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Systematic genomic characterization of cutaneous mosaic constitution (in individuals with intellectual disability) as the key to improved understanding of ID pathogenesis

Systematic genomic characterization of cutaneous mosaic constitution (in individuals with intellectual disability) as the key to improved understanding of ID pathogenesis
Intellectual disability (ID) is the most common developmental disorder worldwide. ID occurs either isolated (non-syndromic) or in combination with complex malformations, behavior deficits or distinct phenotypic changes (syndromic).
Thus, despite of significant technological progress (whole exome sequencing (WES)/ NGS), current understanding of the etiopathogenesis of ID is incomplete. Research suggests that analysis of individuals by WES, predominantly performed on peripheral blood cells, led to the identification of a disease causing germline mutation in only 30% of by then molecularly unsolved patients with ID. This reflects the complexity of the underlying molecular signatures and the demand for new scientific strategies to gain more insights into ID biology. The evidence to date suggests that analysis of likely low-grade mosaicisms (LGM), which are not detectable by standard pipelines, as well as systematic genomic analysis of affected tissues, might be the key towards an improved understanding of ID pathophysiology. However, large systematic studies are missing and precise biological mechanisms are widely unexplored.
In this context, skin is of high interest. Skin lesions often present in exceptional number, unusual location or bizarre configuration. These comprise a broad range of distinct skin manifestations, frequently including pigmentary changes (PC). At least 261 ID syndromes with PC are listed in the currently available LMD version. The high prevalence of PC in patients with ID points to shared underlying disease causing and specific molecular mechanisms. However, knowledge of the underlying basis is widely missing.
The project aims for the first time to establish an in-depth understanding of the pathogenic causes of PC in patients with ID to shed further light on the biology of ID.
By performing comprehensive molecular analyses comprising WES, RNA-sequencing and chip-based methylome approach of affected and matched surrounded healthy skin (fibroblasts, melanocytes) we aim to systematically characterize i) the mutational profile, ii) the gene expression profile and iii) the epigenetic profile. At once, trio-based WES as well as characterization of the transcriptome and methylome of peripheral blood cells shall be performed. Beside standard analysis pipelines, we aim to focus on the detection of LGM. Integrative analysis of genomic, proteomic and epigenetic profile of blood and skin findings will be performed to identify underlying, common and specific molecular pathways.
For the requested project, 10 phenotypically well-defined samples, taken from the German MRNET consortium, are available. Trio-based WES of blood cells was already performed in all of them. Enlargement of the sample by further 10-20 patients (own genetic consultation, local Children’s Hospital, ERN-ITHACA) guarantees a sample of high-quality for the requested project.


Originalarbeiten ab 2013

Mahmoudi H*, Redler S*, Birch P, Drichel D, Dobson K, Tazi-Ahnini R, Teßmann P, Giehl KA, Kruse R, Lutz G, Hanneken S, Wolff H, Blume-Peytavi U, Becker T, Nöthen MM, Messenger AG, Böhm M*, Betz RC*: Selected variants of the melanocortin 4 receptor gene (MC4R) do not confer susceptibility to female pattern hair loss. Arch Dermatol Res 305: 249-253, 2013 *These authors contributed equally to this work.

Heilmann S, Kiefer AK, Fricker N, Drichel D, Hillmer AM, Herold C, Tung JY, Eriksson N, Redler S, Betz RC, Li R, Kárason A, Nyholt DR, Song K, Vermeulen SH, Kanoni S, Dedoussis G, Martin NG, Kiemeney LA, Mooser V, Stefansson K, Richards JB, Becker T, Brockschmidt FF, Hinds DA, Nöthen MM: Androgenetic alopecia: identification of four genetic risk loci and evidence for the contribution of WNT-signaling to its etiology. J Invest Dermatol 133(6): 1489-96Jan, 2013

Redler S, Dobson K, Drichel D, Heilmann S, Wolf S, Brockschmidt FF, Tazi-Ahnini R, Birch P, Teßmann P, Giehl KA, Kruse R, Lutz G, Garcia Bartels N, Hanneken S, Wolff H, Böhm M, Becker T, Blume-Peytavi U, Nöthen MM, Messenger AG, Betz RC: Investigation of six novel susceptibility loci for male androgenetic alopecia in women with female pattern hair loss. J Dermatol Sci.;72(2): 186-8, 2013

