Diagnostic yield of clinical exome sequencing as a first-tier genetic test for the diagnosis of genetic disorders in pediatric patients: results from a referral center study.

The emergence of next-generation sequencing enabled a cost-effective and straightforward diagnostic approach to genetic disorders using clinical exome sequencing (CES) panels. We performed a retrospective observational study to assess the diagnostic yield of CES as a first-tier genetic test in 128 consecutive pediatric patients addressed to a referral center in the North-East of France for a suspected genetic disorder, mainly an inborn error of metabolism between January 2016 and August 2020. CES was performed using the TruSight One (4811 genes) or the TruSight One expanded (6699 genes) panel on an Illumina sequencing platform. The median age was 6.5 years (IQR 2.0-12.0) with 43% of males (55/128), and the median disease duration was 7 months (IQR 1-47). In the whole analysis, the CES diagnostic yield was 55% (70/128). The median test-to-report time was 5 months (IQR 4-7). According to CES indications, the CES diagnostic yields were 81% (21/26) for hyperlipidemia, 75% (6/8) for osteogenesis imperfecta, 64% (25/39) for metabolic disorders, 39% (10/26) for neurological disorders, and 28% (8/29) for the subgroup of patients with miscellaneous conditions. Our results demonstrate the usefulness of a CES-based diagnosis as a first-tier genetic test to establish a molecular diagnosis in pediatric patients with a suspected genetic disorder with a median test-to-report time of 5 months. It highlights the importance of a close interaction between the pediatrician with expertise in genetic disorders and the molecular medicine physician to optimize both CES indication and interpretation. Diagnostic yield of clinical exome sequencing (CES) as a first-tier genetic test for diagnosing genetic disorders in 128 consecutive pediatric patients referred to a reference center in the North-East of France for a suspected genetic disorder, mainly an inborn error of metabolism between January 2016 and August 2020. The CES diagnostic yields are reported in the whole population and patients' subgroups (hyperlipidemia, osteogenesis imperfecta, metabolic diseases, neurological disorders, miscellaneous conditions) (Icons made by Flaticon, flaticon.com; CC-BY-3.0).

Clinical, phenotypic and genetic landscape of case reports with genetically proven inherited disorders of vitamin B12 metabolism: A meta-analysis.

Inherited disorders of B12 metabolism produce a broad spectrum of manifestations, with limited knowledge of the influence of age and the function of related genes. We report a meta-analysis on 824 patients with a genetically proven diagnosis of an inherited disorder of vitamin B12 metabolism. Gene clusters and age categories are associated with patients' manifestations. The "cytoplasmic transport" cluster is associated with neurological and ophthalmological manifestations, the "mitochondrion" cluster with hypotonia, acute metabolic decompensation, and death, and the "B12 availability" and "remethylation" clusters with anemia and cytopenia. Hypotonia, EEG abnormalities, nystagmus, and strabismus are predominant in the younger patients, while neurological manifestations, such as walking difficulties, peripheral neuropathy, pyramidal syndrome, cerebral atrophy, psychiatric disorders, and thromboembolic manifestations, are predominant in the older patients. These results should prompt systematic checking of markers of vitamin B12 status, including homocysteine and methylmalonic acid, when usual causes of these manifestations are discarded in adult patients.