Homozygous loss-of-function variants of TASP1, a gene encoding an activator of the histone methyltransferases KMT2A and KMT2D, cause a syndrome of developmental delay, happy demeanor, distinctive facial features, and congenital anomalies
| Autor: | Korbinian M. Riedhammer, Ayman W. El-Hattab, Fowzan S. Alkuraya, Hessa S. Alsaif, Mirjana Gusic, Timothy Jicinsky, Maha Abdulrahim, Moeenaldeen Al-Sayed, Jehan Suleiman, Weimin Bi, Manal Nicolas-Jilwan, Nabil Moghrabi, Laurie Werner, Srirangan Sampath, Anna L. Burgemeister, Melinda Mundt |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Microcephaly Methyltransferase Developmental Disabilities 03 medical and health sciences Exon Loss of Function Mutation Histone methylation Exome Sequencing Genetics medicine Missense mutation Humans Abnormalities Multiple Genetics (clinical) Genetic Association Studies 030304 developmental biology 0303 health sciences biology 030305 genetics & heredity Homozygote Facies Infant Exons Histone-Lysine N-Methyltransferase Syndrome medicine.disease Chromosomal Microarray Histone Methylation Novel Gene Novel Syndrome Tasp1 Whole Exome Sequencing Hypotonia Neoplasm Proteins Pedigree DNA-Binding Proteins KMT2A Phenotype Histone methyltransferase Child Preschool biology.protein Female medicine.symptom Myeloid-Lymphoid Leukemia Protein |
| Zdroj: | Hum. Mutat. 40, 1985-1992 (2019) |
| ISSN: | 1098-1004 |
| Popis: | We report four unrelated children with homozygous loss-of-function variants in TASP1 and an overlapping phenotype comprising developmental delay with hypotonia and microcephaly, feeding difficulties with failure-to-thrive, recurrent respiratory infections, cardiovascular malformations, cryptorchidism, happy demeanor, and distinctive facial features. Two children had a homozygous founder deletion encompassing exons 5–11 of TASP1, the third had a homozygous missense variant, c.701 C>T (p.Thr234Met), affecting the active site of the encoded enzyme, and the fourth had a homozygous nonsense variant, c.199 C>T (p.Arg67*). TASP1 encodes taspase 1 (TASP1), which is responsible for cleaving, thus activating, the lysine methyltransferases KMT2A and KMT2D, which are essential for histone methylation and transcription regulation. The consistency of the phenotype, the critical biological function of TASP1, the deleterious nature of the TASP1 variants, and the overlapping features with Wiedemann–Steiner and Kabuki syndromes respectively caused by pathogenic variants in KMT2A and KMT2D all support that TASP1 is a disease-related gene. |
| Databáze: | OpenAIRE |
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