Skeletal dysplasia
Gene: ALX1
Two cases with disorder described - one had cranium bifidum. Variant in cat has similar phenotype (Lyons et al 2016).Dysostoses with predominant craniofacial involvement gp of SD - AR.Sufficient cases to make green? Note added by AW - ALX1 no No skeletal (non-cranial) features described in Uz et al AJHG 10 or Ullah Clin Genet 17. Do you report variants in this gene as part of your current diagnostic practice? YES - FMD; Review on behalf of Tracy Lester/Andrew WilkieCreated: 6 Mar 2019, 11:44 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Frontonasal dysplasia type 3 613456
Variants in this GENE are reported as part of current diagnostic practice
Comment on list classification: Rating green due to association with FRONTONASAL DYSPLASIA TYPE 3. Other Frontonasal dysplasia genes ALX3 and ALX4 have been included on this panel. Including on the panel following the advice of Prof Lyn Chitty.Created: 12 Dec 2019, 9:01 p.m. | Last Modified: 12 Dec 2019, 9:01 p.m.
Panel Version: 1.341
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: 12 Dec 2019, 8:58 p.m. | Last Modified: 12 Dec 2019, 8:58 p.m.
Panel Version: 1.340
Comment from Tracy Lester - ALX1 should stay on the skeletal dysplasia panel in the absence of a specific craniofacial panel. It is currently red on the Craniosynostosis panel (https://panelapp.genomicsengland.co.uk/panels/168/gene/ALX1/)Created: 28 Nov 2019, 11:22 a.m. | Last Modified: 28 Nov 2019, 11:22 a.m.
Panel Version: 1.244
This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: ALX1; Initial rating suggestion: Red List (low evidence)Created: 6 Mar 2019, 11:36 a.m.
Comment when marking as ready: Associated with phenotype in OMIM. Two variants reportedCreated: 27 Jul 2016, 12:30 p.m.
Comment on list classification: Only two variants reportedCreated: 27 Jul 2016, 12:28 p.m.
Tier 1Created: 17 Jun 2016, 8:01 a.m.
Mode of inheritance
Unknown
Phenotypes
Frontonasal dysplasia 3 613456
Variants in this GENE are reported as part of current diagnostic practice
Gene: alx1 has been classified as Green List (High Evidence).
Added phenotypes Frontonasal dysplasia type 3 613456 for gene: ALX1
Source NHS GMS was added to ALX1.
Promoted to version 1 9th August 2016
This gene has been classified as Red List (Low Evidence).
Publications for ALX1 were set to 27324866; 20451171;
This gene has been classified as Red List (Low Evidence).
ALX1 was added to Unexplained skeletal dysplasiapanel. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert list
Phenotypes for ALX1 were set to Frontonasal dysplasia 3 613456
Mode of inheritance for ALX1 was changed to BIALLELIC, autosomal or pseudoautosomal
ALX1 was added to Unexplained skeletal dysplasiapanel. Sources:
ALX1 was created by sleigh