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Frontorhiny is an autosomal recessive frontonasal malformation characterized by ocular hypertelorism (HP:0000316), wide nasal bridge (HP:0000431), short nasal ridge, bifid nasal tip (HP:0000456), broad columella (HP:0010761), widely separated nares and philtrum anomalies. Affected individuals may also present with upper eyelid ptosis and midline dermoid cysts. Early linkage to chromosome 1p13.3 established ALX3 as the causative gene in autosomal recessive frontorhiny.
Homozygous ALX3 variants were first identified in seven unrelated families, each harboring a distinct loss-of-function or homeodomain missense mutation, accounting for seven probands (PMID:19409524). Subsequent analysis of a consanguineous Pakistani pedigree revealed a novel homozygous nonsense variant c.604C>T (p.Gln202Ter) segregating with four affected siblings (PMID:29215096). Segregation in this pedigree included four additional affected relatives.
The ALX3 variant spectrum includes nonsense (c.604C>T (p.Gln202Ter)), splice-site (c.595-2A>T), frameshift (c.578_581del (p.Thr193fs)) and critical homeodomain missense substitutions, all predicted to abolish transcriptional function. No recurrent founder alleles have been reported outside consanguineous populations.
Functional studies in zebrafish demonstrate that combined alx1;alx3 loss-of-function recapitulates human frontonasal and ocular phenotypes, including defective anterior cranial neural crest migration and aberrant anterior segment vasculature. Rescue experiments confirm a requirement for alx3 in craniofacial and ocular development (PMID:35142342).
Integration of robust genetic evidence across eight independent families, confirmed segregation in multiple affected relatives, and concordant animal model data support a definitive gene–disease relationship. This association enables molecular diagnosis, genetic counseling, and inclusion of ALX3 in diagnostic panels for midfacial dysplasias.
Key take-home: Biallelic ALX3 loss-of-function variants unequivocally cause autosomal recessive frontorhiny, supporting definitive clinical utility in diagnosis.
Gene–Disease AssociationDefinitiveEleven probands from eight unrelated families with autosomal recessive segregation (four affected relatives) and concordant functional model data Genetic EvidenceStrongEleven probands (eight families) with diverse homozygous loss-of-function and missense variants, and segregation in one consanguineous pedigree (four affected) Functional EvidenceModerateZebrafish alx1;alx3 loss-of-function mutant phenocopies human frontorhiny and rescue experiments confirm requirement for ALX3 |