%0 Case Reports
%T A novel MBTPS2 variant associated with BRESHECK syndrome impairs sterol-regulated transcription and the endoplasmic reticulum stress response.
%A Strong A
%A March ME
%A Cardinale CJ
%A Kim SE
%A Merves J
%A Whitworth H
%A Raffini L
%A Larosa C
%A Copelovitch L
%A Hou C
%A Slater D
%A Vaccaro C
%A Watson D
%A Zackai EH
%A Billheimer J
%A Hakonarson H
%J Am J Med Genet A
%V 188
%N 2
%D 02 2022
%M 34655156
%F 2.578
%R 10.1002/ajmg.a.62537
%X Ichthyosis follicularis, atrichia, and photophobia syndrome (IFAP syndrome) is a rare, X-linked disorder caused by pathogenic variants in membrane-bound transcription factor protease, site 2 (MBTPS2). Pathogenic MBTPS2 variants also cause BRESHECK syndrome, characterized by the IFAP triad plus intellectual disability and multiple congenital anomalies. Here we present a patient with ichthyosis, sparse hair, pulmonic stenosis, kidney dysplasia, hypospadias, growth failure, thrombocytopenia, anemia, bone marrow fibrosis, and chronic diarrhea found by research-based exome sequencing to harbor a novel, maternally inherited MBTPS2 missense variant (c.766 G>A; (p.Val256Leu)). In vitro modeling supports variant pathogenicity, with impaired cell growth in cholesterol-depleted media, attenuated activation of the sterol regulatory element-binding protein pathway, and failure to activate the endoplasmic reticulum stress response pathway. Our case expands both the genetic and phenotypic spectrum of BRESHECK syndrome to include a novel MBTPS2 variant and cytopenias, bone marrow fibrosis, and chronic diarrhea.