Hey everyone I indexed through my SV and CNV files and found the below findings. To my knowledge this means I had SV deletions that were the length listed at the locations in the genes. I am uncertain about the significance of this information so if anyone was able to provide insight, I would be appreciative. I used the LUMPY CANVAS MANTA and ANOTSV linux open source software applications to go through these files. this is what came up.

2. SULT1A1/SULT1A2-region

   MantaDEL PASS

   chr16:28,597,997–28,611,011

   GT=0/1

   GQ=655

   PR=21,11

   SR=39,13

   IGV reciprocal discordant pairs

   Depth \~35.06x; flanks \~33.02x/\~33.33x

   AnnotSV SULT1A1 CDS overlap 906 bp / 100%

   Frameshift: no

   ACMG 3

3. PIAS1

   MantaDEL PASS

   chr15:68,133,664–68,136,607

   GT=1/1

   GQ=103

   PR=0,25

   SR=0,26

   AnnotSV intron2-intron2

   CDS overlap 0

   ACMG 3

4. ESR1

   MantaDEL PASS

   chr6:152,068,854–152,071,103

   GT=0/1

   GQ=356

   PR=12,3

   SR=27,10

   AnnotSV intron8-intron8

   CDS overlap 0

   ACMG 3

5. UGT1A cluster

   MantaDEL PASS

   chr2:233,722,831–233,725,356

   GT=0/1

   GQ=93

   PR=3,8

   SR=12,15

   AnnotSV intronic across UGT1A8/10/9/7/6/5/4

   CDS overlap 0

   ACMG 1

6. FKBP5 Manta

   MantaDEL PASS

   chr6:35,658,655–35,661,969

   GT=0/1

   GQ=352

   PR=15,6

   SR=22,12

   AnnotSV intron1/5'UTR

   CDS overlap 0

   B\_loss\_AFmax 0.6895

   ACMG 1

7. SUMF1-region / LOC102723512

   MantaDEL PASS

   chr3:4,025,240–4,027,884

   GT=1/1

   GQ=56

   PR=0,12

   SR=0,22

   AnnotSV LOC102723512 intron1/UTR

   CDS overlap 0

   ACMG 1

8. CHD2

   Canvas gain/PASS signal

   Depth region \~41.87x

   Flanks \~35.53x/\~35.63x

   Ratio \~1.18x

9. SLC22A3

   Manta breakpoint-near-gene candidate

   Region depth \~31.69x

   Flanks \~33.43x/\~31.01x

10. THRB

LUMPY INV

chr3:24,264,558–24,264,604

Size \~45 bp

SU=5

PE=1

SR=4

Hey everyone I indexed through my SV and CNV files and found the below findings. To my knowledge this means I had SV deletions that were the length listed at the locations in the genes. I am uncertain about the significance of this information so if anyone was able to provide insight, I would be appreciative. I used the LUMPY CANVAS MANTA and ANOTSV linux open source software applications to go through these files. this is what came up.

2. SULT1A1/SULT1A2-region

   MantaDEL PASS

   chr16:28,597,997–28,611,011

   GT=0/1

   GQ=655

   PR=21,11

   SR=39,13

   IGV reciprocal discordant pairs

   Depth ~35.06x; flanks ~33.02x/~33.33x

   AnnotSV SULT1A1 CDS overlap 906 bp / 100%

   Frameshift: no

   ACMG 3

3. PIAS1

   MantaDEL PASS

   chr15:68,133,664–68,136,607

   GT=1/1

   GQ=103

   PR=0,25

   SR=0,26

   AnnotSV intron2-intron2

   CDS overlap 0

   ACMG 3

4. ESR1

   MantaDEL PASS

   chr6:152,068,854–152,071,103

   GT=0/1

   GQ=356

   PR=12,3

   SR=27,10

   AnnotSV intron8-intron8

   CDS overlap 0

   ACMG 3

5. UGT1A cluster

   MantaDEL PASS

   chr2:233,722,831–233,725,356

   GT=0/1

   GQ=93

   PR=3,8

   SR=12,15

   AnnotSV intronic across UGT1A8/10/9/7/6/5/4

   CDS overlap 0

   ACMG 1

6. FKBP5 Manta

   MantaDEL PASS

   chr6:35,658,655–35,661,969

   GT=0/1

   GQ=352

   PR=15,6

   SR=22,12

   AnnotSV intron1/5'UTR

   CDS overlap 0

   B_loss_AFmax 0.6895

   ACMG 1

7. SUMF1-region / LOC102723512

   MantaDEL PASS

   chr3:4,025,240–4,027,884

   GT=1/1

   GQ=56

   PR=0,12

   SR=0,22

   AnnotSV LOC102723512 intron1/UTR

   CDS overlap 0

   ACMG 1

8. CHD2

   Canvas gain/PASS signal

   Depth region ~41.87x

   Flanks ~35.53x/~35.63x

   Ratio ~1.18x

9. SLC22A3

   Manta breakpoint-near-gene candidate

   Region depth ~31.69x

   Flanks ~33.43x/~31.01x

10. THRB

LUMPY INV

chr3:24,264,558–24,264,604

Size ~45 bp

SU=5

PE=1

SR=4

Hello! I really think these instructions can help all Dr. Powers patients here. https://www.reddit.com/r/DrWillPowers/s/7q3H6NVuBf

