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Report for Clinical Trial NCT02720822

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

A Pragmatic, Phase III, Multi-site, Double-blind, Placebo Controlled, Parallel Arm, Dose Increment Randomised Trial of Regular, Low Dose Extended Release Morphine for Chronic Refractory Breathlessness

Breathlessness is an overwhelming symptom affecting tens of thousands of Australians every day. For many people, it persists even when all the underlying causes have been optimally managed (chronic breathlessness). In these circumstances, it often occurs at rest or with minimal exertion. Evidence from a number of clinical studies suggests that a small, regular dose of morphine helps to reduce safely the sensation of breathlessness. However, it is not well established which patients derive more benefit and what is the net clinical effect of this treatment (weighing benefits and harms). This is a phase III, multi-site, randomised, double-blind, placebo-controlled trial with patients with chronic obstructive pulmonary disease (COPD) and severe chronic breathlessness which will explore several important questions: - Are regular, low doses of morphine at four possible doses over 3 weeks more effective than placebo at improving breathlessness? - Does increasing the dose in people who already are experiencing some benefit provide even greater reduction in worst breathlessness? - Does the medication have any effect on daily activity and quality of life? - What are the common or serious side effects of this intervention? - Does the benefit from the medication outweigh the side effects it produces? - Are there specific characteristics of people who are more likely to receive benefit from extended release morphine? Participants will receive once daily extended release morphine (plus laxative, docusate with senna), or placebo (placebo laxative) in addition to their usual medication for up to 3 weeks at increasing doses. Participants will have a medical interview and physical examination to collect some general health information, and baseline measurements including; daily activity, symptoms, and quality of life. A small amount of blood may be required to check eligibility. Further blood samples may be taken at week 1 and 3 to enable testing on how individuals respond to opioids, further consent will be obtained for these samples. Data on benefits, side effects, and medical care will be collected during comprehensive weekly visits. Participants will also fill out a simple diary twice daily for weeks one to three of the study, and for one day each week during an optional 6 month extension stage. The outcome of this study may enable better management of symptoms and activity in people COPD with medicines that are shown to be effective and safe.

NCT02720822 Chronic Obstructive Pulmonary Disease Dyspnea
MeSH: Lung Diseases, Obstructive Pulmonary Disease, Chronic Obstructive Dyspnea
HPO: Chronic obstructive pulmonary disease Dyspnea Obstructive lung disease Respiratory distress

5 Interventions

Name: Placebo

Description: Treatment with placebo is given as one double-blind capsule in the morning.

Type: Drug

Morphine Sulfate (0, 0, 8 mg) Morphine sulfate (0, 8, 16 mg) Morphine sulfate (0, 8, 8 mg) Placebo

Name: Morphine Sulfate

Description: Treatment with sustained-release morphine sulfate is given as one double-blind capsule in the morning.

Type: Drug

Morphine Sulfate (0, 0, 8 mg) Morphine sulfate (0, 8, 16 mg) Morphine sulfate (0, 8, 8 mg) Morphine sulfate (16, 16, 16 mg) Morphine sulfate (16, 16, 24 mg) Morphine sulfate (16, 24, 24 mg) Morphine sulfate (16, 24, 32 mg) Morphine sulfate (8, 16, 16 mg) Morphine sulfate (8, 16, 24 mg) Morphine sulfate (8, 8, 16 mg) Morphine sulfate (8, 8, 8 mg)

Name: Plus laxative (Docusate with senna)

Description: If patients are taking morphine, a laxative will be offered. This applies whatever the dose of morphine being taken (8mg, 16mg, 24mg or 32 mg).

Type: Drug

Morphine Sulfate (0, 0, 8 mg) Morphine sulfate (0, 8, 16 mg) Morphine sulfate (0, 8, 8 mg) Mo Morphine sulfate (16, 16, 16 mg) Morphine sulfate (16, 16, 24 mg) Morphine sulfate (16, 24, 24 mg) Morphine sulfate (16, 24, 32 mg) Morphine sulfate (8, 16, 16 mg) Morphine sulfate (8, 16, 24 mg) Morphine sulfate (8, 8, 16 mg) Morphine sulfate (8, 8, 8 mg)

Name: Plus placebo laxative

Description: If the patients are taking placebo, a placebo laxative will be offered.

