2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Long-Term Outcomes of Adult Siblings with TRIT1-related Disorder

Long-Term Outcomes of Adult Siblings with TRIT1-related Disorder
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This document discusses the long-term outcomes of adult siblings with TRIT1-related disorder, which is an autosomal recessive disorder of mitochondrial dysfunction. TRIT1 is a gene that encodes for a tRNA isopentenyl transferase. The modification of tRNA by TRIT1 is important in mitochondrial function. The clinical report focuses on two siblings who were diagnosed with an unspecified form of intellectual disability and epilepsy in 1982. They were recently referred to genetics for an updated evaluation. Both siblings had severe to profound intellectual disabilities and limited speech. They did not have any brain malformations identified by MRI. The brother had lower limb spasticity and used a wheelchair for mobility, while the sister was ambulatory with a walker. The siblings had various medical conditions and symptoms, including cataracts, oral dysphagia, constipation, diverticulitis, osteopenia, depression, and epilepsy. However, there was no evidence of mitochondrial dysfunction in their metabolic testing. Exome sequencing revealed compound heterozygosity for variants in the TRIT1 gene in both siblings, confirming the diagnosis. The missense variant initially classified as having uncertain significance was reclassified as likely pathogenic after confirming its phase. The document also provides a summary of reported cases of TRIT1-related disorder. The age range of reported patients is from 4 years to over 23 years. Seizures, developmental delays/intellectual disability, and poor growth parameters are common features among patients. Other features include microcephaly, spasticity, congenital brain malformations, dysmorphic features, and ocular anomalies. In conclusion, TRIT1-related disorder is characterized by intellectual disability, epilepsy, and other associated features. While there is a known role of TRIT1 in mitochondrial function, not all patients with TRIT1 variants exhibit biochemical evidence of mitochondrial dysfunction. Further research is needed to fully understand the phenotypic spectrum and long-term outcomes of this disorder.

Asset Subtitle

Presenting Author - Drew M. Cratsenberg, MS, CGC; Co-Author - Omar Abdul-Rahman, MD;

Meta Tag

Biochemical genetics

Brain/Nervous System

Clinical History

Cognitive Disorders

Delineation of Diseases

Genotype-Phenotype Correlations

Intellectual disability

Mitochondria

Natural History

Phenotype

Phenotypic delineation of disorders

Co-Author Omar Abdul-Rahman, MD

Presenting Author Drew M. Cratsenberg, MS, CGC

Keywords

TRIT1-related disorder

autosomal recessive disorder

mitochondrial dysfunction

tRNA isopentenyl transferase

intellectual disability

epilepsy

genetics evaluation

brain malformations

mitochondrial function

compound heterozygosity