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De novo TLK1 and MDM1 mutations in a patient with a neurodevelopmental disorder and immunodeficiency

ABSTRACT: De novo TLK1 and MDM1 mutations in a patient with a neurodevelopmental disorder and immunodeficiency

PROVIDER: PRJNA1006072 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25658772_1.fastq.gz	Fastqsanger.gz
	SRR25658772_2.fastq.gz	Fastqsanger.gz
	SRR25658773_1.fastq.gz	Fastqsanger.gz
	SRR25658773_2.fastq.gz	Fastqsanger.gz
	SRR25658774_1.fastq.gz	Fastqsanger.gz

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De novo TLK1 and MDM1 mutations in a patient with a neurodevelopmental disorder and immunodeficiency

Project description:The Tousled-like kinases 1 and 2 (TLK1/TLK2) regulate DNA replication, repair and chromatin maintenance. TLK2 variants are associated with ‘Intellectual Disability, Autosomal Dominant 57’ (MRD57), a neurodevelopmental disorder (NDD) characterized by intellectual disability (ID), autism spectrum disorder (ASD) and microcephaly. Several TLK1 variants have been reported in NDDs but their functional significance is unknown. A male patient presenting with ID, seizures, global developmental delay, hypothyroidism, and primary immunodeficiency was determined to have a novel, heterozygous variant in TLK1 (c.1435C>G, p.Q479E) by genome sequencing (GS). Transcriptome sequencing in patient-derived cells confirmed expression of TLK1 transcripts carrying the p.Q479E variant and revealed alterations in genes involved in class switch recombination and cytokine signaling.

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Project description:The Tousled-like kinases 1 and 2 (TLK1/TLK2) regulate DNA replication, repair and chromatin maintenance. TLK2 variants are associated with ‘Intellectual Disability, Autosomal Dominant 57’ (MRD57), a neurodevelopmental disorder (NDD) characterized by intellectual disability (ID), autism spectrum disorder (ASD) and microcephaly. Several TLK1 variants have been reported in NDDs but their functional significance is unknown. A male patient presenting with ID, seizures, global developmental delay, hypothyroidism, and primary immunodeficiency was determined to have a heterozygous TLK1 variant (c.1435C>G, p.Q479E), as well as a mutation in MDM1 (c.1197dupT, p.K400*). Cells expressing TLK1 p.Q479E exhibited reduced cytokine responses and elevated DNA damage, but not increased radiation sensitivity or DNA repair defects. The TLK1 p.Q479E variant impaired kinase activity but not proximal protein interactions.

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