Ann Pediatr Endocrinol Metab.  2019 Dec;24(4):253-256. 10.6065/apem.2019.24.4.253.

First identified Korean family with Tatton-Brown-Rahman Syndrome caused by the novel DNMT3A variant c.118G>C p.(Glu40Gln)

• Lee CG
• Jang JH
• Seo JY

• KMID: 2468728
• DOI: http://doi.org/10.6065/apem.2019.24.4.253

Abstract

Tatton-Brown-Rahman Syndrome (TBRS), an overgrowth syndrome caused by heterozygous mutation of DNMT3A, first was described in 2014. Approximately 60 DNMT3A variants, including 32 missense variants, have been reported, with most missense mutations located on the DNMT3A functional domains. Autosomal dominant inheritance by germ-line mutation of DNMT3A has been reported, but vertical transmission within a family is extremely rare. Herein, we report the first Korean family with maternally inherited TBRS due to the novel heterozygous DNMT3A variant c.118G>C p.(Glu40Gln), located outside the main functional domain and identified by multigene panel sequencing. The patient and her mother had typical clinical features, including tall stature during childhood, macrocephaly, intellectual disability, and characteristic facial appearance. TBRS shows milder dysmorphic features than other overgrowth syndromes, potentially leading to underdiagnosis and underestimated prevalence; thus, targeted multigene panel sequencing including DNMT3A will be a useful tool in cases of overgrowth and unexplained mild intellectual disability for early diagnosis and genetic counseling.

Keyword

DNMT3A; Germ-line mutation; Tatton-Brown-Rahman syndrome; Growth disorder; Intellectual disability; High throughput nucleotide sequencing; DNA sequence analysis

MeSH Terms

Early Diagnosis
Genetic Counseling
Germ-Line Mutation
Growth Disorders
High-Throughput Nucleotide Sequencing
Humans
Intellectual Disability
Megalencephaly
Mothers
Mutation, Missense
Prevalence
Sequence Analysis, DNA
Wills

Figure

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  Fig. 1. (A) Pedigree of the family. Asterisks indicate sampled subjects. (B) Photograph of the proband (III-1). At 11 years of age, she exhibits a round face, horizontal eyebrows, depressed nasal bridge, and anteverted nares. (C) Photograph of the patient’s mother (II-4). At 40 years of age, she exhibits a round face. (D) Sanger sequencing confirmed the DNMT3A variant c.118G>C p.(Glu40Gln) in the patients (II-4 and III-1) and the wild-type genotype in an unaffected family member (III-2).

Reference

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