But they are not comprehensive. That is why I am asking the Dr. Will Powers community to help me improve this instruction set. If you see something that could be improved or that is missing please let me know! Also big Thank you to both Dr Powers Community members that helped confirm that UGT2B7 variant

I figured out how to run my VCF and TBI files through PharmaCAT, which took hours, but ended up giving me useful pharmacogenomic information that I was not able to pick up from my VCF and BAM alone.

The PharmaCAT output opens in any web browser. I also manually confirmed the genes marked with an asterisk against my BAM, so I’m comfortable treating those findings as reliable.

The biggest finding from my report is that I’m a CYP2C19 ultra-rapid metabolizer, while also being heterozygous for a CYP2D6 loss-of-function variant. I have not fully verified phase yet, but I strongly suspect that at least one of the other high-REVEL CYP2D6 variants I found may be on my remaining functional copy.

The reason I think this matters is because, in our group, we keep seeing CYP2D6 disruption show up again and again in PSSD genomes. Variants that either wipe out or significantly slow CYP2D6 seem way more common in the people we have looked at than I would have expected. Out of all the genes I’ve seen while helping people dig through their genomic data, CYP2D6 has been one of the loudest “something is going on here” signals.

I brought this up to Dr. Powers, and his response was:

“It just increases exposure to some SSRIs. Basically, 10mg can feel like 30 or 40 to these people.

Also it directly synths dopamine in the brain from tyrosine.

Aka, thank you, but I saw this awhile back. I am very aware of it.

It’s not ‘the answer’ but it’s a risk variable.”

That makes sense generally, but in my specific case, Zoloft is primarily metabolized through CYP2C19, and I am a CYP2C19 ultra-rapid metabolizer. So the simple “increased SSRI exposure” explanation does not seem like the cleanest fit for me personally.

What makes this more interesting is that CYP2D6 keeps showing up even in people whose original drug was not primarily metabolized by CYP2D6. That makes me wonder if its relevance is less about drug clearance alone and more about the second point Powers mentioned: CYP2D6’s role in dopamine/tyrosine-related brain chemistry, or possibly some other mechanism we have not explored yet.

Even more confusing, we are also starting to see CYP2D6-related findings in some PFS genomes, not just PSSD. I’m working on getting that data organized and posted separately.

I’m not saying CYP2D6 is “the answer,” but based on what we are seeing across multiple people, it is starting to look like a legitimate risk variable worth paying attention to.

Hello everyone here are the variants that I pulled from my BAM. ordered first by quality then by importance separated into 3 quality tiers. One thing that I noticed is that a lot of these are 0.0 allele frequency. Even for the ones that are sufficient quality. does this perhaps suggest that maybe not a lot of the BAM variants are in the gene.iobio.io database? For example the UGT2B7 variant. So far I have had two non PFS/PSSD patients check their data for the specific variant I had. one of them had the variant and the other didnt. Its possible that this is an error from sequencing but it is also possible that the allele frequency listed in gene.iobio.io is not accurate for variants read from the BAM. u/drwillpowers What are your thoughts on this? linked here are the variants that I pulled from my VCF and the UGT2B17 deletion that I confirmed. https://www.reddit.com/r/DrWillPowers/comments/1tudi8k/dr_powers_i_went_through_every_gene_you_were/

Tier 1 — Sufficient depth and allele counts

Gene: UGT2B7
Variant: c.801_802delinsTC
Protein: p.Tyr268His
rsID: rs386675647
Zygosity: Het
Ref Allele: AT
Alt Allele: TC
Freq: 0% absent from gnomAD
REVEL: not shown
Quality: Sufficient depth and allele counts
Reads: not clearly shown

Gene: STAG2
Variant: c.363del
Protein: p.Phe121LeufsTer24
rsID: not shown
Zygosity: Het
Ref Allele: CT
Alt Allele: C
Freq: 0% absent from gnomAD
REVEL: not applicable / frameshift
Quality: Sufficient depth and allele counts
Reads: not clearly shown

Gene: TAF4
Variant: c.1191del
Protein: p.Thr398ProfsTer11
rsID: not shown
Zygosity: Het
Ref Allele: TG
Alt Allele: T
Freq: 0% genomes shown; 0.00000162 exomes
REVEL: not applicable / frameshift
Quality: Sufficient depth and allele counts
Reads: 20

Gene: KDM4C
Variant: c.2781+2T>A
Protein: no protein change shown
rsID: not shown
Zygosity: Het
Ref Allele: T
Alt Allele: A
Freq: 0% absent from gnomAD
REVEL: not applicable / splice donor
Quality: Sufficient depth and allele counts
Reads: 30

