PuSH - Publikationsserver des Helmholtz Zentrums München: Suleiman-El-Hattab syndrome: A histone modification disorder caused by TASP1 deficiency.

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Riedhammer, K.M.* ; Burgemeister, A.L.* ; Cantagrel, V.* ; Amiel, J.* ; Siquier, K.* ; Boddaert, N.* ; Hertecant, J.* ; Kannouche, P.L.* ; Pouvelle, C.* ; Htun, S.* ; Slavotinek, A.M.* ; Beetz, C.* ; Diego-Alvarez, D.* ; Kampe, K.* ; Fleischer, N.* ; Awamleh, Z.* ; Weksberg, R.* ; Kopajtich, R. ; Meitinger, T.* ; Suleiman, J.* ; El-Hattab, A.W.*

Suleiman-El-Hattab syndrome: A histone modification disorder caused by TASP1 deficiency.

Hum. Mol. Genet. 31, 3083-3094 (2022)

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BACKGROUND: TASP1 encodes an endopeptidase activating histone methyltransferases of the KMT2 family. Homozygous loss-of-function variants in TASP1 have recently been associated with Suleiman-El-Hattab syndrome. We report six individuals with Suleiman-El-Hattab syndrome and provide functional characterization of this novel histone modification disorder in a multi-omics approach. Methods Chromosomal microarray/exome sequencing in all individuals. Western blotting from fibroblasts in two individuals. RNA sequencing and proteomics from fibroblasts in one individual. Methylome analysis from blood in two individuals. Knock-out of tasp1 orthologue in zebrafish and phenotyping. RESULTS: All individuals had biallelic TASP1 loss-of-function variants and a phenotype including developmental delay, multiple congenital anomalies (including cardiovascular and posterior fossa malformations), a distinct facial appearance, and happy demeanor. Western blot revealed absence of TASP1. RNA sequencing/proteomics showed HOX gene downregulation (HOXA4, HOXA7, HOXA1, HOXB2) and dysregulation of transcription factor TFIIA. A distinct methylation profile intermediate between control and Kabuki syndrome (KMT2D) profiles could be produced. Zebrafish tasp1 knock-out revealed smaller head size and abnormal cranial cartilage formation in tasp1 crispants. CONCLUSION: This work further delineates Suleiman-El-Hattab syndrome, a recognizable neurodevelopmental syndrome. Possible downstream mechanisms of TASP1 deficiency include perturbed HOX gene expression and dysregulated TFIIA complex. Methylation pattern suggests that Suleiman-El-Hattab syndrome can be categorized into the group of histone modification disorders including Wiedemann-Steiner and Kabuki syndrome.

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