Mode of inheritance for Orphanet entries

[pnrobinson]

There are many orphanet entries such as ORPHA:791 Retinitis pigmentosa - autosomal dominant/recessive that group together many specific diseases that are either dominant or recessive but not both. It would be good to choose the MOI for the specific genes - this can be done with HPO resources, among other sources. Otherwise, this leads to false positive results.

[julesjacobsen]

Orphanet again... @damiansm perhaps it's time to test removing the Orphanet annotations again? Otherwise I'll look into removing Orphanet nodes which contain multiple OMIM nodes.

[damiansm]

Lets review how we are doing this again but I think we try and take HPO MOI annotations where possible? But for https://hpo.jax.org/browse/disease/ORPHA:791 there is no MOI HPO code as it is so mixed presumably and the individual genes such as https://hpo.jax.org/browse/gene/NCBIGene:50939 have a code for AD and AR as it is at the gene rather disease-gene level. Is only when we get to OMIM annotations that things make sense.

I think a lot of Orphanet nodes group together OMIM codes so removing all of those is probably not going to work well either.

Is there a MONDO solution?

On Thu, Jul 17, 2025 at 12:39 PM Jules Jacobsen @.***> wrote:

julesjacobsen left a comment (exomiser/Exomiser#603) https://github.com/exomiser/Exomiser/issues/603#issuecomment-3083729462

Orphanet again... @damiansm https://github.com/damiansm perhaps it's time to test removing the Orphanet annotations again? Otherwise I'll look into removing Orphanet nodes which contain multiple OMIM nodes.

— Reply to this email directly, view it on GitHub https://github.com/exomiser/Exomiser/issues/603#issuecomment-3083729462, or unsubscribe https://github.com/notifications/unsubscribe-auth/ABHO4PCPH563DFQKGO3B6C33I6DOXAVCNFSM6AAAAAB73G5TTWVHI2DSMVQWIX3LMV43OSLTON2WKQ3PNVWWK3TUHMZTAOBTG4ZDSNBWGI . You are receiving this because you were mentioned.Message ID: @.***>

[pnrobinson]

I think it would be difficult to use Mondo in its current state because it also is not accurate about the genetics of CNV syndromes (e.g. https://monarchinitiative.org/MONDO:0008678 shows two causal genes using the same relationship as Mendelian diseases. A good workaround could be to just manually mark certain ORPHA entries as CNVs -- this is where the problem is coming from. I have seen artefacts related to Williams syndrome very frequently, but also occasionally see other CNV related artefacts. To do this in an easy way, we could look for strings like this in the Orpha data:

https://www.orpha.net/en/disease/detail/904

Deletion 7q11.23 Monosomy 7q11.23

and if we see keywords such as "Deletion" and the entry contains multiple genes, then flag it for manual review. Then we can create a list of items to be excluded. Is this coming from HPOA file or somewhere else though?

[damiansm]

We are probably mixing up a couple of related issues now in this issue.

For the original RP example, I think most of these genes really are single gene associated with non-syndromic RP in OMIM but there are just so many of RP genes nowadays with different MOIs. We know dropping Orphanet annotations completely reduces performance but in this example it would be much nicer if we were just matching to the individual OMIM annotations where we know the exact gene and MOI. The problem is how to identify these examples. Maybe something pragmatic like don't use the Orphanet annotations where there are > X genes associated and/or with mixed MOIs for the genes.

Then there are the CNV syndromes associated with lots of genes but where you don't want to treat them all the same as Mendelian single gene diseases as you say. I have a feeling we already have that one solved in Exomiser IF the entry is flagged as a CNV syndrome but I may be getting mixed up and Jules and will know better. Maybe only the OMIM entries are correctly flagged?

On Thu, 17 Jul 2025, 13:31 Peter Robinson, @.***> wrote:

pnrobinson left a comment (exomiser/Exomiser#603) https://github.com/exomiser/Exomiser/issues/603#issuecomment-3083890587

I think it would be difficult to use Mondo in its current state because it also is not accurate about the genetics of CNV syndromes (e.g. https://monarchinitiative.org/MONDO:0008678 shows two causal genes using the same relationship as Mendelian diseases. A good workaround could be to just manually mark certain ORPHA entries as CNVs -- this is where the problem is coming from. I have seen artefacts related to Williams syndrome very frequently, but also occasionally see other CNV related artefacts. To do this in an easy way, we could look for strings like this in the Orpha data:

https://www.orpha.net/en/disease/detail/904

Deletion 7q11.23 Monosomy 7q11.23

and if we see keywords such as "Deletion" and the entry contains multiple genes, then flag it for manual review. Then we can create a list of items to be excluded. Is this coming from HPOA file or somewhere else though?

