Aortic root dilatation and dilated cardiomyopathy in an adult with Tatton‐Brown‐Rahman syndrome

Abstract

Tatton‐Brown‐Rahman syndrome is an autosomal dominant overgrowth syndrome caused by pathogenic DNMT3A variants in the germline. Clinical findings of tall stature due to postnatal overgrowth, intellectual disability, and characteristic facial features, are the most consistent findings observed in patients with Tatton‐Brown‐Rahman syndrome (TBRS). Since the syndrome was first described in 2014, an expanding spectrum of neuropsychiatric, musculoskeletal, neurological, and cardiovascular manifestations have been reported. However, most TBRS cases described in the literature are children with de novo DNMT3A variants, signaling a need to better characterize the phenotypes in adults. In this report, we describe a 34 year old referred to genetics for possible Marfan syndrome with aortic root dilatation, mitral valve prolapse, and dilated cardiomyopathy, who was diagnosed with TBRS due to a heterozygous de novo DNMT3A variant. This represents the third reported TBRS case with aortic root dilation and the second with cardiomyopathy. Collectively, these data provide evidence for an association with aortic disease and cardiomyopathy, highlight the clinical overlap with Marfan syndrome, and suggest that cardiovascular surveillance into adulthood is indicated.

Genetic basis of sudden death after COVID-19 vaccination in Thailand

“…17 Case 9 was also heterozygous for a nonsense variant, c.939G.A (p.Trp313Ter) in DNMT3A, mutations in which cause Tatton-Brown-Rahman syndrome, a syndrome with possible cardiac abnormalities, inherited in an autosomal dominant manner. 18 Case 10 with underlying beta thalassemia was heterozygous for the c.6668A.T (p.His2223Leu) variant in TTN previously reported in a patient with cardiomyopathy. 19 Case 11 was homozygous for the TTN c.18530T.G (p.Leu6177Arg) variant, which was recently identified heterozygously in a 25-year-old Thai male victim Q9 of SUD.…”

Melanoma in a patient with DNMT3A overgrowth syndrome

“…DNMT3A overgrowth syndrome (MIM #615879) consists of a constellation of clinical manifestations with three principal features, including overgrowth (tall stature, increased head circumference, elevated body mass index), impaired intellectual development, and characteristic facial features, and is associated with de novo germline heterozygous mutations in the DNA methyltransferase gene DNMT3A ( Tatton-Brown et al 2014 ). Since its first description, the number of patients with documented DNMT3A overgrowth syndrome (DOS) has grown to more than 300 at present, whereas the repertoire of clinical manifestations has expanded to include obesity, cardiac defects, umbilical hernia, hypotonia, joint hypermobility, seizures, behavioral disorders, and other phenotypes ( Hollink et al 2017 ; Kosaki et al 2017 ; Shen et al 2017 ; Xin et al 2017 ; Tatton-Brown et al 2018 ; Jeffries et al 2019 ; Balci et al 2020 ; Ferris et al 2021 ; Smith et al 2021 ; Cecchi et al 2022 ).…”