RESUMO
PURPOSE: This study aimed to provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids program. METHODS: Extensive analyses of 960 families with suspected genetic disorders included short-read exome sequencing and short-read genome sequencing (srGS); PacBio HiFi long-read genome sequencing (HiFi-GS); variant calling for single nucleotide variants (SNV), structural variant (SV), and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants, and pedigrees were stored in PhenoTips database, with data sharing through controlled access the database of Genotypes and Phenotypes. RESULTS: Diagnostic rates ranged from 11% in patients with prior negative genetic testing to 34.5% in naive patients. Incorporating SVs from genome sequencing added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with >4-fold more rare coding SVs compared with srGS. Variants and genes of unknown significance remain the most common finding (58% of nondiagnostic cases). CONCLUSION: Computational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated using HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation and by providing HiFi variant (SNV/SV) resources from >1000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.
Assuntos
Genômica , Doenças Raras , Criança , Genoma , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linhagem , Doenças Raras/diagnóstico , Doenças Raras/genética , Análise de Sequência de DNARESUMO
Primary musculoskeletal etiologies, such as stress fractures, strains, facet arthropathy, and sacroiliac joint dysfunction, are more common causes of pediatric pain than systemic diseases, both in the office setting and the emergency room. Systemic features, young age, and atypical pain should clue physicians to causes other than a primary musculoskeletal cause and prompt an intensive search for other conditions.