SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT03999788

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

Clinical Relevance of miR-142-3p as Potential Biomarker of Synaptopathy in Multiple Sclerosis

Inflammatory synaptopathy is a prominent pathogenic mechanism in multiple sclerosis (MS) and in its mouse model, which can cause excitotoxic damage by long-lasting excessive synaptic excitation and, consequentially, drives disease progression by leading to motor and cognitive deficits. As synaptopathy occurs early during the disease course and is potentially reversible, it represents an appealing therapeutic target in MS. Although reliable biomarkers of MS synaptopathy are still missing, recent researches highlighted miR-142-3p as a possible candidate. Indeed, miR-142-3p has been described to promote the IL-1beta-dependent synaptopathy by downregulating GLAST/EAAT1, a crucial glial transporter involved in glutamate homeostasis. Furthermore, mir-142-3p has been suggested as a putative negative MS prognostic factor and a target of current MS disease modifying therapies. The hypothesis of this study is that miR-142-3p represents a good biomarker for excitotoxic synaptopathy to predict MS course, and, possibly, treatment efficacy at individual level, including both pharmacological strategies and non-pharmacological interventions, like therapeutic transcranial magnetic stimulation (TMS) to ameliorate MS spasticity. To this aim, the role of miR-142-3p in MS synaptopathy, its potential impact on the efficacy of disease-modifying treatments currently used in MS therapy as well as the influence of genetic variants (SNPs) of miR-142-3p and GLAST/EAAT1 coding genes on the responsiveness to therapeutic TMS, will be further investigated in the study. By validating miR-142-3p as potential biomarker of synaptopathy, it is expect to improve MS prognosis and personalized therapies. Patients with MS, who will undergo neurological assessment, conventional brain MRI scan, and CSF and blood withdrawal for diagnostic and clinical reasons at the Neurology Unit of IRCCS INM-Neuromed will be enrolled in the study. Neurophysiological, biochemical and genetic parameters together with lower limb spasticity will be evaluated. Subjects, who will undergo blood sampling and/or lumbar puncture for clinical suspicions, later on not confirmed, will be recruited as control group. A subgroup of MS patients showing lower limb spasticity will be included in a two-week repetitive TMS stimulation protocol (iTBS) to correlate the patient responsiveness to this non-pharmacological treatment with MS-significant SNPs of both miR-142-3p and GLAST/EAAT1 coding genes.

NCT03999788 Multiple Sclerosis Spasticity
MeSH: Sclerosis Multiple Sclerosis Muscle Spasticity
HPO: Spasticity

2 Interventions

Name: lumbar puncture and blood withdrawal

Description: lumbar puncture performed to detect OCB for diagnostic purposes and blood withdrawal for SNP screening

Type: Procedure

multiple sclerosis patients control subjects

Name: Intermittent theta burst stimulation (iTBS) therapeutic protocol for spasticity

Description: iTBS will be delivered over the scalp site corresponding to the leg area of primary motor cortex contralateral to the affected limb. The active motor threshold (AMT) will be defined as the minimum stimulation intensity required to evoke a liminal motor potential from the Soleus muscle during voluntary contraction. The stimulation intensity will be about 80% of AMT. The iTBS stimulation protocol consists of 10 bursts, each burst composed of three stimuli at 50 Hz, repeated at a theta frequency of 5 Hz every 10 s for a total of 600 stimuli (200 s). If no MEP will be detectable from the contralateral leg, the site of stimulation will be determined as symmetrical to the motor hot spot. If no MEP will be detectable even from the contralateral leg the coil will be held tangentially to the scalp with its centre placed 1 cm ahead and 1 cm lateral from CZ (10-20 EEG system). In these cases, stimulation intensity will be set to 50% of the maximum stimulator output.

Type: Procedure

multiple sclerosis patients with spasticity and selected SNPs


Primary Outcomes

Description: Quantification of CSF levels of miR-142-3p by qPCR analysis. Relative quantification will be performed by 2^(-ddCt) method.

Measure: CSF concentration of miR-142-3p

Time: T0 (enrollment); MS patients vs Control subjects

Description: Quantification of CSF inflammatory molecules (TNF, IL-1β, IL-6, IL-17, IFN-γ, IL1ra, IL-22, IL-2, IL-2ra, IL-10, IL-4, IL-5, IL-13, IL-12p40, IL-8) by Luminex multiplex assays; neurofilaments, beta amyloid, tau proteins and growth factors (like NGF, PDGF and BDNF) by Luminex multiplex assays. Data will be expressed as pg/ml.

