Endocrinopathies in TAOK1-Related Neurodevelopmental Disorders: An Expanded Case Series on the Evolution of Symptoms in Adolescents and Young Adults
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction:
The TAO kinase 1 gene on chromosome 17q11.2 encodes the thousand and one amino-acid protein kinase 1 (TAOK1), a serine/threonine kinase. TAOK1 performs critical modulatory functions in cell differentiation, proliferation, and stress response. Along with its pleiotropic functions in fundamental cellular processes, TAOK1 is expressed ubiquitously across most human tissues, with the highest levels in the brain, endocrine, and reproductive tissues. The association of heterozygous pathogenic variants in TAOK1 and neurodevelopmental disorders was first described in 2019. Over 30 individuals with heterozygous TAOK1 variants have been reported to date, with pediatric patients under age 12 comprising the vast majority. Hence, further clinical reports of symptoms, diagnosis, treatment, and follow-up in older TAOK1 individuals are necessary to document any changes or developments that generally occur beyond early childhood and to enhance the understanding of the phenotypic diversity and long-term prognosis of TAOK1-related neurodevelopmental disorders.
Methods:
All patients were identified while receiving care at Cincinnati Children’s Hospital Medical Center. Chart review was performed to obtain relevant patient and family history. The disease-causing variants in TAOK1 were discovered via exome sequencing and genome sequencing.
Results:
Here, we report the identification of novel heterozygous pathogenic and likely pathogenic TAOK1 variants in 6 adolescent and young adult patients (3 males and 3 females) from 5 families. Three TAOK1 variants were frameshift variants, while the other 2 were missense variants. Two variants (1 missense and 1 frameshift) were de novo, and the other 3 were of unknown origin. All patients in this cohort demonstrate the common clinical features of TAOK1-associated syndrome, including variable developmental delay, intellectual disability, hypotonia, distinctive craniofacial features, and behavioral concerns. Five patients had brain MRI abnormalities, representing a higher percentage in our cohort than in previous studies. Some patients in our cohort display additional neurological features, including sensory disturbance, abnormal gait, dystonia, spasticity, motor tic, and mild action tremor, which were uncommon or unreported in other TAOK1 patients. All 3 male patients were of short stature, making it a more prevalent presentation in our cohort than previously reported. Most significantly, all patients have complex clinical manifestations that incur endocrinology evaluations, ranging from delayed puberty in adolescence, hypogonadotropic hypogonadism, premature adrenarche, type 1 diabetes mellitus, obesity, and seizures associated with menses. These endocrine manifestations have not been well-represented previously in patients with TAOK1 variants reported in the literature.
Conclusion:
Our study expands the understanding of TAOK1-related disorders by identifying novel pathogenic variants in a cohort of adolescent and young adult patients. The diverse clinical manifestations observed, including notable neurological and endocrinological abnormalities, underscore the complexity of TAOK1-associated disorders. The findings highlight the importance of ongoing clinical evaluations and documentation of symptoms beyond early childhood, as they may reveal critical insights into the long-term prognosis and phenotypic variability of TAOK1-associated syndrome. Given the increased prevalence of specific features, such as short stature and unique endocrine complications in our cohort, further research is essential to develop comprehensive management strategies and improve patient outcomes. This work emphasizes the need for continued exploration of TAOK1's role in human health and development, paving the way for better diagnostic and therapeutic approaches in affected individuals.
The TAO kinase 1 gene on chromosome 17q11.2 encodes the thousand and one amino-acid protein kinase 1 (TAOK1), a serine/threonine kinase. TAOK1 performs critical modulatory functions in cell differentiation, proliferation, and stress response. Along with its pleiotropic functions in fundamental cellular processes, TAOK1 is expressed ubiquitously across most human tissues, with the highest levels in the brain, endocrine, and reproductive tissues. The association of heterozygous pathogenic variants in TAOK1 and neurodevelopmental disorders was first described in 2019. Over 30 individuals with heterozygous TAOK1 variants have been reported to date, with pediatric patients under age 12 comprising the vast majority. Hence, further clinical reports of symptoms, diagnosis, treatment, and follow-up in older TAOK1 individuals are necessary to document any changes or developments that generally occur beyond early childhood and to enhance the understanding of the phenotypic diversity and long-term prognosis of TAOK1-related neurodevelopmental disorders.
Methods:
All patients were identified while receiving care at Cincinnati Children’s Hospital Medical Center. Chart review was performed to obtain relevant patient and family history. The disease-causing variants in TAOK1 were discovered via exome sequencing and genome sequencing.
Results:
Here, we report the identification of novel heterozygous pathogenic and likely pathogenic TAOK1 variants in 6 adolescent and young adult patients (3 males and 3 females) from 5 families. Three TAOK1 variants were frameshift variants, while the other 2 were missense variants. Two variants (1 missense and 1 frameshift) were de novo, and the other 3 were of unknown origin. All patients in this cohort demonstrate the common clinical features of TAOK1-associated syndrome, including variable developmental delay, intellectual disability, hypotonia, distinctive craniofacial features, and behavioral concerns. Five patients had brain MRI abnormalities, representing a higher percentage in our cohort than in previous studies. Some patients in our cohort display additional neurological features, including sensory disturbance, abnormal gait, dystonia, spasticity, motor tic, and mild action tremor, which were uncommon or unreported in other TAOK1 patients. All 3 male patients were of short stature, making it a more prevalent presentation in our cohort than previously reported. Most significantly, all patients have complex clinical manifestations that incur endocrinology evaluations, ranging from delayed puberty in adolescence, hypogonadotropic hypogonadism, premature adrenarche, type 1 diabetes mellitus, obesity, and seizures associated with menses. These endocrine manifestations have not been well-represented previously in patients with TAOK1 variants reported in the literature.
Conclusion:
Our study expands the understanding of TAOK1-related disorders by identifying novel pathogenic variants in a cohort of adolescent and young adult patients. The diverse clinical manifestations observed, including notable neurological and endocrinological abnormalities, underscore the complexity of TAOK1-associated disorders. The findings highlight the importance of ongoing clinical evaluations and documentation of symptoms beyond early childhood, as they may reveal critical insights into the long-term prognosis and phenotypic variability of TAOK1-associated syndrome. Given the increased prevalence of specific features, such as short stature and unique endocrine complications in our cohort, further research is essential to develop comprehensive management strategies and improve patient outcomes. This work emphasizes the need for continued exploration of TAOK1's role in human health and development, paving the way for better diagnostic and therapeutic approaches in affected individuals.