Holoprosencephaly - NOT chromosomal

Gene: DISP1

Green List (high evidence)

Comment on list classification: As reviewed by Nour Elkhateeb, there are at least 25 individuals reported in literature with DISP1 variants, who presented with Holoprosencephaly of variable severity. Hence, DISP1 should be rated green on the Holoprosencephaly - NOT chromosomal panel. The MOI should be set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.

Created: 17 Oct 2025, 2:08 p.m. | Last Modified: 17 Oct 2025, 2:08 p.m.

Panel Version: 5.3

PMID: 38529886 Lavillaureix et al., 2024
25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. Sequencing method: WES. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7/25). As 5/9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1.

This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025).

Created: 17 Oct 2025, 2:01 p.m. | Last Modified: 17 Oct 2025, 2:04 p.m.

Panel Version: 5.3

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Holoprosencephaly 10, OMIM:621143; holoprosencephaly 10, MONDO:0976262

Publications

• 38529886

25 individuals with variable types of holoprosencephaly (alobar, semi-lobar, lobar or microform) reported in PMID: 38529886.

Created: 16 May 2025, 9:20 a.m. | Last Modified: 16 May 2025, 9:20 a.m.

Panel Version: 5.3

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
holoprosencephaly

Publications

• 38529886

I don't know

The rating of this gene has been demoted to Amber following NHS Genomic Medicine Service approval.

Created: 2 May 2024, 10:42 a.m. | Last Modified: 2 May 2024, 10:44 a.m.

Panel Version: 4.9

Added the Q2_21_rating tag so that it is clear that this gene is being assessed for its rating.

Created: 6 Oct 2022, 1:35 p.m. | Last Modified: 6 Oct 2022, 1:35 p.m.

Panel Version: 2.30

I don't know

The to_be_confirmed_NHSE tag has been added, as further NHSE review is required.

Created: 15 Mar 2022, 5:36 p.m. | Last Modified: 15 Mar 2022, 5:36 p.m.

Panel Version: 2.27

The Q2_21_expert_review tag has been added, based on the review from Zornizta Stark and the views of Helen Brittain (GEL Clinical Fellow), a review of the evidence is requested from Test Evaluation Working Group via NHSE.

Created: 22 Jun 2021, 4:15 p.m. | Last Modified: 22 Jun 2021, 4:15 p.m.

Panel Version: 2.17

I don't know

Two individuals originally reported with truncating variants in this gene and HPE but variants inherited from unaffected parents; another case report suggesting digenic/AR inheritance; and another case report of small deletion and dev delay but no HPE, inherited from unaffected parent.

Created: 24 Apr 2021, 7:56 a.m. | Last Modified: 24 Apr 2021, 7:56 a.m.

Panel Version: 2.16

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Holoprosencephaly

Publications

• 19184110
• 26748417
• 23542665

As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: The Specialist Test Group all agreed that there is enough evidence to rate this gene Green

Created: 29 Jul 2019, 2:13 p.m. | Last Modified: 29 Jul 2019, 2:13 p.m.

Panel Version: 1.20

Comment on list classification: 3 cases in PMID 27363716 (2 missense, 1 nonsense)

Created: 30 May 2017, 3:45 p.m.

I don't know

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 27363716