Clefting
Gene: ALX1
Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.Created: 29 Sep 2023, 2:16 p.m. | Last Modified: 29 Sep 2023, 2:16 p.m.
Panel Version: 4.96
ALX1 variants have been associated with Frontonasal dysplasia 3 (OMIM:613456) and as definitive Gen2Phen gene for the same condition. At least four ALX1 variants have been reported. Extreme microphthalmia and severe facial clefting was seen in three sibling carrying a 3.7 Mb deletion containing the ALX1 gene (PMID: 20451171). Microphthalmia and other clefting defects we observed in a case with biallelic ALX1 variant c.531-1G>A (PMID: 20451171). PMID: 32914578 reported a family with four siblings who were biallelic for ALX1 c.493C>T (p.F165F). Three of these cases were anophthalmic, the fourth case had coloboma and all four of the case had bilateral oblique facial clefts. Supportive functional studies are presented by PMID: 23059813 & 32914578.Created: 29 Sep 2023, 2:15 p.m. | Last Modified: 29 Sep 2023, 2:15 p.m.
Panel Version: 4.95
Comment on list classification: Changed to Amber based on Eleanor Williams review.Created: 21 Aug 2019, 10:55 a.m. | Last Modified: 21 Aug 2019, 10:55 a.m.
Panel Version: 1.44
Amber rating confirmed by Genomics England clinical team.Created: 1 Oct 2019, 2:30 p.m. | Last Modified: 1 Oct 2019, 2:30 p.m.
Panel Version: 1.59
This gene is provisionally associated with ?Frontonasal dysplasia 3 (#613456) in OMIM. Has a confirmed association with FRONTONASAL DYSPLASIA TYPE 3 in Gene2Phenotype.
PMID: 20451171 - Uz et al. (2010) - 2 families presenting with autosomal-recessive frontonasal dysplasia (FND) characterized by bilateral extreme microphthalmia, bilateral oblique facial cleft, complete cleft palate, hypertelorism, wide nasal bridge with hypoplasia of the ala nasi, and low-set, posteriorly rotated ears in two distinct families. In one family they found a three siblings were affected, and CNV analysis of the critical region showed a homozygous 3.7 Mb deletion containing the ALX1 (CART1) gene. In the second family a homozygous donor-splice-site mutation (c.531+1G > A) in the ALX1 gene was found.
PMID: 27324866 - Ullah et al 2017 - report a consanguineous family from Pakistan with four individuals presenting a milder form of Frontonasal dysplasia. Using exome sequencing, a homozygous splice acceptor site variant has been identified in the ALX1 gene. The affected individuals had ptosis (drooping upper eyelid), small and upslanting palpebral fissures, blepharophimosis, broad nasal root, wide prominent nasal bridge, short and wide nasal ridge, broad columella, smooth philtrum, and mouth protrusion accompanied by teeth protrusion NOTE: no clefting reported in the individuals from this family.
PMID: 26610632 - Lyons et al 2015 - The “Contemporary” Burmese lineage of cats has a more brachycephalic head type. Offspring from “Contemporary” style mating produced a craniofacial defect in 25% of offspring (Noden and Evans, 1986; Sponenberg and Graf-Webster, 1986). The abnormality is characterized by agenesis of all derivatives of the medial nasal prominence; lateral duplication of most derivatives of the maxillary process; including the canine teeth and whiskers fields; telencephalic meningoencephalocele; and secondary ocular degeneration . The midline facial defect is autosomal recessive, however, carriers of the mutation are more brachycephalic individuals than wildtype, The entire ALX1 CDS sequence was analyzed in ten cats, including five affected Burmese and five controls. A 12 bp deletion (c.496delCTCTCAGGACTG) was identified in the coding region of ALX1. All the unaffected cats in the pedigree were confirmed to be homozygous wild-type or carrier of the 12 bp deletion while all the affected cats were homozygous for the identified variant. The average CDS homology between human and cat is 93.8% and the protein identity is 97.5%.
Created: 11 Jun 2019, 4:31 p.m.
Gene suggested by Andrew Wilkie, University of Oxford
Sources: Expert listCreated: 11 Jun 2019, 3:51 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ALX1 were changed from ?Frontonasal dysplasia 3, 613456 to Frontonasal dysplasia 3, OMIM:613456; frontonasal dysplasia - severe microphthalmia - severe facial clefting syndrome, MONDO:0013271
Publications for gene: ALX1 were set to 20451171; 27324866; 26610632
Tag Q3_23_promote_green tag was added to gene: ALX1.
Gene: alx1 has been classified as Amber List (Moderate Evidence).
Gene: alx1 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: ALX1 were changed from to ?Frontonasal dysplasia 3, 613456
Publications for gene: ALX1 were set to
gene: ALX1 was added gene: ALX1 was added to Clefting. Sources: Expert list Mode of inheritance for gene: ALX1 was set to BIALLELIC, autosomal or pseudoautosomal Review for gene: ALX1 was set to AMBER