A case of MBTPS1‐related disorder due to compound heterozygous variants in MBTPS1 gene: Genotype–phenotype expansion and the emergence of a novel syndrome

Abstract MBTPS1 (NM_003791.4) encodes Site‐1 protease, a serine protease that functions sequentially with Site‐2 protease regulating cholesterol homeostasis and endoplasmic reticulum stress response. MBTPS1 pathogenic variants are associated with spondyloepiphyseal dysplasia, Kondo‐Fu type (MIM:618392; cataract, alopecia, oral mucosal disorder, and psoriasis‐like syndrome, and Silver–Russell‐like syndrome). In this report, we describe a 14‐year‐old female with a complex medical history including white matter volume loss, early‐onset cataracts, retrognathia, laryngomalacia, inguinal hernia, joint hypermobility, feeding dysfunction, and speech delay. Additionally, features of ectodermal dysplasia that she has include decreased sweating, heat intolerance, dysplastic nails, chronically dry skin, and abnormal hair growth issues. Exome sequencing analysis identified compound heterozygous variants in the MBTPS1 gene: c.2255G > T p.(Gly752Val) predicted to affect important function of the protein, which was inherited from the mother, and a splice site variant c.2831 + 5G > T, which was inherited from the father. The RNA‐seq analysis of the splice variant showed skipping of exon 21, predicted to result in frameshifting p.(Ser901fs28*) leading to non‐sense mediated decay. To our knowledge, only eight studies have been published that described the MBPTS1‐ related disorders. Interestingly, we observed the features of ectodermal dysplasia in our patient that further expands the phenotypic spectrum of MBTPS1 gene‐related disorders.