IMPORTANCE Recent advances in newborn screening (NBS) have improved the diagnosis of inborn errors of metabolism (IEMs); however, many potentially treatable IEMs are not included on NBS panels, nor are they covered in standard, first-line biochemical testing.OBJECTIVE To examine the utility of untargeted metabolomics as a primary screening tool for IEMs by comparing the diagnostic rate of clinical metabolomics with the recommended traditional metabolic screening approach.

Purpose: A primary barrier to improving exome sequencing diagnostic rates is the interpretation of variants of uncertain clinical significance. We aimed to determine the contribution of integrated untargeted metabolomics in the analysis of exome sequencing data by retrospective analysis of patients evaluated by both whole exome sequencing and untargeted metabolomics within the same clinical laboratory. Methods: Exome sequencing and untargeted metabolomic data were collected and analyzed for 170 patients. Pathogenic variants, likely pathogenic variants, and variants of uncertain significance in genes associated with a biochemical phenotype were extracted. Metabolomic data were evaluated to determine if these variants resulted in biochemical abnormalities which could be used to support their interpretation using current ACMG guidelines. Results: Metabolomic data contributed to the interpretation variants in 74 individuals (43.5%) over 73 different genes. The data allowed for the re-classification of 9 variants as likely benign, 15 variants as likely pathogenic, and 3 variants as pathogenic. Metabolomic data confirmed a clinical diagnosis in 21 cases, for a diagnostic rate of 12.3% in this population. Conclusion: Untargeted metabolomics can serve as a useful adjunct to exome sequencing by providing valuable functional data that may not otherwise be clinically available, resulting in improved variant classification.

Smith–Magenis syndrome (SMS) is a complex neurobehavioural disorder caused by haploinsufficiency of the RAI1 gene on chromosome 17p11.2. Key clinical features include intellectual disability, self‐injurious behaviours, sleep disturbance and craniofacial and skeletal anomalies. Diagnostic strategies are focused towards identification of a 17p11.2 microdeletion encompassing RAI1 or a mutation of RAI1 . G‐banding and fluorescent in situ hybridization are classical methods used to detect the SMS deletions, whereas multiplex ligation‐dependent probe amplification, comparative genomic hybridization and real‐time quantitative PCR (polymerase chain reaction) are the newer technologies. Most SMS features are due to RAI1 haploinsufficiency, whereas variability and severity are modified by other genes in the 17p11.2 region. The functional role for RAI1 is not completely understood, but it is likely involved in transcription and functions in several different biological pathways. Management of SMS is a multidisciplinary approach and involves treatment for sleep disturbance, speech and occupational therapies, minor medical interventions and management of behaviours. Synonyms: SMS, del(17)(p11.2), del(17)(p11.2p11.2), RAI1 mutation Key concepts Smith–Magenis syndrome (SMS) is a multiple congenital anomalies disorder caused by an interstitial deletion of chromosome 17p11.2 containing the retinoic acid induced 1 ( RAI1 ) gene or by mutation of RAI1 . Typically a sporadic genomic disorder with an estimated prevalence of 1:15 000–25 000. Individuals with SMS have intellectual disability, distinctive behavioural features, craniofacial and skeletal anomalies, speech and developmental delay and sleep disturbance. Hypotonia, hearing loss and chronic ear infections, eye abnormalities, cardiac and renal defects, and occasionally, cleft lip and/or palates are also observed. Approximately 90% of SMS cases have a FISH detectable 17p11.2 microdeletion (ranging from 650 kb to 9 Mb), whereas the remaining 10% have a mutation in RAI1 . Haploinsufficiency of RAI1 results in most features of SMS, but variabliity and severity are modified by other genes in the 17p11.2 deletion region. RAI1 is a putative transcription factor functioning in multiple biological pathways resulting in the pleiotropic effects seen in SMS. Management includes therapy for sleep disturbance, early childhood intervention programmes, special education and vocational training, and multidisciplinary evaluation for behavioural and systemic manifestations. Recurrence risk for sibs of the proband, if the parental chromosome/gene analyses are normal, is less than 1%. Risk increases if a parent of the proband carries a balanced chromosomal rearrangement or if mosaicism for either a deletion or RAI1 mutation is present in either parent. Mosaicism in a parent of an affected child is estimated at 3–5%.