Gene: KDM5C
Variant: c.4355del
Protein: p.Gly1452AlafsTer26
rsID: not shown
Zygosity: Het
Ref Allele: GC
Alt Allele: G
Freq: 0% absent from gnomAD
REVEL: not applicable / frameshift
Quality: Sufficient depth and allele counts
Reads: 18

Gene: KMT2C
Variant: c.1139G>T
Protein: p.Arg380Leu
rsID: rs138908625
Zygosity: Het
Ref Allele: C
Alt Allele: A
Freq: 0.0775% rare
REVEL: 0.847
Quality: Sufficient depth and allele counts
Reads: 50

Gene: SOX2
Variant: c.17A>G
Protein: p.Glu6Gly
rsID: not shown
Zygosity: Het
Ref Allele: A
Alt Allele: G
Freq: 0% absent from gnomAD
REVEL: 0.781
Quality: Sufficient depth and allele counts
Reads: 27

Gene: MED12
Variant: c.3953A>G
Protein: p.Gln1318Arg
rsID: not shown
Zygosity: Het
Ref Allele: A
Alt Allele: G
Freq: 0% absent from gnomAD
REVEL: 0.772
Quality: Sufficient depth and allele counts
Reads: 18

Gene: SOD2
Variant: c.106_107delinsTC
Protein: p.Gly36Ser
rsID: not shown
Zygosity: Het
Ref Allele: CC
Alt Allele: GA
Freq: 0% absent from gnomAD
REVEL: not shown
Quality: Sufficient depth and allele counts
Reads: not clearly shown

Gene: SIRT7
Variant: c.138G>T
Protein: p.Glu46Asp
rsID: not shown
Zygosity: Het
Ref Allele: C
Alt Allele: A
Freq: 0% absent from gnomAD
REVEL: 0.089
Quality: Sufficient depth and allele counts
Reads: 42

Gene: PPARA
Variant: c.800A>G
Protein: p.Glu267Gly
rsID: not shown
Zygosity: Het
Ref Allele: A
Alt Allele: G
Freq: 0% absent from gnomAD
REVEL: 0.440
Quality: Sufficient depth and allele counts
Reads: 32

Gene: SLC22A3
Variant: c.92C>T
Protein: p.Thr31Ile
rsID: not shown
Zygosity: Het
Ref Allele: C
Alt Allele: T
Freq: 0% absent from gnomAD
REVEL: 0.233
Quality: Sufficient depth and allele counts
Reads: not clearly shown

Gene: ABCB4
Variant: c.3544_3547delinsCGGG
Protein: p.Ile1183Val
rsID: not shown
Zygosity: Het
Ref Allele: TCCT
Alt Allele: CCCG
Freq: 0% absent from gnomAD
REVEL: not shown
Quality: Sufficient depth and allele counts
Reads: 37

Gene: ATP5F1B
Variant: c.1078A>G
Protein: p.Ile360Val
rsID: rs372401715
Zygosity: Het
Ref Allele: T
Alt Allele: C
Freq: 0.0436% very rare
REVEL: 0.299
Quality: Sufficient depth and allele counts
Reads: not clearly shown

Gene: MFN2
Variant: c.1679A>G
Protein: p.Lys560Arg
rsID: rs754458177
Zygosity: Het
Ref Allele: A
Alt Allele: G
Freq: 0.00131% very rare
REVEL: 0.380
Quality: Sufficient depth and allele counts
Reads: 23

Gene: KDM1A
Variant: c.1734+1073_1734+1076delinsCTGC
Protein: no protein change shown
rsID: not shown
Zygosity: Hom
Ref Allele: TTGT
Alt Allele: CTGC
Freq: 0% absent from gnomAD
REVEL: not applicable / intron or missense annotation
Quality: Sufficient depth and allele counts
Reads: 26

Gene: KDM1A
Variant: c.1734+1058A>G
Protein: no protein change shown
rsID: not shown
Zygosity: Het
Ref Allele: A
Alt Allele: G
Freq: 0.000657% ultra rare
REVEL: not applicable / intron or splice acceptor effect
Quality: Sufficient depth and allele counts
Reads: 28

Gene: HDAC9
Variant: c.1468-8170_1468-8169delinsTA
Protein: no protein change shown
rsID: rs386710893
Zygosity: Het
Ref Allele: GT
Alt Allele: TA
Freq: 0% absent from gnomAD
REVEL: not applicable / intron or splice-region effect
Quality: Sufficient depth and allele counts
Reads: 43

Gene: KDM5B
Variant: c.711+492T>C
Protein: no protein change shown
rsID: not shown
Zygosity: Het
Ref Allele: A
Alt Allele: G
Freq: 0% absent from gnomAD
REVEL: not applicable / intron effect
Quality: Sufficient depth and allele counts
Reads: 31

