Tatton-Brown-Rahman syndrome: Six individuals with novel features

Area of Science:

• Genetics
• Molecular Biology
• Clinical Medicine

Background:

• Tatton-Brown Rahman syndrome (TBRS) is characterized by overgrowth and intellectual disability, linked to heterozygous variants in the DNMT3A gene.
• Previously, 78 cases were reported, defining a consistent phenotype of somatic overgrowth, intellectual disability, and dysmorphisms.

Observation:

• This report details six new TBRS cases, including the youngest reported patient and individuals with DNMT3A variants in the Arg882 domain.
• New clinical features observed include congenital diaphragmatic hernia, specific tumor development (ganglioneuroblastoma, T-cell lymphoblastic lymphoma), and autonomic dysfunction symptoms.
• One patient with a recurrent DNMT3A variant had previously been described with a CLTC gene variant phenotype.

Findings:

• The study brings the total reported TBRS cases to 82, confirming DNMT3A variants as the cause.
• The findings highlight previously unreported clinical manifestations in TBRS, broadening the syndrome's phenotypic spectrum.
• Specific DNMT3A variants, including those at the Arg882 domain, are further characterized.

Implications:

• This research expands the understanding of the clinical variability and genetic basis of Tatton-Brown Rahman syndrome.
• The identification of new features like autonomic dysfunction and specific tumor risks necessitates updated diagnostic and management strategies for TBRS patients.
• Further investigation into the genotype-phenotype correlations in TBRS is warranted to improve patient care and genetic counseling.