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

Setleis syndrome (SS), or focal facial dermal dysplasia type III (FFDD3, MIM #227260), is an autosomal recessive condition caused by biallelic loss-of-function variants in TWIST2. It is characterized by bitemporal atrophic skin lesions and distinctive facial features. Individuals with de novo or inherited duplication or triplication of the chromosomal region 1p36.22p36.21 have also been reported to have the SS phenotype with additional neurodevelopmental challenges (rarely seen in individuals with TWIST2 mutations) and variable expressivity and penetrance. Triplication of this region is also associated with more severe manifestations compared to a duplication. We report a 2-year-old female patient with features of SS associated with a de novo 3.603 Mb triplication at 1p36.23p36.22 identified on postnatal microarray analysis. Her triplication shares a 281.263 kb overlap with gains at 1p36.22, reported by previous groups, delineating the shortest region of overlap (SRO) to date. This SRO involves 10 RefSeq and 4 OMIM morbid map genes and highlights the candidate dosage-sensitive element(s) underlying the cardinal features of SS phenotype in individuals with gains at 1p36.

Barber-Say syndrome and Ablepharon-Macrostomia syndrome: An overview.

Barber-Say syndrome (BSS) and Ablepharon-Macrostomia syndrome (AMS) are congenital malformation syndromes caused by heterozygous mutations in TWIST2. Here we provide a critical review of all patients published with these syndromes. We excluded several earlier reports due to misdiagnosis or insufficient data for reliable confirmation of the diagnosis. There remain 16 reliably diagnosed individuals with BSS and 16 with AMS. Major facial characteristics present in both entities, albeit often in differing frequencies, are excessive facial creases, hypertelorism, underdevelopment of the anterior part of the eyelids (anterior lamella), ectropion, broad nasal ridge and tip, thick and flaring alae nasi, protruding maxilla, wide mouth, thin upper vermillion, and attached ear lobes. In BSS a remarkable extension of the columella on the philtrum can be seen, and in both the medial parts of the cheeks bulge towards the corners of the mouth (cheek pads). Scalp hair is sparse in AMS only, but sparse eyebrows and eyelashes occur in both entities, and general hypertrichosis occurs in BSS. We compare these characteristics with those in Setleis syndrome which can also be caused by TWIST2 mutations. The resemblance between the three syndromes is considerable, and likely differences seem larger than they actually are due to insufficiently complete evaluation for all characteristics of the three entities in the past. It is likely that with time it can be concluded that BSS. AMS and Setleis syndrome form a continuum. © 2016 Wiley Periodicals, Inc.

Setleis syndrome: clinical, molecular and structural studies of the first TWIST2 missense mutation.

Setleis syndrome is characterized by bitemporal scar-like lesions and other characteristic facial features. It results from recessive mutations that truncate critical functional domains in the basic helix-loop-helix (bHLH) transcription factor, TWIST2, which regulates expression of genes for facial development. To date, only four nonsense or small deletion mutations have been reported. In the current report, the clinical findings in a consanguineous Turkish family were characterized. Three affected siblings had the characteristic features of Setleis syndrome. Homozygosity for the first TWIST2 missense mutation, c.326T>C (p.Leu109Pro), was identified in the patients. In silico analyses predicted that the secondary structure of the mutant protein was sustained, but the empirical force field energy increased to an unfavorable level with the proline substitution (p.Leu109Pro). On a crystallographically generated dimer, p.Leu109 lies near the dimer interface, and the proline substitution is predicted to hinder dimer formation. Therefore, p.Leu109Pro-TWIST2 alters the three dimensional structure and is unable to dimerize, thereby hindering the binding of TWIST2 to its target genes involved in facial development.

Chromosome 1p36.22p36.21 duplications/triplication causes Setleis syndrome (focal facial dermal dysplasia type III).

Focal facial dermal dysplasias (FFDD) are characterized by congenital bitemporal or preauricular atrophic skin lesions, and either autosomal dominant or autosomal recessive inheritance. Setleis syndrome (SS), FFDD type III, is a severe form of FFDD with the ectodermal lesions plus other striking facial features. Autosomal recessive nonsense and frameshift mutations in TWIST2 have been found to cause SS in some but not all individuals. Here, we report on four unrelated individuals, one with an unclassified FFDD and the other three with classic SS. Chromosomal microarray analyses revealed unique copy number variants of 1p36 in two individuals with duplications at 1p36.22p36.21 and one with a triplication at 1p36.22p36.21. The fourth patient had normal chromosomes by microarray analysis. All four patients had normal TWIST2 exonic sequences. We propose that a dosage effect of one or more of the 30 genes in the 1.3 Mb 1p36.22p36.21 region of overlap is responsible for FFDD/SS manifestations in some individuals, and this mechanism would be inherited as an autosomal dominant trait. In patients with no duplication/triplication of the 1p36.22p36.21 region and no mutations in TWIST2, there are mutation(s) in one of the 30 genes in this region or mutations in other as yet unidentified genes at different locations that may affect the expressions of genes in this region or act independently to cause this developmental disease phenotype.

Mechanisms of Regulation of the CHRDL1 Gene by the TWIST2 and ADD1/SREBP1c Transcription Factors.

Setleis syndrome (SS) is a rare focal facial dermal dysplasia caused by recessive mutations in the basic helix-loop-helix (bHLH) transcription factor, TWIST2. Expression microarray analysis showed that the chordin-like 1 (CHRDL1) gene is up-regulated in dermal fibroblasts from three SS patients with the Q119X TWIST2 mutation. METHODS: Putative TWIST binding sites were found in the upstream region of the CHRDL1 gene and examined by electrophoretic mobility shift (EMSA) and reporter gene assays. RESULTS: EMSAs showed specific binding of TWIST1 and TWIST2 homodimers, as well as heterodimers with E12, to the more distal E-boxes. An adjoining E-box was bound by ADD1/SREBP1c. EMSA analysis suggested that TWIST2 and ADD1/SREBP1c could compete for binding. Luciferase (luc) reporter assays revealed that the CHRDL1 gene upstream region drives its expression and ADD1/SREBP1c increased it 2.6 times over basal levels. TWIST2, but not the TWIST2-Q119X mutant, blocked activation by ADD1/SREBP1c, but overexpression of TWIST2-Q119X increased luc gene expression. In addition, EMSA competition assays showed that TWIST2, but not TWIST1, competes with ADD1/SREBP1c for DNA binding to the same site. CONCLUSIONS: Formation of an inactive complex between the TWIST2 Q119X and Q65X mutant proteins and ADD1/SREBP1c may prevent repressor binding and allow the binding of other regulators to activate CHRDL1 gene expression.

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

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.

Setleis syndrome: genetic and clinical findings in a new case with epilepsy.

BACKGROUND: Focal facial dermal dysplasias are a group of inherited ectodermal disorders characterized by congenital bitemporal or periauricular scar-like depressions as well as other facial and nonfacial developmental defects. Four subtypes have been delineated, and mutations in the TWIST2 gene have been identified in type III focal facial dermal dysplasia (Setleis syndrome). PATIENTS: We describe a sporadic patient with the hallmark bitemporal scar-like lesions, severe intellectual disability, and focal epilepsy. RESULTS: The boy has typical features of Setleis syndrome, and he developed focal epilepsy, a previously unreported feature of this syndrome. No mutations in the TWIST2 gene were found, and there were no pathologic copy number abnormalities. CONCLUSIONS: Epilepsy could represent a new manifestation, and the patient described broadens the spectrum of clinical features associated with Setleis syndrome, including central nervous system involvement.