A mutation can hide another one: Think Structural Variants!

Abstract

Next Generation Sequencing (NGS) using capture or amplicons strategies allows the detection of a large number of mutations increasing the rate of positive diagnosis for the patients. However, most of the detected mutations are Single Nucleotide Variants (SNVs) or small indels. Structural Variants (SVs) are often underdiagnosed in inherited genetic diseases, probably because few user-friendly tools are available for biologists or geneticists to identify them easily. We present here the diagnosis of two brothers presenting a demyelinating motor-sensitive neuropathy: a presumed homozygous c.5744_5745delAT in exon 10 of SACS gene was initially detected, while actually these patients were heterozygous for this mutation and harbored a large deletion of SACS exon 10 in the other allele. This hidden mutation has been detected thanks to the user-friendly CovCopCan software. We recommend to systematically use such a software to screen NGS data in order to detect SVs, such as Copy Number Variations, to improve diagnosis of the patients.

GDAP1 Involvement in Mitochondrial Function and Oxidative Stress, Investigated in a Charcot-Marie-Tooth Model of hiPSCs-Derived Motor Neurons

“…In the GDAP1 gene genetic analyses detected the c.581C>G (p.Ser194*) mutation, homozygous in the patient and his affected brother, and heterozygous in the other family members. No other mutation in CMT-and peripheral neuropathies-associated genes was detected by targeted Next Generation Sequencing (NGS) (see [34] for the detailed protocol). Two control subjects, without any clinical neurological signs, were enrolled in this study: Ctrl-1, a 24-year-old man, and Ctrl-2, a 28-year old woman.…”

Genetic Spectrum and Clinical Features in a Cohort of Chinese Patients with Autosomal Recessive Cerebellar Ataxias

“…Thus, whether the truncation variant in SACS is linked to a typical clinical manifestation of ARSACS is an issue that requires further exploration. Even this de novo large deletion containing SACS was the second report in the world [24], the CNV in SACS were already reported in many populations including Belgian, French, Italian, Canadian, German and Chinese [24][25][26][27][28][29][30]. Thus, SV might not be extremely rare, and we suggested that tools for detecting SVs such as CNVs should be used routinely for NGS data analysis in order to increase the rate of positive diagnosis.…”

“…Second, large genomic rearrangements and trinucleotide expansions cannot be reliably detected from exome-capture data, even though there are some detecting CNVs tools developed and based on the readdepth of NGS data, such as Exome Depth used in this study, cannot easily detect inversion or translocation [41]. Third, it is also likely that some causal variants will outside the coding regions and adjacent splice sites [42].…”

New structural variations responsible for Charcot-Marie-Tooth disease: The first two large KIF5A deletions detected by CovCopCan software

“…NGS strategy was performed using a 93-gene custom panel designed for diagnosis of CMT and associated neuropathies (as described by Miressi et al [22] ). The amplified library was prepared with Ion-P1-HiQ-Template-OT2-200 kit (Ampliseq-Custom; Life Technologies), sequenced on Ion-Proton sequencer (Life-Technologies), and mapped to the human-reference-genome GHCh37.…”