Measure: CSF concentration of soluble molecules

Time: T0 (enrollment); MS patients vs Control subjects

Description: Clinical disability will be certified by a qualified neurologist through the Progression Index (PI) calculated as EDSS combined with disease duration (EDSS/disease duration). Disease duration is estimated as the number of years from onset to the most recent assessment of disability and EDSS scale ranging from 0 to 10 in 0.5 unit increments that represent higher levels of disability.

Measure: Clinical disability assessment by Progression Index calculation for correlation analysis with CSF-miR-142-3p levels

Time: Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up

Description: The Multiple Sclerosis Functional Composite (MSFC) is a three-part composite clinical measure. Three variables were recommended as primary measures: Timed 25-Foot walk; 9-Hole Peg Test; and Paced Auditory Serial Addition Test (PASAT- 3"). The results from each of these three tests are transformed into Z-scores and averaged to yield a composite score for each patient at each time point. There are 3 components: the average scores from the four trials on the 9-HPT; the average scores of two 25-Foot Timed Walk trials; the number correct from the PASAT-3. The scores for these three dimensions are combined to create a single score that can be used to detect change over time. This is done by creating Z-scores for each component. MSFC Score = {Zarm, average + Zleg, average + Zcognitive} / 3.0 (Where Zxxx =Z-score) Increased scores represent deterioration in the 9-HPT and the 25-Foot Timed Walk, whereas decreased scores represent deterioration in the PASAT-3.

Measure: Clinical disability assessment by MSFC calculation for correlation analysis with CSF-miR-142-3p levels

Time: Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up

Description: By conventional MRI (1.5 Tesla) the following parameters will be evaluated: dual-echo proton density, FLAIR, T1-WI, T2-WI, and contrast-enhanced T1-WI after intravenous gadolinium (Gd) infusion (0.2 ml/kg). A new Gd+ lesion is defined as a typical area of hyperintense signal on postcontrast T1-WI. A new or newly enlarging lesion on T2-WI is defined as a rounded or oval lesion arising from an area previously considered as normal appearing brain tissue and/or showing an identifiable increase in size from a previously stable-appearing lesion. An active scan is defined as showing any new, enlarging or recurrent lesion(s) on postcontrast T1- and T2-WI.

Measure: Neuroradiological assessment for correlation analysis with CSF-miR-142-3p levels

Time: Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up

Description: To assess synaptic excitability by SICI, ICF and LICI, motor thresholds will be calculated at rest as the lowest stimulus intensity able to evoke MEPs of about 50uV in 5 out of 10 consecutive trials (cts), and during a slight voluntary contraction of the target muscle (20-30% of the max voluntary contraction) as the lowest intensity able to evoke MEPs > 100uV in 5 out of 10 cts. The mean peak-to-peak amplitude of the conditioned MEP (cMEP), at each interstimulus interval (ISI), will be expressed as a percentage of the mean peak-to-peak amplitude of the test MEP (tMEP). PAS-induced LTP-like plasticity will be expressed as changes of the average MEPs size at each time point after PAS compared to the average baseline MEPs size. Before PAS, 25 MEPs, evoked by single TMS pulses over the APB motor hot spot set at an intensity to obtain MEPs size of about 1mV peak-to-peak, will be collected. The same stimulus intensity will be used to obtain 25 MEPs 0', 30' and 60' after PAS.

Measure: Neurophysiological assessments for correlation analysis with CSF-miR-142-3p levels

Time: Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up

Description: To investigate miR-142-3p association with synaptopathy-driven disease progression (measured in terms of clinical or radiological changes and TMS variables), multivariable generalized linear models (GLM) will be applied considering miR level in the CSF as an independent variable adjusting for demographical, clinical, neuroradiological, neurophysiological, biochemical factors and treatments. In the case of unsuccessful identification, Principal Component Analysis (PCA) will be performed to evaluate the miR contribution with other molecules in the CSF (as cytokines, chemokines, growth factors, neurofilaments, beta amyloid and tau protein) to synaptopathy-driven disease progression to reduce the number of variable examined and increase the power of multivariate analysis. Statistical correlations will be repeated on the identified PCA components including miR-142-3p as part of the component. The significance level is established at p<0.05.