Gene: KAT6B
Variant: c.3246A>C
Protein: p.Glu1082Asp
rsID: rs533495849
Zygosity: Het
Ref Allele: A
Alt Allele: C
Freq: 0% absent from gnomAD
REVEL: 0.065
Quality: Sufficient depth and allele counts
Reads: 60

Gene: KAT6B
Variant: c.3252G>C
Protein: p.Glu1084Asp
rsID: rs766869621
Zygosity: Het
Ref Allele: G
Alt Allele: C
Freq: 0% absent from gnomAD
REVEL: 0.062
Quality: Sufficient depth and allele counts
Reads: 60

Gene: SF1
Variant: c.1480T>C
Protein: p.Ser494Pro
rsID: rs745538700
Zygosity: Het
Ref Allele: A
Alt Allele: G
Freq: 0% genomes shown; 7.46e-7 exomes
REVEL: 0.046
Quality: Sufficient depth and allele counts
Reads: not clearly shown

Gene: SF1
Variant: c.31+12dup
Protein: no protein change shown
rsID: not shown
Zygosity: Het
Ref Allele: C
Alt Allele: CG
Freq: 0% absent from gnomAD
REVEL: not applicable / intron or possible frameshift annotation
Quality: Sufficient depth and allele counts
Reads: not clearly shown

Gene: SF1
Variant: c.1521T>C
Protein: p.Pro507=
rsID: rs1428950598
Zygosity: Het
Ref Allele: A
Alt Allele: G
Freq: 0% absent from gnomAD
REVEL: not applicable / synonymous
Quality: Sufficient depth and allele counts
Reads: not clearly shown

Gene: TET3
Variant: c.4910A>G
Protein: p.Glu1637Gly
rsID: not shown
Zygosity: Het
Ref Allele: A
Alt Allele: G
Freq: 0% absent from gnomAD
REVEL: 0.360
Quality: Sufficient depth and allele counts
Reads: not clearly shown

Gene: TAF3
Variant: c.2086_2087delinsCC
Protein: p.Val696Pro
rsID: rs386740632
Zygosity: Het
Ref Allele: GT
Alt Allele: CC
Freq: 0% absent from gnomAD
REVEL: not shown
Quality: Sufficient depth and allele counts
Reads: not clearly shown

Gene: TAF1
Variant: c.3064T>A
Protein: p.Ser1022Thr
rsID: not shown
Zygosity: Het
Ref Allele: T
Alt Allele: A
Freq: 0% absent from gnomAD
REVEL: 0.122
Quality: Sufficient depth and allele counts
Reads: not clearly shown

Gene: SUV39H1
Variant: no HGVS cDNA shown
Protein: no protein change shown
rsID: not shown
Zygosity: Het
Ref Allele: A
Alt Allele: T
Freq: 0% absent from gnomAD
REVEL: not applicable / upstream or non-canonical effect
Quality: Sufficient depth and allele counts
Reads: not clearly shown

Gene: PGR
Variant: c.1288A>C
Protein: p.Thr430Pro
rsID: not shown
Zygosity: Het
Ref Allele: T
Alt Allele: G
Freq: 0% absent from gnomAD
REVEL: 0.055
Quality: Sufficient depth and allele counts
Reads: 21

Gene: CHD2
Variant: c.3734del
Protein: p.Lys1245AsnfsTer4
rsID: rs752940775
Zygosity: Het
Ref Allele: GA
Alt Allele: G
Freq: 0.000676% ultra rare
REVEL: not applicable / frameshift
Quality: Sufficient depth and allele counts
Reads: 27

Gene: MED14
Variant: c.703A>T
Protein: p.Thr235Ser
rsID: not shown
Zygosity: Het
Ref Allele: T
Alt Allele: A
Freq: 0% absent from gnomAD
REVEL: 0.422
Quality: Sufficient depth and allele counts
Reads: 13

Gene: MAOB
Variant: c.1441T>C
Protein: p.Phe481Leu
rsID: not shown
Zygosity: Het
Ref Allele: A
Alt Allele: G
Freq: 0% absent from gnomAD
REVEL: 0.305
Quality: Sufficient depth and allele counts
Reads: not clearly shown

Gene: GNB3
Variant: c.382T>A
Protein: p.Ser128Thr
rsID: not shown
Zygosity: Het
Ref Allele: T
Alt Allele: A
Freq: 0% absent from gnomAD
REVEL: 0.132
Quality: Sufficient depth and allele counts
Reads: 35

Gene: BRD4
Variant: c.2942A>C
Protein: p.Gln981Pro
rsID: not shown
Zygosity: Het
Ref Allele: T
Alt Allele: G
Freq: 0% genomes shown; 0.00510% exomes
REVEL: 0.177
Quality: Sufficient depth and allele counts
Reads: 14

Gene: EHMT1
Variant: c.843A>T
Protein: p.Leu281Phe
rsID: rs1485591700
Zygosity: Het
Ref Allele: A
Alt Allele: T
Freq: 0.00156% very rare
REVEL: 0.074
Quality: Sufficient depth and allele counts
Reads: not clearly shown

