Focal facial dermal dysplasias type III: Two families with Setleis syndrome in China

Abstract

Focal facial dermal dysplasias type III (FFDD III), commonly known as Setleis syndrome (SS; Online Mendelian Inheritance in Man #227260), is a type of focal facial dermal dysplasia, characterized by bitemporal atrophic skin lesion. The homozygous mutations in the TWIST2 gene and copy number variants (CNV) at chromosome 1p36.22p36.21 were reported as the pathogenic mechanism. In this study, we collected DNA samples from a large Chinese family affected by FFDD and found no mutation of TWSIT2. To determine the underlying genetic cause, we performed a multipoint parameter linkage analysis and haplotype analysis of the family 1 and mapped SS to a region Chr1:14.074–20.524cM (rs2401090–rs2294642). Copy number variant was identified by Sanger sequencing, which breakpoints were Chr1:11695972 and Chr1:11829858. The region contains eight genes, including FBXO2, FBXO44, FBXO6, MAD2L2, DRAXIN, AK125437, AGTRAP, and C1orf167. There were no candidate gene mutations of the second family with SS. Our study further reduced the size of CNV resulting in SS (Chr1:11696993–11829858) and focused on eight genes.

De novo triplication at 1p36.23p36.22 further refines the dosage sensitive region of overlap in Setleis syndrome (focal facial dermal dysplasia type III)

“…It is important to note that recently, there was a large Chinese family with multiple individuals with features of SS associated with 1p36.22 duplication (chr1:11,695,972‐11,829,858) identified on whole‐genome sequencing (Cao et al, 2022). No pathogenic variants in the TWIST2 gene were identified in the affected individuals and from this finding and the repeat dose‐sensitive region was further refined to be a 134‐kb region in chr1:11,696,993‐11,829,858 (Cao et al, 2022). This region contains seven RefSeq genes including FBXO2 , FBXO44 , FBXO6 , DRAXIN , AGTRAP , a part of C1orf167 , and MAD2L2 , which is also the only OMIM Morbid gene in this region.…”

“…So far, a proposed mechanism of SS is that the duplication or triplication of gene(s) in the 1p36 region overcomes the inhibitory, downstream effect of TWIST2 (Li et al, 1995; Weaver et al, 2015). Sequencing of TWIST2 in several unrelated familial and/or sporadic SS patients did not identify disease‐causing mutations, highlighting the genetic heterogeneity of the FFDD/SS phenotype (Cao et al, 2022; Lee et al, 2015; Weaver et al, 2015). A characteristic feature of SS is the bitemporal atrophic lesions with deficient subcutaneous fat and evidence of mesodermal dysplasia, which provides insights on the possible pathogenetic mechanism of SS (Matsumoto et al, 1991).…”

The F-box-only protein 44 regulates pregnane X receptor protein level by ubiquitination and degradation

“…Single nucleotide polymorphisms in FBXO44 were identified in a Spanish population with aggressive periodontitis, but the association was not statistically significant 56 . Copy-number variants in a region of chromosome 1 containing FBXO44 and seven other genes were discovered in a Chinese family with a type of focal facial dermal dysplasia 57 . A bioinformatics analysis named FBXO44 as a candidate target for the diagnosis and treatment of atherosclerosis 58 .…”