Measure: Statistical correlation of miR-142-3p levels in MS CSF with disease and neurophysiological parameters

Time: T0 (enrollment), T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months).

Secondary Outcomes

Description: miR-142-3p levels in the CSF will be assessed at T0, as reported above. The responsiveness to the DMT, who MS patients underwent as part of their clinical routine, will be evaluated according to clinical and neuroradiological parameters considered in the primary outcomes. Changes in such parameters will be evaluated at different time points during a six-year follow-up (T12-T0; T24-T0, T24-T12, etc). Both univariable and multivariable approaches and stratification of patients based on DMT treatment will be performed.The significance level is established at p<0.05.

Measure: Statistical correlation of miR-142-3p levels in MS CSF with patient's responsiveness to disease modifying therapies (DMTs).

Time: Time Frame: T0 (enrollment); Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up

Description: Genetic screening will be performed on peripheral blood withdrawn from MS patients at T0. The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed. Univariable and multivariable correlations of minor allele presence of each screened SNP with clinical, neuroradiological and neurophysiological parameters, detected in the primary outcomes (T0, T12, T24, T36, T48, T60, T72), will allow the identification of SNPs relevant to disease progression. The significance level is established at p<0.05.

Measure: Genotyping of SNPs in SLC1A3 and MIR-142 genes for correlation analysis with disease parameters

Time: Time Frame: T0 (enrollment); Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up

Description: Lower limb spasticity will be evaluated in all recruited MS patients at T0 and during 6-year-follow-up. A subgroup of MS patients with lower-limb spastic symptoms and carrying SNPs in in SLC1A3 and MIR-142 genes relevant to disease progression will undergo therapeutic iTBS protocol daily for two weeks (interventional substudy) and spasticity will be assessed also immediately before the beginning (W0) and after 2 weeks at the end of the protocol (W2). The H/M amplitude ratio of the Soleus H reflex will be evaluated by EMG recordings as an index of spinal excitability. Compound motor action potentials (cMAPs) and H reflex will be evoked by electrical stimulation of the tibial nerve. The maximum amplitudes of the H reflex (H) and CMAP (M) potentials will be measured from peak to peak and H/M ratio was calculated by dividing the maximal amplitude of H wave by that of M wave.

Measure: Lower limb spasticity assessment by H/M amplitude ratio for the therapeutic TMS substudy

Time: Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up; Changes from the starting day (W0) to the end of the 2-week iTBS protocol (W2).

Description: Lower limb spasticity will be evaluated in all recruited MS patients at T0 and during 6-year-follow-up. A subgroup of MS patients with lower-limb spastic symptoms and carrying SNPs in in SLC1A3 and MIR-142 genes relevant to disease progression will undergo therapeutic iTBS protocol daily for two weeks (interventional substudy) and spasticity will be assessed also immediately before the beginning (W0) and after 2 weeks at the end of the protocol (W2). The Modified Ashworth Scale (MAS) assesses resistance during passive soft-tissue stretching ranging from 0 to 4 score.

Measure: Lower limb spasticity assessment by MAS score for the therapeutic TMS substudy

Time: Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up; Changes from the starting day (W0) to the end of the 2-week iTBS protocol (W2).

Description: Minor allele presence of each screened SNP in SLC1A3 and MIR-142, identified at T0 as relevant to disease progression (see above), will be correlated with changes in spasticity parameters (the H/M amplitude ratio of the Soleus H reflex and MAS score) upon the iTBS treatment (W2-W0). The significance level is established at p<0.05.

Measure: Statistical correlation of response to iTBS treatment with MS-significant SNPs of both SLC1A3 and MIR-142.

Time: T0 (enrollment); Changes from the starting day (W0) to the end of the 2-week iTBS protocol (W2).

Purpose: Treatment

Allocation: Non-Randomized

Parallel Assignment


There are 18 SNPs

SNPs


1 rs1049522

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


2 rs1049524

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


3 rs137852620

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


4 rs2032892

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


5 rs2269272

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


6 rs2269273

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


7 rs2562582

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


8 rs2731886

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


9 rs377637047

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


10 rs4869675

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


11 rs4869676

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


12 rs529802001

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


13 rs544684689

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


14 rs547987105

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


15 rs549927573

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


16 rs550842646

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


17 rs562696473

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


18 rs573562920

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.