Gene: APOB
Variant: c.6936_6937inv
Protein: p.Ile2313Val
rsID: rs386643884
Zygosity: Het
Ref Allele: TG
Alt Allele: CA
Freq: 0% absent from gnomAD
REVEL: not shown
Quality: Sufficient depth and allele counts
Reads: 22

Gene: APOB
Variant: c.13235A>G
Protein: p.Lys4412Arg
rsID: not shown
Zygosity: Het
Ref Allele: T
Alt Allele: C
Freq: 0% absent from gnomAD
REVEL: 0.021
Quality: Sufficient depth and allele counts
Reads: 24

Gene: ARID1A
Variant: c.868A>C
Protein: p.Thr290Pro
rsID: rs560787659
Zygosity: Het
Ref Allele: A
Alt Allele: C
Freq: 0% absent from gnomAD
REVEL: 0.151
Quality: Sufficient depth and allele counts
Reads: 15

Gene: KDM5D
Variant: c.2737G>A
Protein: p.Glu913Lys
rsID: not shown
Zygosity: Het
Ref Allele: C
Alt Allele: T
Freq: 0% absent from gnomAD
REVEL: not shown
Quality: Sufficient depth and allele counts
Reads: 13

Tier 2 — Questionable sequence depth

Gene: UBE2E3
Variant: c.-27_-26+2delinsGGGG
Protein: no protein change shown
rsID: not shown
Zygosity: Het
Ref Allele: AGGT
Alt Allele: GGGG
Freq: 0% absent from gnomAD
REVEL: not applicable / splice donor or 5 prime UTR effect
Quality: Questionable sequence depth
Reads: 7

Gene: KDM5C
Variant: c.1322G>A
Protein: p.Gly441Glu
rsID: not shown
Zygosity: Het
Ref Allele: C
Alt Allele: T
Freq: 0% absent from gnomAD
REVEL: 0.893
Quality: Questionable sequence depth
Reads: 9

Tier 3 — Poor evidence of alternate allele

Gene: ABCC4
Variant: c.542T>C
Protein: p.Leu181Pro
rsID: not shown
Zygosity: Het
Ref Allele: A
Alt Allele: G
Freq: 0% absent from gnomAD
REVEL: 0.942
Quality: Poor evidence of alternate allele
Reads: not clearly shown

Gene: POLG
Variant: c.2465C>T
Protein: p.Pro822Leu
rsID: rs1012514400
Zygosity: Het
Ref Allele: G
Alt Allele: A
Freq: 0% genomes shown; 0.000159% exomes
REVEL: 0.946
Quality: Poor evidence of alternate allele
Reads: not clearly shown

Gene: GJB2
Variant: c.173C>A
Protein: p.Pro58Gln
rsID: rs894732036
Zygosity: Het
Ref Allele: G
Alt Allele: T
Freq: 0% absent from gnomAD
REVEL: 0.938
Quality: Poor evidence of alternate allele
Reads: 24

Gene: HTR3A
Variant: c.863T>C
Protein: p.Leu288Pro
rsID: not shown
Zygosity: Het
Ref Allele: T
Alt Allele: C
Freq: 0% absent from gnomAD
REVEL: 0.886
Quality: Poor evidence of alternate allele
Reads: 21

Gene: CYP1A2
Variant: c.962C>T
Protein: p.Thr321Ile
rsID: not shown
Zygosity: Het
Ref Allele: C
Alt Allele: T
Freq: 0% genomes shown; 0.000240% exomes
REVEL: 0.816
Quality: Poor evidence of alternate allele
Reads: 23

Gene: ABCC3
Variant: c.1172G>T
Protein: p.Arg391Met
rsID: not shown
Zygosity: Het
Ref Allele: G
Alt Allele: T
Freq: 0% absent from gnomAD
REVEL: 0.815
Quality: Poor evidence of alternate allele
Reads: 22

Gene: SLC7A5
Variant: c.1496T>C
Protein: p.Leu499Pro
rsID: not shown
Zygosity: Het
Ref Allele: A
Alt Allele: G
Freq: 0% absent from gnomAD
REVEL: 0.806
Quality: Poor evidence of alternate allele
Reads: 33

Gene: CHRM2
Variant: c.1187T>C
Protein: p.Phe396Ser
rsID: not shown
Zygosity: Het
Ref Allele: T
Alt Allele: C
Freq: 0% absent from gnomAD
REVEL: 0.800
Quality: Poor evidence of alternate allele
Reads: 22

Gene: SLCO3A1
Variant: c.155_157delinsTGT
Protein: p.Ala52_Gln53delinsValTer
rsID: not shown
Zygosity: Het
Ref Allele: CGC
Alt Allele: TGT
Freq: 0% absent from gnomAD
REVEL: not applicable / stop gained
Quality: Poor evidence of alternate allele
Reads: 24

