Objective: To investigate the impact of movement disorder gene panels in clinical practice and the proportion of patients receiving a definite genetic diagnosis through Next Generation Sequencing (NGS) in a tertiary referral centre.

Background: Genetic biobanks are a powerful tool in basic, translational and clinical research in rare diseases. In the biobank of our institute, part of the Telethon Network of Genetic Biobank, a large number of DNAs from patients with movement disorders (MD) are available. The number of MD-associated genes has greatly increased recently thanks to the advances in molecular techniques; the use of NGS allowed us to simultaneously analyze a large number of these genes.

Methods: DNAs from 170 patients with genetically undiagnosed movement disorders were selected from our MD biobank and tested by targeted re-sequencing using customized gene panels including known genes associated with dystonia (19 genes), Parkinson’s disease (PD) (19) and Neurodegeneration with Brain Iron Accumulation (9)

Panel’s Genes

PD	Dystonia	NBIA
PINK1	TOR1A	PANK2
PARK2	THAP1
LRRK2	PRKRA	PLA2G6
ATP13A2	TAF1
PARK7	TIMM8A	FTH1
SNCA	GCH1
FBXO7	TH	FTL
SYNJ1	SGCE
DNAJC6	ATP1A3	C19ORF12
VPS35	PNKD
EIF4G1	PRRT2	WDR45
DNAJC13	SLC2A1
UCHL1	CIZ1	FA2H
GIGYF2	ANO3
HTRA2	GNAL	CoAsy
GBA	BCAP31
MAPT	NKX2-1	CP
GRN	TOR1AIP1
ATP6AP2	GLB1

The design of panels is based on the TruSeq Custom Amplicon assay for target resequencing (Illumina). The regions of interest of the target genes were amplified and the amplicons generated sequenced through the MiSeq platform. Variants with a frequency >1% in the 1000 Genomes Project and Exome Variant Server databases were filtered out. We then focused on missense, splice site, stop-gain/loss and frameshift variants. Sanger sequencing was performed to validate identified variants.

Results: 77 patients recruited had PD (45%), 25 NBIA (15%) and 68 isolated or combined dystonia (40%). In 20/170 patients (11.7%) pathogenic variants in one of the genes analyzed were found, leading to a definite genetic diagnosis. Among them, 11 (55%) had PD, 3 (15%) NBIA and 6 (30%) dystonia. A positive family history was present in 7/20 mutated patients. Mutated genes in each MD category are shown in Figure 1.

Conclusions: Despite advanced diagnostic techniques and the availability of a large number of genetically undefined MD patients, the proportion (11.7%) of cases sorted in our series remains scarce. This may be due to either technique limitations (repeat expansions or large insertions and deletions are missed by NGS) or to a still limited knowledge of MD causative genes. Dedicated gene panels seem to have a limited impact in clinical practice, helping reaching a genetic diagnosis in a small number of cases.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-relevance-of-movement-disorders-gene-panels-in-clinical-practice-how-many-patients-are-we-sorting-out/