Type: Drug

Morphine Sulfate (0, 0, 8 mg) Morphine sulfate (0, 8, 16 mg) Morphine sulfate (0, 8, 8 mg) Placebo

Name: FitBit charge HR (Accelerometer)

Description: A Fitbit will be worn by patients during week 1 and week 3.

Type: Device

Morphine Sulfate (0, 0, 8 mg) Morphine sulfate (0, 8, 16 mg) Morphine sulfate (0, 8, 8 mg) Morphine sulfate (16, 16, 16 mg) Morphine sulfate (16, 16, 24 mg) Morphine sulfate (16, 24, 24 mg) Morphine sulfate (16, 24, 32 mg) Morphine sulfate (8, 16, 16 mg) Morphine sulfate (8, 16, 24 mg) Morphine sulfate (8, 8, 16 mg) Morphine sulfate (8, 8, 8 mg) Placebo


Primary Outcomes

Description: Rated on a 0-10 numerical rating scale (NRS). Measured at baseline, Stage1-3 (daily diary) and Stage 4 (weekly diary). The primary endpoint is: The difference between morphine sulphate 8mg and placebo (end of week1) The difference of morphine sulphate 16 mg and placebo (end of week 1)

Measure: Change from baseline worst breathlessness intensity over the previous 24 hours

Time: Week 1

Description: Difference from the baseline in the number of steps per day measured using the Fitbit(Charge HR). Measured at baseline, end of week 1, and end of week 3. The primary endpoint is: The difference between morphine sulphate 8mg and placebo (end of week 1) The difference between morphine sulphate 16mg and placebo (end of week 1) Comparison between baseline and end of week 3

Measure: Change from the baseline in the number of steps per day

Time: Week 3

Secondary Outcomes

Description: Measured at baseline and at the weekly visit for the randomisation phase, and then at the study exit in order to assess the theoretical risk of opioids worsening respiratory failure. Stages 1-4.

Measure: Change from baseline end-tidal carbon dioxide

Time: Up to week 15

Description: Measured at baseline and at the weekly visit for the randomisation phase, and then at the study exit in order to assess the theoretical risk of opioids worsening respiratory failure. Concomitant use of oxygen will be recorded. Stages 1-4.

Measure: Change from baseline pulse oximetry

Time: Up to week 15

Description: Rated on a 0-10 numerical rating scale (NRS). Measured at baseline, weeks 1-3 (daily diary) and stage 4 (weekly diary).

Measure: Change from baseline intensity of breathlessness "average"

Time: Up to week 15

Description: Rated on a 0-10 numerical rating scale (NRS). Measured at baseline, weeks 1-3 (daily diary) and stage 4 (weekly diary).

Measure: Change from baseline distress from breathlessness over the previous 24 hours

Time: Up to week 15

Description: Chronic Respiratory Questionnaire - Dyspnoea and Mastery Subscales. Baseline and end of Weeks 1-3.

Measure: Change from baseline perceived-impact of breathlessness

Time: Up to week 3

Description: Rated on the Modified Medical Research Council Breathlessness Scale (mMRC). Measured at baseline and at the conclusion of the study.

Measure: Change from baseline functional impact of breathlessness

Time: Up to week 15

Description: Measured using the Fitbit(Charge HR). Assessed at baseline (2 days), weeks 1 and 3.

Measure: Change from baseline sleep minutes

Time: Week 3

Description: Measured using the Fitbit(Charge HR). Given in number of movements per night (e.g. rolling over). Assessed at baseline (2 days), weeks 1 and 3.

Measure: Change from baseline sleep activity

Time: Week 3

Description: Measured using the Fitbit(Charge HR). Difference from baseline in the number of active minutes per day. Assessed at baseline (2 days), weeks 1 and 3.

Measure: Change from baseline in activity levels

Time: Week 3

Description: Measured using the Fitbit(Charge HR). Difference from baseline number of calories spent per day. Assessed at baseline (2 days), weeks 1 and 3.

Measure: Change from baseline total energy expenditure

Time: Week 3

Description: Measured using Australian-modified Karnofsky Performance Status (AKPS). Baseline, Stage1, Stage2, Stage3 and Stage 4.

Measure: Change from baseline performance status

Time: Up to week 15

Description: Measured using Barthel Index. Baseline and Stage 4.