Gene: NFYA
Variant: c.67C>T
Protein: p.Gln23Ter
rsID: not shown
Zygosity: Het
Ref Allele: C
Alt Allele: T
Freq: 0% absent from gnomAD
REVEL: not applicable / stop gained
Quality: Poor evidence of alternate allele
Reads: 25

Gene: MED23
Variant: c.2103del
Protein: p.Phe701LeufsTer20
rsID: rs1419084791
Zygosity: Het
Ref Allele: TA
Alt Allele: T
Freq: 0% genomes shown; 0.000206% exomes
REVEL: not applicable / frameshift
Quality: Poor evidence of alternate allele
Reads: 21

Gene: DICER1
Variant: c.2384del
Protein: p.Pro795LeufsTer11
rsID: not shown
Zygosity: Het
Ref Allele: AG
Alt Allele: A
Freq: 0% absent from gnomAD
REVEL: not applicable / frameshift
Quality: Poor evidence of alternate allele
Reads: 23

Gene: ABCC9
Variant: c.2348C>T
Protein: p.Ala783Val
rsID: rs1195562877
Zygosity: Het
Ref Allele: G
Alt Allele: A
Freq: 0.000592% ultra rare
REVEL: 0.750
Quality: Poor evidence of alternate allele
Reads: 25

Gene: LRP2
Variant: c.5531C>T
Protein: p.Ser1844Leu
rsID: not shown
Zygosity: Het
Ref Allele: G
Alt Allele: A
Freq: 0% absent from gnomAD
REVEL: 0.631
Quality: Poor evidence of alternate allele
Reads: not clearly shown

Gene: SP3
Variant: c.1909C>T
Protein: p.His637Tyr
rsID: not shown
Zygosity: Het
Ref Allele: G
Alt Allele: A
Freq: 0% absent from gnomAD
REVEL: 0.565
Quality: Poor evidence of alternate allele
Reads: not clearly shown

Gene: RAD21
Variant: c.1529C>A
Protein: p.Pro510Gln
rsID: not shown
Zygosity: Het
Ref Allele: G
Alt Allele: T
Freq: 0% absent from gnomAD
REVEL: 0.032
Quality: Poor evidence of alternate allele
Reads: 22

Gene: KMT2D
Variant: c.10185A>T
Protein: p.Gln3395His
rsID: not shown
Zygosity: Het
Ref Allele: T
Alt Allele: A
Freq: 0% absent from gnomAD
REVEL: 0.367
Quality: Poor evidence of alternate allele
Reads: not clearly shown

Gene: NSD3
Variant: c.1144A>G
Protein: p.Thr382Ala
rsID: not shown
Zygosity: Het
Ref Allele: T
Alt Allele: C
Freq: 0% absent from gnomAD
REVEL: 0.328
Quality: Poor evidence of alternate allele
Reads: not clearly shown

Gene: KAT6A
Variant: c.5183A>T
Protein: p.Asn1728Ile
rsID: not shown
Zygosity: Het
Ref Allele: T
Alt Allele: A
Freq: 0% absent from gnomAD
REVEL: 0.311
Quality: Poor evidence of alternate allele
Reads: 21

Gene: AVPR2
Variant: c.1054G>A
Protein: p.Gly352Ser
rsID: not shown
Zygosity: Het
Ref Allele: G
Alt Allele: A
Freq: 0% absent from gnomAD
REVEL: 0.026
Quality: Poor evidence of alternate allele
Reads: 21

Gene: BRPF3
Variant: c.3614T>C
Protein: p.Leu1205Pro
rsID: not shown
Zygosity: Het
Ref Allele: T
Alt Allele: C
Freq: 0% absent from gnomAD
REVEL: 0.245
Quality: Poor evidence of alternate allele
Reads: 25

Gene: CUBN
Variant: c.8839A>G
Protein: p.Thr2947Ala
rsID: not shown
Zygosity: Het
Ref Allele: T
Alt Allele: C
Freq: 0% genomes shown; 0.000205% exomes
REVEL: 0.225
Quality: Poor evidence of alternate allele
Reads: 25

Gene: AKR1C4
Variant: c.191C>T
Protein: p.Ala64Val
rsID: not shown
Zygosity: Het
Ref Allele: C
Alt Allele: T
Freq: 0% absent from gnomAD
REVEL: 0.209
Quality: Poor evidence of alternate allele
Reads: not clearly shown

Gene: SRCAP
Variant: c.4603C>T
Protein: p.Pro1535Ser
rsID: rs117804715
Zygosity: Het
Ref Allele: C
Alt Allele: T
Freq: 0% absent from gnomAD
REVEL: 0.205
Quality: Poor evidence of alternate allele
Reads: 22

Gene: PHF8
Variant: c.2778_2785delinsCCAGCTTC
Protein: p.Val929Leu
rsID: not shown
Zygosity: Het
Ref Allele: CAAGTTGT
Alt Allele: GAAGCTGG
Freq: 0% absent from gnomAD
REVEL: not shown
Quality: Poor evidence of alternate allele
Reads: 21