HPO Nodes


HPO:
Spasticity
Genes 631
VAPB NHLRC1 GPHN MAG TACO1 PIGN UBA5 SDHAF1 TMEM67 EPRS TREX1 RAB11B AARS GLRX5 ERBB4 ERCC2 ERCC3 ERCC4 ERCC5 ERCC6 CRLF1 REPS1 ZFYVE27 MAN2B1 STUB1 ACER3 MICOS13 ACAT1 AIMP1 SIGMAR1 PDHA1 MAPT DNAJC19 MARS AMACR KDM5C ACP2 RPS6KA3 ACP5 COPB2 GLYCTK KATNB1 SCYL1 NAA10 PEX1 PEX6 PEX7 PEX10 PEX12 L2HGDH PEX13 DHDDS PEX14 EXOSC8 LAGE3 ISCA2 HMGCL NUP62 PCDH12 PFN1 EZH2 TFG ADAR ATXN8 HNRNPA1 REEP2 MECP2 TTR RTN2 ARSI WARS2 TUBG1 TUFM STN1 ADD3 RNU4ATAC SPG21 PRUNE1 TYROBP HEPACAM TUBB3 TUBB4A GUF1 PANK2 KIDINS220 PLAA PIGA ADSL CLCN4 AARS2 NALCN ATXN1 ATXN2 CLIC2 ATXN7 ATXN8OS FDX2 AGA UBTF CPT1C UCHL1 DSTYK HPRT1 SCN1B FRRS1L RAB3GAP2 SCN2A PGAP1 RNASEH2C SCN3A HACE1 CLTC SCN8A ATXN3 RETREG1 FBXO7 PEX16 GTF2H5 CC2D2A CYP7B1 PLA2G6 FGF12 FGFR1 ATXN10 ABCD1 FLRT1 TP53RK MTO1 FAR1 HSD17B4 ALDH3A2 MED17 PYCR2 TRMT5 TXN2 ITM2B PLP1 SLC30A10 KCNT1 MOCS1 FOXG1 MOCS2 SDHA SDHB VCP SDHD WDR48 HSPD1 COL4A1 COL4A2 MRE11 FLNA COG2 AMPD2 PSAT1 EXOSC9 FOXRED1 VPS37A UBQLN2 ANG NDUFAF5 ANK3 ARV1 OSTM1 CLIP2 RNASEH2A PMPCB CTC1 NACC1 HIKESHI IARS FA2H UFC1 POLG ANXA11 PEX3 CNTNAP1 RTTN NDUFAF3 ARX POLR1C APC PON1 IKBKG PON2 KLC2 PON3 NTNG1 COX10 POMGNT1 COX15 OPA3 ALS2 NPC2 TSEN54 SPG11 CNKSR2 SAMHD1 XPA XPC FXN MTHFS OSGEP GABBR2 GTF2IRD1 IDUA NUBPL GBA2 WDR26 SLC1A2 YWHAG SLC1A4 COA8 ADAM22 UFM1 SLC2A1 SLC2A3 TOE1 ERLIN1 PEX26 ARF1 CYFIP2 NECAP1 STAMBP CHMP2B TRAK1 CASK MTFMT ARG1 TPK1 SLC6A8 LIPT1 RAB3GAP1 RAB18 GTPBP2 NDUFAF4 RPIA POLR3B BCL11B ARSA PPP3CA SLC25A12 CSF1R ATP6 PPT1 CCT5 SLC16A2 ZNF592 FARS2 SLC18A2 OTUD6B ZNF335 TBK1 NUS1 C12ORF65 ND1 ASNS SETBP1 ND2 ND3 ND4 ASPA RNASET2 ND5 ND6 CNTNAP2 TIMM50 NT5C2 MPLKIP CNPY3 MRPS34 SLC13A5 TRNF ZFR PNPLA8 FTL NDUFAF6 SMPD1 FUCA1 TRNI TRNK TRNL1 ATM CTNNA2 SELENOI FUS COASY CTNNB1 TRNP AP4B1 TBC1D23 SNCA C9ORF72 OCLN TDP1 TRNV PUM1 TRNW CTSD GFM1 SPATA5 ABHD12 ATP2B3 UNC13A UNC80 PRNP SOD1 SON KIF1C PRPH PHACTR1 LYRM7 GABRB2 SOX2 SOX10 ATP6V1A GAD1 