Clinical exome sequencing: results from 2819 samples reflecting 1000 families

Abstract

We report our results of 1000 diagnostic WES cases based on 2819 sequenced samples from 54 countries with a wide phenotypic spectrum. Clinical information given by the requesting physicians was translated to HPO terms. WES processes were performed according to standardized settings. We identified the underlying pathogenic or likely pathogenic variants in 307 families (30.7%). In further 253 families (25.3%) a variant of unknown significance, possibly explaining the clinical symptoms of the index patient was identified. WES enabled timely diagnosing of genetic diseases, validation of causality of specific genetic disorders of PTPN23, KCTD3, SCN3A, PPOX, FRMPD4, and SCN1B, and setting dual diagnoses by detecting two causative variants in distinct genes in the same patient. We observed a better diagnostic yield in consanguineous families, in severe and in syndromic phenotypes. Our results suggest that WES has a better yield in patients that present with several symptoms, rather than an isolated abnormality. We also validate the clinical benefit of WES as an effective diagnostic tool, particularly in nonspecific or heterogeneous phenotypes. We recommend WES as a first-line diagnostic in all cases without a clear differential diagnosis, to facilitate personal medical care.

Mutations in SCN3A cause early infantile epileptic encephalopathy

“…Trujillano et al (2017) reported a single patient with febrile seizures and epilepsy with a de novo SCN3A p.Pro1333Leu mutation, which is the same mutation seen in Patient 3 in our study, although additional details regarding the patient phenotype were not provided. 39 …”

GRIN2Bencephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects

“…Three diagnostic WES trio cohorts reported 8051 patients with neurodevelopmental disorders (defined as human phenotype ontology terms (1) abnormality of the nervous system, (2) multiple congenital anomalies, (3) seizures or (4) ASD. 20–22 Overall, 15 pathogenic/likely pathogenic GRIN2B variants (14 missense, 1 frameshift) were identified, equalling a similar frequency of 0.19%. Expanding the data of the Deciphering Developmental Disorders Study, 23 14 de novo missense variants in GRIN2B are significantly enriched (p value 2×10 −17 ) in a combined cohort of WES trio data (n=8051) of patients with neurodevelopmental disorders (see online supplement 3).…”

Use of Exome Sequencing for Infants in Intensive Care Units

“…In another study, more complex phenotype has been noted to yield a higher diagnosis rate comparing to isolated phenotype. 25 Further studies in larger sample size are needed to corroborate these data for selecting infants most likely to benefit from exome sequencing in ICUs.…”