Clefting

Gene: RIC1

Comment on list classification: As reviewed by Luke Stuart, there is emerging evidence for RIC1 association with CATIFA syndrome, which includes clefting, in individuals with biallelic variants (1 extended consanguineous family with a founder variant, plus a supportive functional model). Non-syndromic clefting was reported in 3 individuals with monoallelic variants, though little variant and clinical detail was provided. Xenopus and zebrafish knock-down model also support this association. Based on available evidence, this gene can be rated Amber, with MOI set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal. A 'watchlist' tag was added in anticipation of further cases.

Created: 19 Aug 2026, 10:52 a.m. | Last Modified: 19 Aug 2026, 10:55 a.m.

Panel Version: 7.10

I don't know

RIC1 is associated with autosomal recessive CATIFA syndrome (OMIM #618761; accessed 08/2026).

Patel et al., 2017 (PMID 27878435) reported two unrelated males from consanguineous families who were homozygous for the same founder variant, RIC1 p.Arg1265Pro (R1265P), within a shared autozygous interval. Both had syndromic cataracts with global developmental delay, microcephaly, and structural brain anomalies detectable on MRI, with variable cleft lip and palate.

Unlu et al., 2020 (PMID 31932796) described eight additional affected individuals from the same extended familes, all homozygous for RIC1 p.Arg1265Pro (affecting the final coding residue of exon 24). Phenotypes included global developmental delay, intellectual disability, motor, speech and cognitive impairment, hypotonia with clumsy gait, variable craniofacial dysmorphism, tooth eruption/alignment abnormalities, and cleft lip and/or palate in 5/8 individuals. Behavioural abnormalities and ADHD were reported in all seven affected males. In zebrafish, ric1−/− animals showed intracellular collagen retention, defective cartilage matrix formation, craniofacial malformations, tooth defects, tendon and muscle attachment abnormalities, impaired locomotion, and reduced forebrain and cerebellar structures. Wild-type human RIC1 rescued collagen secretion and craniofacial defects, whereas RIC1 p.Arg1265Pro failed to do so effectively. cDNA analysis of patient fibroblasts identified two distinct transcripts: one correctly spliced transcript encoding the p.Arg1265Pro variant, and a second transcript with intron 24 retention, introducing a premature stop codon at position 1266 and predicted to undergo NMD. Fibroblasts from CATIFA patients also had reduced levels of RIC1 transcript (<50% of control cells), supporting a hypomorphic splicing defect.

Landson et al., 2023 (PMID 36493769) reported three individuals with non-syndromic cleft lip/palate carrying a deletion encompassing the RIC1 5′UTR and exons 1–2. Inheritance data were available for two individuals: one deletion occurred de novo and one was inherited from an affected mother. In Xenopus (splice-blocking morpholino knockdown and F0 CRISPR knockout) and zebrafish (F0 CRISPR knockout), loss of ric1 caused cleft-like midfacial defects and hypoplastic jaw cartilages. Sequencing was not performed, thus the presence of a second pathogenic hit on the non-deleted allele cannot be excluded.

Summary: Homozygosity for the founder variant p.Arg1265Pro segregated with CATIFA syndrome in a large consanguineous family. Functional studies in zebrafish and Xenopus support a role for RIC1 in craniofacial development and clefting. Additional evidence suggests a possible association between heterozygous loss of RIC1 (haploinsufficiency) and non-syndromic cleft lip/palate. An amber rating with BOTH monoallelic and biallelic inheritance is recommended for clefting.
Sources: Literature

Created: 19 Aug 2026, 10:26 a.m.

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
CATIFA syndrome, OMIM:618761; Catifa syndrome, MONDO:0032901

Publications

• 27878435
• 31932796
• 36493769