— Reply to this email directly, view it on GitHub https://github.com/exomiser/Exomiser/issues/603#issuecomment-3083890587, or unsubscribe https://github.com/notifications/unsubscribe-auth/ABHO4PFQETGJ72TDGUPBVLL3I6JSZAVCNFSM6AAAAAB73G5TTWVHI2DSMVQWIX3LMV43OSLTON2WKQ3PNVWWK3TUHMZTAOBTHA4TANJYG4 . You are receiving this because you were mentioned.Message ID: @.***>

[julesjacobsen]

Hang on, @pnrobinson where are you seeing a problem? Exomiser stores Disease-Gene-MOI triplets as a 'disease', so this is all as it should be, no?

SELECT * from DISEASE WHERE DISEASE_ID = 'ORPHA:791';

DISEASE_ID	OMIM_GENE_ID	DISEASENAME	GENE_ID	TYPE	INHERITANCE
ORPHA:791	OMIM:611611	Retinitis pigmentosa	49855	D	R
ORPHA:791	OMIM:600595	Retinitis pigmentosa	8100	D	B
ORPHA:791	OMIM:609346	Retinitis pigmentosa	92840	D	R
ORPHA:791	OMIM:616432	Retinitis pigmentosa	23370	D	R
ORPHA:791	OMIM:209901	Retinitis pigmentosa	582	D	B
ORPHA:791	OMIM:613344	Retinitis pigmentosa	57670	D	R
ORPHA:791	OMIM:608894	Retinitis pigmentosa	54806	D	B
ORPHA:791	OMIM:615900	Retinitis pigmentosa	60509	D	R
ORPHA:791	OMIM:612013	Retinitis pigmentosa	57545	D	R
ORPHA:791	OMIM:601691	Retinitis pigmentosa	24	D	R
ORPHA:791	OMIM:610598	Retinitis pigmentosa	768206	D	R
ORPHA:791	OMIM:607301	Retinitis pigmentosa	9129	D	D
ORPHA:791	OMIM:606419	Retinitis pigmentosa	26121	D	D
ORPHA:791	OMIM:607300	Retinitis pigmentosa	10594	D	D
ORPHA:791	OMIM:179605	Retinitis pigmentosa	5961	D	B
ORPHA:791	OMIM:608830	Retinitis pigmentosa	145226	D	B
ORPHA:791	OMIM:600342	Retinitis pigmentosa	5995	D	B
ORPHA:791	OMIM:180380	Retinitis pigmentosa	6010	D	B
ORPHA:791	OMIM:180090	Retinitis pigmentosa	6017	D	B
ORPHA:791	OMIM:180721	Retinitis pigmentosa	6094	D	B
ORPHA:791	OMIM:603937	Retinitis pigmentosa	6101	D	B
ORPHA:791	OMIM:300757	Retinitis pigmentosa	6102	D	X
ORPHA:791	OMIM:607331	Retinitis pigmentosa	6100	D	D
ORPHA:791	OMIM:180069	Retinitis pigmentosa	6121	D	D
ORPHA:791	OMIM:180069	Retinitis pigmentosa	6121	D	R
ORPHA:791	OMIM:312610	Retinitis pigmentosa	6103	D	X
ORPHA:791	OMIM:181031	Retinitis pigmentosa	6295	D	D
ORPHA:791	OMIM:181031	Retinitis pigmentosa	6295	D	R
ORPHA:791	OMIM:606151	Retinitis pigmentosa	583	D	R
ORPHA:791	OMIM:607854	Retinitis pigmentosa	7439	D	D
ORPHA:791	OMIM:114760	Retinitis pigmentosa	762	D	B
ORPHA:791	OMIM:608381	Retinitis pigmentosa	375298	D	R
ORPHA:791	OMIM:608132	Retinitis pigmentosa	123016	D	R
ORPHA:791	OMIM:602280	Retinitis pigmentosa	7287	D	R
ORPHA:791	OMIM:608400	Retinitis pigmentosa	7399	D	R
ORPHA:791	OMIM:606397	Retinitis pigmentosa	7401	D	R
ORPHA:791	OMIM:123825	Retinitis pigmentosa	1259	D	R