Gene: BPTF
Variant: c.1073A>T
Protein: p.Glu358Val
rsID: not shown
Zygosity: Het
Ref Allele: A
Alt Allele: T
Freq: 0% absent from gnomAD
REVEL: 0.390
Quality: Poor evidence of alternate allele
Reads: 24

Gene: DNMT1
Variant: c.2179G>A
Protein: p.Glu727Lys
rsID: not shown
Zygosity: Het
Ref Allele: C
Alt Allele: T
Freq: 0% absent from gnomAD
REVEL: 0.115
Quality: Poor evidence of alternate allele
Reads: 21

Gene: FOXO1
Variant: c.1742T>C
Protein: p.Val581Ala
rsID: not shown
Zygosity: Het
Ref Allele: A
Alt Allele: G
Freq: 0% absent from gnomAD
REVEL: 0.137
Quality: Poor evidence of alternate allele
Reads: 25

Gene: NCOR2
Variant: c.4543G>A
Protein: p.Ala1515Thr
rsID: rs896684336
Zygosity: Het
Ref Allele: C
Alt Allele: T
Freq: 0.00328% very rare
REVEL: 0.074
Quality: Poor evidence of alternate allele
Reads: not clearly shown

Gene: TAF10
Variant: c.335C>T
Protein: p.Ser112Phe
rsID: rs747673992
Zygosity: Het
Ref Allele: G
Alt Allele: A
Freq: 0.000657% ultra rare
REVEL: 0.062
Quality: Poor evidence of alternate allele
Reads: not clearly shown

Gene: SLCO3A1
Variant: c.173_174delinsTT
Protein: p.Ala58Val
rsID: not shown
Zygosity: Het
Ref Allele: CC
Alt Allele: TT
Freq: 0% absent from gnomAD
REVEL: not shown
Quality: Poor evidence of alternate allele
Reads: 24

Gene: SETD2
Variant: c.5668G>A
Protein: p.Asp1890Asn
rsID: not shown
Zygosity: Het
Ref Allele: C
Alt Allele: T
Freq: 0% absent from gnomAD
REVEL: 0.149
Quality: Poor evidence of alternate allele
Reads: 21

Dear Dr. Powers,

I'm a psychiatrist based in Asia who has personally been suffering from PSSD since 4 years. I have been trying to revert to my premorbid self but have only been able to do so

partially.

I recently came across your findings and am now

writing to share my own PSSD case and my insights and would value your perspective.

Timeline:

Wanted to start by saying that I was infected with a severe strain of Covid 5 years ago while working in the hospital. Infection resolved but I got diarrhea from it which I was unable to treat inspite of multiple medications. Also started developing anxiety after this.

After a few months of having the above issues I was started On escitalopram (Lexapro) for anxiety, immediate relief in anxiety (and very surprisingly my post Covid diarrhea went away after the 1st dose itself), however developed non-sexual side effects like sedation, fatigue,emotional blunting,hypersomnia and concentration issues. Note that I had a very strong response at a very low dose and almost immediately.

- After a few weeks of hypersomnia and finding it really hard to work. Bupropion 150mg was added and was initially therapeutic for these side effects (more energy, reduced head pressure, less sedation) — which I read as dopamine and Norepi helping counter lexapro side effects.

- After a few weeks accidental bupropion double-dose caused unbearable anxiety, along with complete loss of its ability to counter the the non-sexual side effects of lexapro entirely — only anxiety, no benefit. I interpret this as a lasting NE-axis sensitization event. Tried to take it multiple times after that but lost its effectivness.

- Escitalopram was eventually stopped, but the non-sexual symptoms persisted unrelieved.

- Months later, methylphenidate (Ritalin) was trialed for the residual non-sexual symptoms with aim to boost dopamine and help reduce the hypersomnia and anhedonia. It produced no benefit for those — but added the sexual symptoms outright, precipitating full-blown PSSD (ED, atypical PE, blunted arousal/orgasm). ONLY 3 DOSES OF 5mg Ritalin gave me Severe sexual side effects which persist till date!!!

- There was zero improvement for a couple of years after that. I personally experimented with a lot of stuff but nothing helped. Some of the things trialed included Agomelatine, Very low dose amisulpride, bromantane etc etc

-

-Eventually I tried Amantadine hoping that it's NMDA antagonism and weak Dopaminergic modulation could help. And it did! I partially improved and have been showing gradual improvement since then. However my condition still fluctuates and the Sexual dysfunction is still pretty bad.

Current symptom map:

- Desire: intact

- Visual arousal: recognition present, but translation into subjective arousal is weak

- Erectile function: initiation impaired; rigidity improved; pain resolved

- Ejaculation: originally numbness-then-sudden-peak (spinal sensory gating failure); now partially resolved into an expanded sensation window with partial control, though ejaculation still fires at sensation peak (desynchrony persists)

- Orgasm: blunted — reward signal appears affected, spinal reflex intact. Even The pleasure from alcohol was blunted. Only felt sedation on taking it.

