Holoprosencephaly: genes and variants
Holoprosencephaly is linked to 2 analyzed proteins (NSD1 and PTCH1). 1 DNA variants are known to cause it; 60 more are uncertain, and 0 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Also known as: Holoprosencephaly 13, X-linked; Holoprosencephaly 2; Holoprosencephaly 7
Genes linked to Holoprosencephaly
NSD1: Histone-lysine N-methyltransferase, H3 lysine-36 specific
It regulates developmental transcription through chromatin modification, including H3K36 methylation. Haploinsufficiency causes Sotos syndrome with childhood overgrowth, characteristic facial features, and developmental delay, while somatic rearrangements occur in some leukemias.
1 disease-causing and 0 uncertain variants in NSD1 are linked to Holoprosencephaly.
PTCH1: Protein patched homolog 1
It suppresses Smoothened in the absence of Hedgehog ligands and thereby keeps Hedgehog developmental signaling inactive until an appropriate signal is received. Germline loss-of-function variants cause Gorlin syndrome, while somatic pathway activation drives basal-cell carcinoma and other tumors.
0 disease-causing and 58 uncertain variants in PTCH1 are linked to Holoprosencephaly.
Weakly linked (only a few uncertain records): STAG2.
Known disease-causing variants in Holoprosencephaly
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| NSD1 S2181F | 2181 | Disease-causing (★★) |
Same protein, different disease
- Sotos syndrome is also caused by NSD1 variants; they fall mostly in different places as the Holoprosencephaly variants (82 disease-causing).
- Beckwith-Wiedemann syndrome is also caused by NSD1 variants; they fall mostly in different places as the Holoprosencephaly variants (3 disease-causing).
Diseases related to Holoprosencephaly
- Sotos syndrome, also linked to NSD1
- Ovarian cancer, also linked to PTCH1
- Acute myeloid leukemia, also linked to NSD1
- Gorlin syndrome, also linked to PTCH1
- Weaver syndrome, also linked to NSD1
- Beckwith-Wiedemann syndrome, also linked to NSD1
- Medulloblastoma, also linked to PTCH1
- Marfanoid habitus and intellectual disability, also linked to NSD1
- Basal cell nevus syndrome 1, also linked to PTCH1
- Basal cell carcinoma, also linked to PTCH1
Frequently asked questions
Which genes are linked to Holoprosencephaly?
In CATVariant, Holoprosencephaly is linked to 2 analyzed proteins: NSD1 (Histone-lysine N-methyltransferase, H3 lysine-36 specific) and PTCH1 (Protein patched homolog 1).
How many genetic variants are linked to Holoprosencephaly?
68 variants: 1 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 60 are of uncertain significance or have conflicting reports.
Which uncertain variants in Holoprosencephaly look disease-causing?
None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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