Measure: Change from baseline activities of daily living

Time: Up to week 15

Description: Rated on a 4 point Likert scale. Measured at baseline, weeks 1-3 (daily diary) and stage 4 (weekly diary).

Measure: Change from baseline in sleep quality

Time: Up to week 15

Description: Thirty (30) participants at the Sydney and Adelaide sites will be invited to undertake a simple, non-invasive home sleep study using the ResMed ApneaLink Plus device. Baseline and Stage3.

Measure: Change from baseline in objective sleep testing

Time: Week 3

Description: Up to ten (10) participants will also undergo two (baseline and Stage 1) in-laboratory overnight sleep studies in Sydney and Adelaide.

Measure: Change from baseline Polysomnography

Time: Week 3

Description: Twenty (20) participants in Adelaide and Sydney. Baseline and on day 2 and 7 of the first week in an office-based simulator - AusEd.

Measure: Change from baseline Driving ability

Time: Week 3 + 2 days

Description: The baseline blood samples will be analysed to detect the presence of UGT2B7*2 and *28 polymorphisms.

Measure: Pharmacogenetic opioid profile - Number of participants with UGT2B7*2 and *28 polymorphisms

Time: Baseline (1 day)

Description: The baseline blood samples will be analysed to detect the presence of P-glycoprotein polymorphism (ABCB1 5SNPs in a haplotype block)

Measure: Pharmacogenetic opioid profile - Number of participants with P-glycoprotein polymorphism (ABCB1 5SNPs in a haplotype block)

Time: Baseline (1 day)

Description: The baseline blood samples will be analysed to detect the presence of 5-hydroxytryptamine type 3B (HTR3B) gene rs7103572 polymorphism

Measure: Pharmacogenetic opioid profile - Number of participants with 5-hydroxytryptamine type 3B (HTR3B) gene rs7103572 polymorphism

Time: Baseline (1 day)

Description: The baseline blood samples will be analysed to detect the presence of Mu receptor (A118G) polymorphism

Measure: Pharmacogenetic opioid profile - Mu receptor (A118G) polymorphism

Time: Baseline (1 day)

Description: In a subset of 55 participants, morphine peak plasma concentrations will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).

Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine Peak Plasma Concentration [Cmax]

Time: Week 1

Description: In a subset of 55 participants, morphine AUC will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).

Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine Area Under the Curve (AUC)

Time: Week 1

Description: In a subset of 55 participants, M6G Peak Plasma Concentration will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).

Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-6-glucuronide (M6G) Peak Plasma Concentration [Cmax]

Time: Week 1

Description: In a subset of 55 participants, M6G AUC will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).

Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-6-glucuronide (M6G) Area Under the Curve (AUC)

Time: Week 1

Description: In a subset of 55 participants, M3G Peak Plasma Concentration will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).

Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-3-glucuronide (M3G) Peak Plasma Concentration [Cmax]

Time: Week 1

Description: In a subset of 55 participants, M3G AUC will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).

Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-3-glucuronide (M3G) Area Under the Curve (AUC)

Time: Week 1

Description: Baseline and study completion. To explore whether longer term morphine treatment is associated with decreased levels of testosterone.

Measure: Change from baseline serum testosterone level

Time: Week 15

Description: Rated on a Lickert Scale. Baseline, weeks 1-3 (daily diary), Stage 4 (weekly diary): Includes constipation, anxiety, appetite, nausea, vomiting, drowsiness, difficulty thinking clearly, problems passing urine, itch, other symptoms.

Measure: Adverse Effects

Time: Up to 15 weeks

Description: Measured using the Edmonton Symptoms Assessment Scale (ESAS)

Measure: Change from baseline in concurrent symptoms

Time: Up to 15 weeks

Description: Rated using the Hospital Anxiety and Depression Scale (HADS). At baseline, completion of randomization stage and study exit.

Measure: Change from the baseline anxiety and depression

Time: Up to Week 15

Description: Participant-rated 7 point scale of the perception of their change, specifically their improvement since the commencement of the study. Measured at the end of Stages 1-3 and conclusion.

Measure: Change in baseline global impression of change

Time: Up to 15 weeks

Description: Measured with EQ-5D-5L questionnaire. Baseline, Stages 1-3, Stage 4, conclusion.