- Non-sexual: absent morning freshness, vitality deficit, effortful cognition, emotional blunting(lesser than earlier), right-sided head pressure (predates Ritalin, present on escitalopram)

.

The dopamine-metabolite question:

I've come across discussion of your finding in PFS patients of testosterone metabolites accumulating intracellularly rather than being cleared normally, and the related observation that a handful of PSSD patients who ran DUTCH tests uniformly showed low HVA.

I tried to map that onto my own exposure history (bupropion at a supratherapeutic dose, then methylphenidate months later), very interesting how my system rejected Dopaminergics so strongly and cemented it into full blown PSSD. Could the Bupropion double dose have overwhelmed certain dopamine/Norepi pathways like finasteride does ?

On closer thought both are pure DAT/NET reuptake blockers rather than substrate releasers — they occupy the transporter without being carried into the neuron, so they shouldn't increase cytoplasmic dopamine or burden vesicular packaging the way amphetamine-class agents can. So I don't think an intracellular-accumulation mechanism analogous to your androgen-metabolite model transfers cleanly to a reuptake-blocker exposure.However I'm really curious if there are other ways in which there could be toxic Dopamine/Nor epi metabolites accumulation which happened due to some sensitization by lexapro.

The more defensible mechanism I can construct for low HVA with reuptake blockers is a turnover deficit rather than an accumulation: blocking DAT reduces the fraction of dopamine cycled back into the nerve terminal for intraneuronal MAO-A metabolism (which generates a large share of HVA), and sustained elevated synaptic dopamine likely drives presynaptic D2 autoreceptor feedback that downregulates tyrosine hydroxylase and dopamine synthesis over time — both routes to chronically reduced dopamine output and lower HVA, without anything getting structurally "stuck" intracellularly. But even in this case why would the DAT still be blocked ?

Given that, I'd value your thoughts on:

1. Whether you think low HVA in PSSD more often reflects a genuine clearance/accumulation failure (as in your PFS model) versus a turnover/synthesis deficit of the kind above — and whether exposure history (reuptake blocker vs. SSRI alone) might predict which mechanism applies.

2. Sequencing — would you prioritize a pharmacological probe of the dopamine axis ?

3. Any other diagnostic or treatment steps you'd suggest?

Happy to share further detail on any part of the case,Thank you for taking the time to consider this.

There were 6K views on the last petition post, and only 100 signatures. If you can’t take ten seconds to sign your name on a petition that is being coordinated by one of the most prolific SSRI advocates who has worked with the FDA, don’t expect to get out of this any time soon. Do your part.

Original post:

*THIS IS NOT JUST ANOTHER PETITION*

The amazing Kim Witzciak recently launched a website serving as a petition for those with PSSD (and other SSRI injuries) to sign and document their experiences of harm with these medications.

It serves as a central place to show the volume of people being injured by these drugs. To convince those in power that these injuries are devastating a massive population size, deferring to Reddit groups won’t cut it/isn’t official enough. As such, this petition will be the MAIN SOURCE of reference when used to show the people we need to convince this is ruining/ending lives.

Please sign this, mention your experience and age if you can!!

We have SUCH power in numbers if we can all band together!

https://www.instagram.com/reel/DZBVGbDuBUH/?igsh=Y3FmYmJubGF5cHQy

Sign if u want https://www.reddit.com/r/PSSD/s/KRbofilkq9

Sign if u want https://www.reddit.com/r/PSSD/s/KRbofilkq9

Sign here https://www.reddit.com/r/PSSD/s/KRbofilkq9

Sign here https://www.reddit.com/r/PSSD/s/KRbofilkq9

Sign if u want https://www.reddit.com/r/PSSD/s/KRbofilkq9

Sign if u want https://www.reddit.com/r/PSSD/s/KRbofilkq9

Sign if u want https://www.reddit.com/r/PSSD/s/KRbofilkq9

Thanks for keeping me in the loop.  Ideally we need to get some Post Isotretinoin folk also

I'm waiting on a meeting with university folk who are operating on university time - so the earliest will be July 9.  If you end up with a group of PSSD genomes, I might be able to persuade the Dutch to take a look at these.  Having an outside view might help

Hello everyone,

*THIS IS NOT JUST ANOTHER PETITION*

The amazing Kim Witzciak recently launched a website serving as a petition for those with PSSD (and other SSRI injuries) to sign and document their experiences of harm with these medications.

It serves as a central place to show the volume of people being injured by these drugs. To convince those in power that these injuries are devastating a massive population size, deferring to Reddit groups won’t cut it/isn’t official enough. As such, this petition will be the MAIN SOURCE of reference when used to show the people we need to convince this is ruining/ending lives.

Please sign this, mention your experience and age if you can!!

We have SUCH power in numbers if we can all band together!

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