Redler S, Birch P, Drichel D, Hofmann P, Dobson K, Böhmer AC, Becker J, Giehl KA, Tazi-Ahnini R, Kruse R, Wolff H, Miesel A, Fischer T, Böhm M, Nuwayhid R, Garcia Bartels N, Lutz G, Becker T, Blume-Peytavi U, Nöthen MM, Messenger AG, Betz RC: The oestrogen receptor 2 (ESR2) gene in female-pattern hair loss: replication of association with rs10137185 in German patients. Br J Dermatol. 170(4): 982-5, 2014

Nuwaihyd R, Redler S, Heilmann S, Drichel D, Wolf S, Birch P, Dobson K, Lutz G, Giehl KA, Kruse R, Tazi-Ahnini R, Hanneken S, Böhm M, Miesel A, Fischer T, Wolff H, Becker T, Garcia-Bartels N, Blume-Peytavi U, Nöthen MM, Messenger AG, Betz RC: Investigation of four novel male androgenetic alopecia susceptibility loci: no association with female pattern hair loss. Arch Dermatol Res. 306(4): 413-8, 2014
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Betz RC, Petukhova L, Ripke S, Huang H, Menelaou A, Redler S, Becker T, Heilmann S, Yamany T, Duvic M, Hordinsky M, Norris D, Price VH, Mackay-Wiggan J, de Jong A, DeStefano GM, Moebus S, Böhm M, Blume-Peytavi U, Wolff H, Lutz G, Kruse R, Bian L, Amos CI, Lee A, Gregersen PK, Blaumeiser B, Altshuler D, Clynes R, de Bakker PI, Nöthen MM, Daly MJ, Christiano AM: Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci. Nat Commun. 22; 6: 5966, 2015

Redler S, Pasternack SM, Wolf S, Stienen D, Wenzel J, Nöthen MM, Betz RC: A novel KRT86 mutation in a Turkish family with monilethrix, and identification of maternal mosaicism. Clin Exp Dermatol. 40(7): 781-5, 2015

Fischer J, Degenhardt F, Hofmann A, Redler S, Basmanav FB, Heilmann-Heimbach S, Hanneken S, Giehl KA, Wolff H, Moebus S, Kruse R, Lutz G, Blaumeiser B, Böhm M, Garcia Bartels N, Blume-Peytavi U, Petukhova L, Christiano AM, Nöthen MM, Betz RC: Genome-wide analysis of copy number variants in alopecia areata in a Central European cohort reveals association with MCHR2. Exp Dermatol. 26(6): 536-541, 2017

Redler S, Basmanav FBÜ, Blaumeiser B, Bartels NG, Lutz G, Tafazzoli A, Kruse R, Wolff H, Böhm M, Blume-Peytavi U, Becker T, Nöthen MM, Betz RC: Parent-of-origin Effect in Alopecia Areata: A Large-scale Pedigree Study. Acta Derm Venereol. 97(7): 862-863, 2017

Redler S, Strom TM, Wieland T, Cremer K, Engels H, Distelmaier F, Schaper J, Küchler A, Lemke JR, Jeschke S, Schreyer N, Sticht H, Koch M, Lüdecke HJ, Wieczorek D: Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID. Eur J Hum Genet. 25(7): 889-893, 2017
Redler S, Messenger AG, Betz RC: Genetics and other factors in the aetiology of female pattern hair loss. Exp Dermatol. 26(6): 510-517, 2017. Review.

Tafazzoli A, Forstner AJ, Broadley D, Hofmann A, Redler S, Petukhova L, Giehl KA, Kruse R, Blaumeiser B, Böhm M, Bertolini M, Rossi A, Garcia Bartels N, Lutz G, Wolff H, Blume-Peytavi U, Soreq H, Christiano AM, Botchkareva NV, Nöthen MM, Betz RC: Genome-wide microRNA analysis implicates miR-30b/d in the etiology of alopecia areata. J Invest Dermatol. 138(3):549-556, 2018.

Rütten A, Hegenbarth W, Kohl PK, Hillen U, Redler S: Primary Cutaneous Adenoid Cystic Carcinoma mimicking dermal Cylindromatosiscylindroma: histology of the complete surgical excision as the clue to diagnosis. J Dtsch Dermatol Ges 2018, accepted, ahead of print.