Measure: Change from baseline health-related quality of life

Time: Up to 15 weeks

Description: Measured with the COPD Assessment Test (CAT) Baseline, Stages 1-3, Stage 4 and conclusion.

Measure: Change from baseline health-status in COPD

Time: Week 3

Description: Asked at the end of week 1 and at the conclusion/drop-out of the study. A 3-point Likert scale will be used.

Measure: Blinded-patient preference to continue the treatment [3-point Likert Scale]

Time: Up to week 15

Description: Scored using the Zarit Burden Interview (ZBI) 12 item short-form questionnaire. Baseline, end of weeks 1-3, stage 4.

Measure: Change from baseline caregiver Impact

Time: Up to week 15

Description: From randomisation to 28 days post treatment or death (whichever is the shorter period). Estimated based on all health-care contacts including length of hospitalizations, emergency department visits, DRG codes, community health visits, GP and community nurse visits, outpatient visits and date of death. These participant level data allow within trial modeling using bootstrapping methods of replicates for costs and consequences of alternative strategies, allowing for covariance between costs and effects. Incremental net monetary benefit and cost-effectiveness acceptability curves will be estimated at potential threshold values for an additional responder.

Measure: Economic Evaluation - Cost per responder

Time: Up to week 4

Description: Evaluation using the Subjective Opioid Withdrawal Scale (SOWS) for 3 consecutive days. After the completion of the study (Weeks 1-15).

Measure: Opioid Withdrawal

Time: Up to week 15 + 3 days

Purpose: Treatment

Allocation: Randomized

Parallel Assignment


There is one SNP

SNPs


1 A118G

Pharmacogenetic opioid profile - Mu receptor (A118G) polymorphism. --- A118G ---

The baseline blood samples will be analysed to detect the presence of Mu receptor (A118G) polymorphism. --- A118G ---



