Clefting

Gene: PRKCI

Green List (high evidence)

Comment on list classification: There are at least 21 individuals from unrelated families reported in literature with monoallelic variants in PRKCI. 18/21 individuals presented with orofacial clefts (as an isolated phenotype in 13 of them). Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders and metabolic disease (variable penetrance); 3 individuals had a syndromic presentation WITHOUT orofacial clefts. Ambiguous functional evidence and segregation studies indicate a complex genetic mechanism. There is not yet enough evidence to ascertain a disease mechanism. Based on a large number of cases reported, this gene should be promoted to Green on the Clefting panel.

Created: 14 Nov 2025, 11:48 a.m. | Last Modified: 14 Nov 2025, 11:48 a.m.

Panel Version: 6.17

PMID: 40902599 Robinson et al., 2025
Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants.
Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios).

Variants confirmed as de novo (7 probands):
c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84.
c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); lower lip pits + hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91.
c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48.

Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter).
c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher).
Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4).
In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ?

Functional evidence: 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01). Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic.

This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025).

Created: 14 Nov 2025, 10:39 a.m. | Last Modified: 14 Nov 2025, 11:52 a.m.

Panel Version: 6.17

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
van der Woude syndrome, MONDO:0019508; orofacial cleft, MONDO:0000358

Publications

• 40902599