Add EP400

[hdashnow]

See also #146

I'm not sure if there's enough evidence here to curate yet, so maybe a provisional tag?

Proposed in https://www.biorxiv.org/content/10.1101/2025.01.06.631535v2
https://gnomad.broadinstitute.org/short-tandem-repeat/EP400?dataset=gnomad_r4
See section "EP400 and FAM193B are promising candidate pathogenic tandem repeat expansions"

EP400 case in the supplementary table of this paper:
https://link.springer.com/article/10.1007/s00439-017-1821-8

ID	Testing Strategy	Gender	Age	Consanguinity	Family hx	Phenotype	Test	Result	Variant(s)	Variant(s)	Zyogsity	HGMD
16N-0280	index	M	5	Yes	Negative	GDD, epilepsy and CHD	WES	Ambiguous (novel candidate)	EP400:NM_015409:exon47:c.8226_8227insGCAACAG:p.Q2742fs		Het

Repeat expansion population evidence:
https://pmc.ncbi.nlm.nih.gov/articles/PMC11176344/
https://www.medrxiv.org/content/10.64898/2026.04.30.26352103v1.full-text
(also mentions FAM193B and BCLAF3)

Gene-level evidence for EP400:
https://www.sciencedirect.com/science/article/pii/S0002929724004191
https://thegencc.org/genes/HGNC:11958
https://panelapp-aus.org/panels/137/gene/EP400/
https://academic.oup.com/nar/article/47/12/6208/5488534?guestAccessKey=
https://www.nature.com/articles/s41398-021-01258-1

[hdashnow]

@bw2 I see a pathogenic range of >70 listed for EP400 in gnomAD. This is larger than the 56 and 58 pure CAG alleles referred to in the All of Us preprint. Do you have a source for that threshold? Is there an EP400 paper in the works?

[bw2]

The AoU preprint is currently the best summary of publicly available evidence.
There is ongoing work to characterize another EP400 expansion case in a second unrelated family (matching phenotype, slightly larger expansion than the 1st family) + ongoing functional work led by Gina in preparation for a future EP400-specific paper.

The threshold (as usual) depends on the locus definition. 56 is correct/equivalent for a narrow definition of the locus.

[hdashnow]

Thanks @bw2! So to summarize 56 perfect CAG motifs is the correct threshold, but using the coordinates in gnomAD (hg38 chr12:132062524-132062611) and allowing for imperfect repeats that corresponds to 70*3 bp?

The hg38 ref at those coordinates is: GCAGCAGCAGCAGCAGCAGCAACAACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAACAGCAGCAGCAGCAACAG
With 3 interruptions.
29 total or 14 perfect

Is that correct?

[bw2]

Yes, a >= 55 repeats threshold (based on ExpansionHunter genotypes in the affected family) is relative to this locus definition:
chr12:132062548-132062590 (0-based)

While this narrow definition produced clean read visualizations in our rare disease cohort + UKB WGS (and even WES) samples, it led to messier genotypes in some gnomAD WGS samples (which include a more diverse mix of library preps), so I ended up switching to the wider definition
chr12:132062524-132062611
for gnomAD (just based on read visualizations).

[hdashnow]

This is very helpful, thanks @bw2 !