ORPHA:791	OMIM:604210	Retinitis pigmentosa	23418	D	R
ORPHA:791	OMIM:602225	Retinitis pigmentosa	1406	D	B
ORPHA:791	OMIM:608845	Retinitis pigmentosa	84100	D	R
ORPHA:791	OMIM:607643	Retinitis pigmentosa	25794	D	D
ORPHA:791	OMIM:610453	Retinitis pigmentosa	138050	D	R
ORPHA:791	OMIM:146690	Retinitis pigmentosa	3614	D	D
ORPHA:791	OMIM:604705	Retinitis pigmentosa	10461	D	R
ORPHA:791	OMIM:604485	Retinitis pigmentosa	10002	D	B
ORPHA:791	OMIM:162080	Retinitis pigmentosa	4901	D	D
ORPHA:791	OMIM:300170	Retinitis pigmentosa	8481	D	XR
ORPHA:791	OMIM:180071	Retinitis pigmentosa	5145	D	R
ORPHA:791	OMIM:180072	Retinitis pigmentosa	5158	D	R
ORPHA:791	OMIM:607292	Retinitis pigmentosa	64218	D	R
ORPHA:791	OMIM:600724	Retinitis pigmentosa	1258	D	R
ORPHA:791	OMIM:609507	Retinitis pigmentosa	10210	D	D
ORPHA:791	OMIM:604365	Retinitis pigmentosa	8842	D	R
ORPHA:791	OMIM:604863	Retinitis pigmentosa	9227	D	R
ORPHA:791	OMIM:612424	Retinitis pigmentosa	346007	D	R
ORPHA:791	OMIM:604526	Retinitis pigmentosa	3420	D	R
ORPHA:791	OMIM:609868	Retinitis pigmentosa	55812	D	R
ORPHA:791	OMIM:602275	Retinitis pigmentosa	2979	D	D
ORPHA:791	OMIM:611119	Retinitis pigmentosa	55975	D	D
ORPHA:791	OMIM:601664	Retinitis pigmentosa	23020	D	D
ORPHA:791	OMIM:613425	Retinitis pigmentosa	388939	D	R
ORPHA:791	OMIM:180073	Retinitis pigmentosa	5148	D	R
ORPHA:791	OMIM:607056	Retinitis pigmentosa	50939	D	R
ORPHA:791	OMIM:613596	Retinitis pigmentosa	84140	D	R
ORPHA:791	OMIM:613598	Retinitis pigmentosa	130557	D	R
ORPHA:791	OMIM:609502	Retinitis pigmentosa	92211	D	R
ORPHA:791	OMIM:608172	Retinitis pigmentosa	79947	D	R
ORPHA:791	OMIM:613979	Retinitis pigmentosa	24148	D	D
ORPHA:791	OMIM:154235	Retinitis pigmentosa	4117	D	R
ORPHA:791	OMIM:180290	Retinitis pigmentosa	5949	D	R
ORPHA:791	OMIM:614477	Retinitis pigmentosa	157657	D	R
ORPHA:791	OMIM:614620	Retinitis pigmentosa	9742	D	R
ORPHA:791	OMIM:616454	Retinitis pigmentosa	79797	D	R
ORPHA:791	OMIM:615407	Retinitis pigmentosa	23568	D	R
ORPHA:791	OMIM:604043	Retinitis pigmentosa	4751	D	R
ORPHA:791	OMIM:607386	Retinitis pigmentosa	26160	D	R
ORPHA:791	OMIM:601197	Retinitis pigmentosa	7275	D	B
ORPHA:791	OMIM:615757	Retinitis pigmentosa	55857	D	R
ORPHA:791	OMIM:615720	Retinitis pigmentosa	57709	D	R
ORPHA:791	OMIM:607795	Retinitis pigmentosa	9128	D	D
ORPHA:791	OMIM:608581	Retinitis pigmentosa	94137	D	R
ORPHA:791	OMIM:600253	Retinitis pigmentosa	196	D	R
ORPHA:791	OMIM:602870	Retinitis pigmentosa	3617	D	B
ORPHA:791	OMIM:601149	Retinitis pigmentosa	3419	D	B
ORPHA:791	OMIM:605584	Retinitis pigmentosa	9785	D	R
ORPHA:791	OMIM:604695	Retinitis pigmentosa	403	D	D
ORPHA:791	OMIM:606822	Retinitis pigmentosa	55624	D	R