Biallelic TYR and TKFC variants in Egyptian patients with OCA1 and new expanded TKFC features.

Autor: Ashaat EA; Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt. ea.ashaat@nrc.sci.eg., Esmaiel NN; Molecular Genetics and Enzymology Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt., El-Saiedi SA; Pediatric Cardiology Department, Cairo University, Cairo, Egypt., Ashaat NA; Professor of Genetics, Ain Shams University, Cairo, Egypt., Hussen DF; Human Cytogenetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt., Ramadan A; Molecular Genetics and Enzymology Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt., Al Kersh MA; Orthopedic Department, Ain Shams University, Cairo, Egypt., AbdelHakim NS; Fetal Medicine Unit, Faculty of Medicine, Cairo University, Cairo, Egypt., Said I; Fetal Medicine Unit, Faculty of Medicine, Cairo University, Cairo, Egypt., Metwally AM; Community Medicine Research Department/Medical Research and Clinical Studies Institute, National Research Centre (Affiliation ID: 60014618), Cairo, Egypt. ammal_mok@yahoo.com., Fayez A; Molecular Genetics and Enzymology Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
Jazyk: angličtina
Zdroj: BMC genomics [BMC Genomics] 2024 Sep 09; Vol. 25 (1), pp. 844. Date of Electronic Publication: 2024 Sep 09.
DOI: 10.1186/s12864-024-10705-4
Abstrakt: Background: Oculocutaneous albinism type1 (OCA1) is caused by the TYR gene's homozygous and compound heterozygous variants. TKFC gene variants cause triokinase & FMN cyclase deficiency syndrome with variable multisystemic disorders.
Objectives: To determine the potential disease-causing variants in two deceased patients presenting atypical OCA1 features by demonstrating three generations for a single family. The two deceased neonates had severe skeletal abnormalities and fatal hypertrophic cardiomyopathy. We also explored the potential mechanisms for the causative relationship between TKFC and multisystem disorders.
Patients and Methods: Due to the new emerging symptoms that weren't reported before with the TYR gene, the following methods were performed: Sanger sequencing for the TYR gene, followed by whole exome sequencing, co-segregation, and computational analyses.
Results: Extensive parental consanguinity was found, and consequently an autosomal recessive mode of inheritance was prioritized. Upon performing sequencing and segregation data, the following has been confirmed: positive co-segregation of nonsense homozygous NM_000372.5:c.346C > T p.(Arg116*) variant in TYR gene and multisystem disease-missense homozygous NM_015533.4:c.598G > A p.(Val200Ile) variant in TKFC gene in the two affected index patients who deceased due to hypertrophic cardiomyopathy. Using computational analysis, we found that c.598G > A p.(Val200Ile) pathogenicity has led to the failure of L2-K1 active site closure due to the potential differential fluctuation between valine and isoleucine residues. Subsequently, disruption of endogenous DHA phosphorylation was found. Two potential mechanisms exploring the causative relationship between TKFC gene and multisystem disorders have been suggested.
Conclusions: This study presented a first family with the co-existence of biallelic variants in TYR and TKFC genes associating severe skeletal abnormalities and lethal hypertrophic cardiomyopathy. Neither of these genes would have been pursued in the standard genetic counseling. Such discovery is paving the way for more efficient genetic counseling. Comparing TKFC results with literature data showed that our relevant expanded TKFC variant is the 3rd worldwide.
(© 2024. The Author(s).)
Databáze: MEDLINE
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