FOXE1 was first reported in relation to AR FOXE1-related athyreosis with cleft palate in 1998 (Clifton-Bligh et al., PMID: 9697705). FOXE1-related athyreosis with cleft palate, also known as Bamforth-Lazarus syndrome, is a rare disorder characterized by congenital hypothyroidism due to thyroid agenesis or thyroid hypoplasia, cleft palate, and spiky hair. Variants in FOXE1 have been reported in individuals with the following disease entities: Bamforth-Lazarus syndrome, thyroid cancer, nonmedullary 4, and athyreosis. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability and inheritance pattern. Therefore, the following disease entities have been split into three disease entities, Bamforth-Lazarus syndrome (MIM:241850), thyroid cancer, nonmedullary 4 (MIM:616534), and athyreosis (no MIM). The split curations for AD thyroid cancer, nonmedullary 4 and athyreosis will be curated separately by a different GCEP.
Five missense and one frameshift variants that have been reported in six probands in six publications (PMIDs: 9697705, 12165566, 16882747, 20453517, 24219130, 35963604) are included in this curation. The mechanism of pathogenicity is unknown at this time. This gene-disease relationship is also supported by functional alteration of patient cells, animal models, and expression data (PMIDs: 9697705, 9697704, 15494458, 21177256). In summary, there is definitive evidence to support the relationship between FOXE1 and Bamforth-Lazarus syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date May 16th, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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