HPO Nodes


HPO:
Chronic obstructive pulmonary disease
Genes 31
HLA-DPA1 TBX1 GP1BB HMOX1 PTPN22 DNAAF4 HIRA CYBB SERPINA1 ARVCF CYBA SEC24C NCF1 NFKB1 MYH7 NCF4 GLA SERPINA1 JMJD1C CTLA4 RREB1 MMP1 WIPF1 PRTN3 HLA-DPB1 TBX1 COMT UFD1 NCF2 WAS CYBC1
Dyspnea
Genes 452
DNAH9 DOK7 COL13A1 ND5 EPHB4 SBDS TBC1D24 SPAG1 ORC1 ZFPM2 ABCG8 GAS2L2 CHRNB1 DNA2 LYRM4 CHRNE CRELD1 TET2 RAPSN ATRX TERT SQSTM1 PLEC CASR PON2 ENG COLQ DNAAF4 ALDH7A1 MYO9A SCN4A IRF2BP2 OPTN SLC18A3 FGFR2 MYL3 CFAP300 MARS1 RUNX2 DNAI1 TRAK1 SFTPA2 COX6B1 RSPH1 CRLF1 MFAP5 SLC2A10 DNAL1 ND2 ZMYND10 FUS NKX2-1 TTN SURF1 COX8A MMAB CYB5A GBA GAS8 PUF60 PRRT2 IFT52 TBL1XR1 SFTPA1 PNKD NPPA FIP1L1 EP300 COX14 MPC1 COL2A1 BMPER NDUFS2 MUC5B BCOR DNAAF1 PRSS1 PET100 SRP54 FAM20C COX20 EOMES TRMT5 CSPP1 RPS28 NABP1 SCN1B TSC1 AIFM1 TGFB2 DNAAF6 NUMA1 STN1 PRRX1 SFTPC ISCU SLC25A3 LAMB2 SLC5A7 VCP SPEF2 LIFR TGFBR1 SMPD1 LDLRAP1 LGI4 MAT2A COA8 RPS26 SERPING1 LAMB3 ADCY6 FOXE3 SMAD4 EIF2AK4 IL1RN ND4 TRIP11 GBA NGLY1 STAT5B POLG CCR6 GATA6 ANG MUSK C1R MMUT DBH SFTPB MRPL3 HNRNPA1 GATA6 CFAP410 PFN1 SFTPC CSF2RB SDCCAG8 DSC2 ADAMTS13 JAK2 GNAS PRKCSH ZIC3 C9ORF72 FASTKD2 ETFB SPP1 CSF2RB NDUFB8 CHAT STK36 CHCHD10 NPM1 PRKAR1A SCN5A KLHL7 CNTNAP1 RSPH3 CYB5R3 GNAI3 PCSK9 FBLN5 CCN2 DRC1 VAMP1 ADNP CPT2 TREM2 LDLR LRRC56 LRRC6 BTNL2 CCDC40 SLC25A1 STX16 CFTR COQ7 GATA6 HLA-DRB1 FOXF1 EFEMP2 DAO GYG1 PLCB4 UBE3B C1QA SMAD3 TSC2 ITGA3 SCNN1B DSP DNAI2 CFTR SOX9 DNAJC21 SCO1 SYT2 USP9X RRM2B DPM2 FGFR2 SSR4 BTNL2 COX10 CDC6 ERBB4 VCL GLA CCDC114 PON3 ACVRL1 DYNC2LI1 GLE1 ZBTB16 CDC45 NEK1 MGME1 RPGR ATP6 CREBBP CLCNKB CTRC DPM2 BMPER SPINK1 STAT5B ERF HYDIN DNAH11 FBN1 APOB TRNW CHRND COA8 ND6 DNAAF3 CCDC151 PRPH UBQLN2 DISC1 ATP11A SCN4A TRNV STT3B TGFBR2 NDUFAF3 IFT81 WIPF1 GATA4 CDT1 ETFA DNAJB6 TRMU RSPH4A GBA HLA-B TACO1 SLC52A3 DPP9 NME8 COL2A1 FBP1 TERC AGRN TWNK CCDC65 GLT8D1 TRNN STAT4 CYB5R3 PML ORC1 LTBP3 MYH11 SOD1 FLNC RARA LRP4 CCDC39 PMM2 TRNK ORC4 BMPR2 AK9 SFTPC DMPK MAPT MYH11 IRF5 KAT6A NR2F2 SLC35A1 NUP214 CHRND ORC6 TET2 CFAP298 DPM1 FGFR1 ATXN2 TRNE DNAAF2 MATR3 GMNN ORC6 NAGS SCN4A NEFH PIGT HLCS SLC25A4 CCNF PRKG1 ANXA11 MYLK VCP HLA-DRB1 CSF2RA FIG4 TARDBP VAPB AIMP2 HCCS DNASE1L3 ELN STT3B DNAH5 SETBP1 OTX2 RTEL1 SFTPA2 ACADM TTC25 UNC13A LOX DNAAF5 STAT3 CHRNE TRIP11 TBX4 NEB ABCG5 TUBB4A NAGS ACADVL CAV1 TK2 GAA ARMC4 CHRNA1 SNAP25 MUC5B ND3 POLG2 COL2A1 EFTUD2 PON1 TNNC1 ARX KCNA1 FOXP3 CFAP221 DNA2 MAPT KCNJ6 EPHA4 COPA DCTN1 TGFB3 MMAA ABCA3 