Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients

Abstract

Although whole-exome sequencing (WES) is the gold standard for the diagnosis of neurodevelopmental disorders (NDDs), it remains expensive for some genetic centers. Commercialized panels comprising all OMIM-referenced genes called "medical exome" (ME) constitute an alternative strategy to WES, but its efficiency is poorly known. In this study, we report the experience of 2 clinical genetic centers using ME for diagnosis of NDDs. We recruited 216 consecutive index patients with NDDs in 2 French genetic centers, corresponded to the daily practice of the units and included non-syndromic intellectual disability (NSID, n = 33), syndromic ID (NSID = 122), pediatric neurodegenerative disorders (n = 7) and autism spectrum disorder (ASD, n = 54). We sequenced samples from probands and their parents (when available) with the Illumina TruSight One sequencing kit. We found pathogenic or likely pathogenic variants in 56 index patients, for a global diagnostic yield of 25.9%. The diagnosis yield was higher in patients with ID as the main diagnosis (32%) than in patients with ASD (3.7%). Our results suggest that the use of ME is a valuable strategy for patients with ID when WES cannot be used as a routine diagnosis tool.

Novel compound heterozygous COG5 mutations in a Chinese male patient with severe clinical symptoms and type�IIi congenital disorder of glycosylation: A case report

“…Compared with lobe A, the patient exhibited a milder phenotype. However, in comparison with the previously reported COG5-CDG case (6)(7)(8), the patient showed severe central and peripheral neurological symptoms.…”

“…To the best of our knowledge, in the 1000 Genomes project (http://www.internationalgenome.org/), the Exome Aggregation Consortium (http://exac.broadinstitute.org/), the gnomAD (http://gnomad-old.broadinstitute.org/) and our in-house database, neither variant had previously been described. The NM_006348.3: c.2324 C>T, p.P775L mutation was recently reported to be pathogenic (8). This was supported by the American College of Medical Genetics (ACMG) guidelines, which classified this variant as pathogenic (categories, PM2, PM3, PP3 and PP5) (11).…”

“…Only 10 COG5-CDG cases have been reported worldwide (2,(5)(6)(7)(8). Common symptoms among these cases include neurological, morphological and hepatic abnormalities (7,8). Defects in the COG5 protein are mainly associated with abnormalities of the brain, liver, bladder and auditory and visual systems (9).…”

Human patientSFPQhomozygous mutation is found deleterious for brain and motor development in a zebrafish model

“…Whole-exome sequencing of the trio revealed a heterozygous de novo mutation (NM:004321: c.920G>A; p.Arg307Gln) affecting a conserved residue within the motor domain (MD) of the KIF1A variant could partially explain the complex neurological phenotype of our patient as established in ClinVar (www.ncbi.nlm.nih.gov/clinvar; accession number: 418275) and in literature reports as a disease-causing mutation, implicated in phenotypes ranging between intellectual disability, spasticity, optic nerve and/or cerebellar atrophy (Cherot et al, 2018;Hotchkiss et al, 2016;Ohba et al, 2015). Thus, the rare homozygous SFPQ variant emerged as a potential candidate genetic variant to explain part of the complex clinical neurological features not previously associated to the KIF1A-related neurodevelopmental disorder, such as the bradykinesia, rest (head) tremor and extrapyramidal rigidity, as well as the MRI findings suggestive of neurodegeneration with brain iron accumulation (NBIA).…”

What do parents expect from a genetic diagnosis of their child with intellectual disability?

“…In addition, the probability of finding a diagnosis strongly depends on the diagnostic techniques that are available. The diagnostic yield has increased dramatically in the last few years (current range: 25%–68%) since NGS technologies were developed (Cherot et al, ; Deciphering Developmental Disorders Study, ; Evers et al, ; Vissers et al, ; Xiao et al, ). Therefore, it is important to explain to families that even in cases where a genetic cause of intellectual disability is strongly suspected, an aetiological clarification is not guaranteed.…”