IBA57 VPS11 ATP6V1E1 TRIT1 CHCHD10 GALC EED HTRA1 NDUFS7 B4GALNT1 SETX NKX6-2 ATP7A ADAT3 SPAST PSAP GPAA1 KMT2B WWOX FRMPD4 PSEN1 SPG7 REEP1 WDR4 ATRX KIF1A MYO5A NDE1 AUH EARS2 SPR PET100 NEXMIF VPS13C INPP5K NADK2 SPTAN1 MATR3 SPTBN2 CYP27A1 RNF113A NAGA GBA SPART GBE1 DAO DARS GCDH NDUFA2 MCCC2 NDUFA4 MCCC1 NDUFA6 PEX11B NDUFA9 BCOR NDUFA10 ZC4H2 SUCLA2 DNAJC6 ANKLE2 DCTN1 NSUN2 BCS1L DCX NDUFB8 DDB2 GFAP NDUFS1 NDUFS2 MRPS22 NDUFS3 PHGDH NDUFV1 MFF NDUFS4 DDX3X TTC19 SNORD118 NDUFS8 NDUFV2 TBC1D20 RUSC2 SYNGAP1 ELOVL4 IFIH1 NEFH CDKL5 GJA1 PPARGC1A NEFL TIMM8A NEK1 GJB1 PRDM8 KANK1 KCNA1 KCNA2 KCNA4 PNPLA6 STXBP1 NDUFA12 GLB1 TMTC3 KCNB1 SYNJ1 PMPCA CLPB ARL6IP1 TELO2 SACS TUBA1A TECPR2 FIG4 WASHC5 MLC1 GLE1 PTS SQSTM1 ABCC8 SURF1 AP5Z1 KCNJ6 C19ORF12 GLRA1 DHCR24 SUMF1 GLRB EIF2B4 EIF2B3 ARNT2 AFG3L2 VAMP1 EIF2B2 EIF2B5 CYB5R3 PEX19 PEX2 PLCB1 PEX5 MFN2 GM2A ALDH18A1 AP1S2 KCNQ2 DLD LIPT2 RARS2 IRF2BPL VWA3B CACNA1G KIF2A KIF5A NIPA1 GNAO1 KIF5C TAF1 TAF2 DENND5A DDHD2 RFT1 SLC52A2 TMEM231 DNM1 CLP1 CARS2 GPT2 TSEN15 RAB27A DYNC1H1 CFAP410 JAM3 NOTCH3 WDR62 AGTPBP1 KIF11 TBCD TBCE DNMT1 PNP TBP NPC1 BICD2 RNASEH2B CACNA1A KRAS MARS2 CACNA1D CACNA1E LIAS SCO2 RANBP2 EPM2A ROGDI ISCA1 RPGRIP1L RARS WASHC4 B4GAT1 SZT2 NDUFAF2 CAMK2A HCN1 BEAN1 NTRK2 PCLO CAPN1 L1CAM TPRKB SLC19A3 EXOSC3 NSD1 BAZ1B LAMB1 DNM1L ALG11 GRIA4 GJC2 GRIN1 GRIN2B GRIN2D COLGALT1 PRRT2 RFC2 GRM1 PQBP1 ECHS1 BOLA3 ATP13A2 MCOLN1 CIT TSEN2 MTPAP OPA1 NARS2 PDHX DARS2 EDNRB ATL1 SIL1 OPHN1 POLR3A GSS EEF1A2 SIX6 RAD50 CCNF SLC25A22 NDUFA13 SLC17A5 CCDC88C AP4E1 KY TARDBP USP8 MFSD2A SNX14 WDR45 LIMK1 GTF2E2 AP4S1 SEPSECS VPS13D OPTN ERLIN2 GTF2I MECR LINGO1 ATAD1 LMNB1 TRAPPC12 ATAD3A AASS EIF2B1 ATP6AP2 EIF2S3 DDHD1 SLC25A15 PPP1R15B PAFAH1B1 AP3B2 ENTPD1 RLIM SLC6A5 MED25 TREM2 CKAP2L MACF1 GAN CYP2U1 WDR45B WDR73 ZFYVE26 SERAC1 ELP2 BSCL2 HSD17B10 TAF15 PAX3 ELN SUZ12 EML1 AP4M1 TANGO2 SLC39A14 VPS53 SLC33A1 TBL2 HTT ATP6V0A2 TCTN2 EPHA4 CHMP1A TPI1