PARN RNU4ATAC CHMP2B XYLT1 NOD2 VPS33A FOXJ1 MEGF10 PRKAR1A CHAT SLC25A1 CAV1 CCNO SERPINA1 PPARGC1A FGFR2 SCN5A TRPM4 TRNS1 POMT1 TRNE DNAH1 RSPH9 TRNL1 PRRX1 TAF15 EDN1 WAS JPH2 PGM1 COX7B CCDC103 ND1 HLA-DRB1 DNAAF3 IKZF1 LAMA3 SH2B3 SLC12A3 CHRNB1 LAMC2 TBK1 ABCA3 SCO2 TERT EDA ALAS2 SCO2 DMPK MGME1 GNAS NKX2-1 GNAS OFD1 TRNK ACTA2 COL13A1 ETFDH COL2A1 FAM13A IRAK1 MYL2 SCNN1A HBB USP9X SCNN1G NDUFB11 CHRNE FGFR2 TRPV6 DNAJB13 MYBPC3 SIK1 CHRNA1 MMUT EPOR FBP1 NKX2-5 AGRN MCIDAS
Obstructive lung disease
Genes 84
HLA-DPA1 DNAH9 CCDC103 PTPN22 DNAH11 DNAAF3 HIRA LRRC56 CYBB GLA LRRC6 GAS8 SERPINA1 CFAP298 SPAG1 CCDC40 ARMC4 CYBA GAS2L2 CCDC151 NCF1 NFKB1 MYH7 DNAAF2 RREB1 MMP1 CFAP221 WIPF1 HLA-DPB1 DNAAF1 RSPH4A APC OFD1 NME8 DNAAF4 SCNN1B DNAI2 CFTR CCDC65 TBX1 GP1BB HMOX1 DNAAF4 ARVCF CFAP300 SCNN1A DNASE1L3 SEC24C FOXJ1 DNAI1 DNAAF6 NCF4 SCNN1G CCNO DNAH5 GLA CCDC114 SERPINA1 RSPH1 CCDC39 STK36 JMJD1C CTLA4 DNAJB13 RPGR MGP PRTN3 TTC25 DNAL1 DNAH1 ZMYND10 RSPH3 TBX1 COMT RSPH9 UFD1 SPEF2 NCF2 DNAAF5 DRC1 WAS CYBC1 MCIDAS HYDIN
Respiratory distress
Genes 230
DNAH9 DNAH11 ND5 EPHB4 SBDS TBC1D24 SPAG1 ORC1 TRNW ZFPM2 ND6 DNAAF3 GAS2L2 CCDC151 LYRM4 DISC1 CHRNE TRNV STT3B NDUFAF3 IFT81 CDT1 ETFA TRMU RSPH4A GBA TACO1 SLC52A3 NME8 COL2A1 COLQ FBP1 DNAAF4 ALDH7A1 MYO9A AGRN CCDC65 SLC18A3 TRNN FGFR2 ORC1 CFAP300 RUNX2 DNAI1 TRAK1 COX6B1 RSPH1 CCDC39 PMM2 ORC4 SLC2A10 DMPK DNAL1 MAPT ND2 ZMYND10 KAT6A NKX2-1 SURF1 COX8A MMAB SLC35A1 NUP214 GBA GAS8 CFAP298 DPM1 FGFR1 PUF60 IFT52 EP300 TRNE COX14 DNAAF2 MPC1 COL2A1 GMNN BMPER NDUFS2 ORC6 NAGS DNAAF1 PRSS1 PET100 SRP54 HLCS FAM20C COX20 EOMES CSF2RA RPS28 AIMP2 AIFM1 HCCS DNAAF6 STT3B DNAH5 SETBP1 PRRX1 SFTPC OTX2 SLC25A3 TTC25 LAMB2 SLC5A7 SPEF2 DNAAF5 TRIP11 LIFR TUBB4A NAGS ACADVL TK2 LGI4 ARMC4 COA8 SNAP25 ND3 RPS26 SERPING1 COL2A1 EFTUD2 ADCY6 KCNA1 FOXP3 CFAP221 IL1RN ND4 TRIP11 NGLY1 STAT5B MAPT COPA GATA6 MMAA MMUT ABCA3 SFTPB XYLT1 GATA6 VPS33A FOXJ1 CSF2RB MEGF10 SDCCAG8 ADAMTS13 ZIC3 CHAT FASTKD2 ETFB CCNO NDUFB8 CHAT STK36 FGFR2 TRNS1 KLHL7 POMT1 TRNE CNTNAP1 DNAH1 RSPH3 RSPH9 GNAI3 FBLN5 TRNL1 PRRX1 EDN1 DRC1 VAMP1 ADNP COX7B CPT2 CCDC103 ND1 DNAAF3 LRRC56 LRRC6 CCDC40 SLC25A1 SLC12A3 CFTR COQ7 SCO2 EDA SCO2 DMPK FOXF1 EFEMP2 PLCB4 UBE3B NKX2-1 OFD1 TRNK COL13A1 ITGA3 ETFDH COL2A1 DNAI2 SOX9 DNAJC21 SCO1 SYT2 USP9X DPM2 FGFR2 SSR4 USP9X COX10 CDC6 NDUFB11 CCDC114 FGFR2 DYNC2LI1 TRPV6 CDC45 DNAJB13 RPGR ATP6 CREBBP CLCNKB SIK1 CTRC DPM2 MMUT BMPER SPINK1 ERF MCIDAS HYDIN