: Demographic and phenotypic data were prospectively collected as patients and their families were enrolled in the Wales Infants' and childreN's Genome Service (WINGS). These data were reviewed alongside trio rWGS results. RESULTS: From April 2020 to March 2023, 82 families underwent WINGS, with a diagnostic yield of 34.1%. The highest diagnostic yields were noted in skeletal dysplasias, neurological or metabolic phenotypes. Mean time to reporting was 9 days. CONCLUSION: This study demonstrates that trio rWGS is having a positive impact on the care of acutely unwell infants and children in an NHS setting. In particular, the study shows that rWGS can be applied in an NHS setting, achieving a diagnostic yield comparable with the previously published diagnostic yields achieved in research settings, while also helping to improve patient care and management.

Börjeson-Forssman-Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families.

Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability syndrome caused by variants in the PHF6 gene. We ascertained 19 individuals from 15 families with likely pathogenic or pathogenic PHF6 variants (11 males and 8 females). One family had previously been reported. Six variants were novel. We analysed the clinical and genetic findings in our series and compared them with reported BFLS patients. Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity. Carrier female relatives of affected males were unaffected or had only mild symptoms. The phenotype of affected females with de novo variants overlapped with the males but included linear skin hyperpigmentation and a higher frequency of dental, retinal and cortical brain anomalies. Complications observed in our series included keloid scarring, digital fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and talipes. Our analysis highlighted sex-specific differences in PHF6 variant types and locations. Affected males often have missense variants or small in-frame deletions while affected females tend to have truncating variants or large deletions/duplications. Missense variants were found in a minority of affected females and clustered in the highly constrained PHD2 domain of PHF6. We propose recommendations for the evaluation and management of BFLS patients. These results further delineate and extend the genetic and phenotypic spectrum of BFLS.

Exon-focused targeted oligonucleotide microarray design increases detection of clinically relevant variants across multiple NHS genomic centres.

In recent years, chromosomal microarrays have been widely adopted by clinical diagnostic laboratories for postnatal constitutional genome analysis and have been recommended as the first-line test for patients with intellectual disability, developmental delay, autism and/or congenital abnormalities. Traditionally, array platforms have been designed with probes evenly spaced throughout the genome and increased probe density in regions associated with specific disorders with a resolution at the level of whole genes or multiple exons. However, this level of resolution often cannot detect pathogenic intragenic deletions or duplications, which represent a significant disease-causing mechanism. Therefore, new high-resolution oligonucleotide comparative genomic hybridisation arrays (oligo-array CGH) have been developed with probes targeting single exons of disease relevant genes. Here we present a retrospective study on 27,756 patient samples from a consortium of state-funded diagnostic UK genomic centres assayed by either oligo-array CGH of a traditional design (Cytosure ISCA v2) or by an oligo-array CGH with enhanced exon-level coverage of genes associated with developmental disorders (CytoSure Constitutional v3). The new targeted design used in Cytosure v3 array has been designed to capture intragenic aberrations that would have been missed on the v2 array. To assess the relative performance of the two array designs, data on a subset of samples (n = 19,675), generated only by laboratories using both array designs, were compared. Our results demonstrate that the new high-density exon-focused targeted array design that uses updated information from large scale genomic studies is a powerful tool for detection of intragenic deletions and duplications that leads to a significant improvement in diagnostic yield.