Submission Details

Variants in MBTPS2 have been observed in males with X-linked IFAP syndrome with or without BRESHECK syndrome. This disease was initially characterized by the triad of Ichthyosis Follicularis, Atrichia, and Photophobia (IFAP syndrome). Later, variants in this gene were also observed in individuals with additional features, including Brain anomalies, severe mental Retardation, Ectodermal dysplasia, Skeletal malformations, Hirschsprung disease, Ear/eye anomalies, Cleft palate/cryptorchidism, and Kidney dysplasia/hypoplasia (BRESHECK syndrome). Evidence suggests that there is no difference in the molecular mechanism underlying IFAP and BRESHECK syndromes and they are within the same phenotypic spectrum. Therefore, for the purposes of this curation, they have been lumped into one disease entity, IFAP syndrome with or without BRESHECK syndrome. Neurodevelopmental features are commonly found in individuals with IFAP syndrome, including developmental delay (32%), intellectual disability (39%), seizures (28%), and hypotonia (8%) (PMID: 21600032). Since 2009, 11 MBTPS2 variants in 17 male probands with X-linked IFAP/BRESHECK syndrome have been reported in 11 publications. In addition to the classic triad of IFAP, all of them had neurodevelopmental phenotypes and were hemizygous for missense variants. Complementation analysis and luciferase reporter assays in cell culture demonstrated impaired protein function for the variants studied, with residual activity (PMID: 19361614, 23316014). These studies indicate a partial loss-of-function disease mechanism, and suggest that complete null alleles may cause embryonic lethality in hemizygous males. In summary, there is definitive evidence to support this gene-disease association. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 11/16/2020 (SOP Version 8).