Contribution of next generation sequencing in pediatric practice in Lebanon. A Study on 213 cases

Abstract

BackgroundAccording to the Catalogue of Transmission Genetics in Arabs, less than half of diseases reported in Lebanese patients are mapped. In the recent years, Next Generation Sequencing (NGS) techniques have significantly improved clinical diagnosis, compared to traditional sequencing methods.MethodsA total of 213 analyses by NGS (167 by whole exome sequencing (WES) and 46 by multigene panels tests) were performed on pediatric patients across different regions of Lebanon over a period of two years (December 2015–December 2017).ResultsNeurological disorders were the most frequent referral demand for both WES and gene panels (122/213). Pathogenic, likely pathogenic, or variants of unknown significance were identified in 69.5% of the WES and panel patients combined. Over half of the patients with such variants had an autosomal recessive disorder. A definite molecular diagnosis (pathogenic or likely pathogenic variants) was achieved in 34.1% and 47.8% of the patients studied by WES and the multigene panels, respectively. Thirty‐three novel variants were found in the cases that were molecularly solved; 26 of these being identified by WES and seven by the multigene panels. In three consanguineous families, autosomal recessive inheritance of genes previously reported as showing dominant inheritance patterns were found. Biallelism was found in six cases, digenism in four cases, and one case was trigenic.ConclusionOur study thus suggests that NGS tools are valuable for an improved clinical diagnosis, and highlights that the increased adoption of such techniques will significantly further improve our understanding of the genetic basis of inherited diseases in Lebanon.

Genotype–phenotype correlation of 33 patients with maple syrup urine disease

“…Previously reported nonsense variants, p.R285* and p.R324*, were found in three patients (P15) and (P16‐17), respectively (Henneke et al, 2003; McConnell et al, 1997). Two other previously reported missense variants, p.P332L and p.A137V, were found in (P13) and (P18), respectively (Nair et al, 2018; Nellis et al, 2003). Two novel frameshift variants due to a single base deletion or insertion (c.287delA, c.908insA) were found in two sets of unrelated patients (P19 and P20) and (P21 and P22), respectively.…”

Systematic evidence-based review: outcomes from exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability

“…Several studies provided only representative case examples documenting outcomes of interest. [16][17][18][19] We summarize the number of studies with N ≥ 20 patients documenting the outcomes of interest and representative examples of reported health outcomes and clinical impacts for each subcategory.…”

“…Twelve studies reported outcomes following ES/GS that had an impact on family members of the patient, such as cascade genetic testing, referral to specialists, or changes in clinical management resulting from the diagnosis of a previously unknown disorder. 7,11,16,19,26,27,31,32,34,41,42,48 In a cohort of 62 families with congenital anomalies of kidney and urinary tract (i.e., CAKUT) who had ES, first-degree relatives of 1 patient were referred for ophthalmological assessment in light of a diagnosis of renal coloboma. The authors reported optic nerve abnormalities were identified in relatives who were PAX2 variant carriers.…”

The Lebanese Allele in the PET100 Gene: Report on Two New Families with Cytochrome c Oxidase Deficiency

“…The frequency of this variant is unknown in the Lebanese population and the variant was absent from our in-house WES database of 339 individuals as well as in our recent study of 167 patients who underwent WES analysis. 13 The variable clinical description necessitates reporting recurrent variants. This study emphasizes the importance of next generation sequencing in providing a fast and accurate clinical diagnosis.…”