A case of familial transmission of the newly described DNMT3A-Overgrowth Syndrome

DNMT3A-Overgrowth Syndrome (also known as Tatton-Brown-Rahman Syndrome) (MIM 615879) has recently been described in 13 individuals with de novo heterozygous mutations in DNMT3A gene. This autosomal dominant condition is characterized by overgrowth, dysmorphic facial features and moderate intellectual disability. Missense and truncating point mutations, a small in-frame deletion, as well as microdeletion 2p23 have been reported. Moreover, DNMT3A is commonly somatically mutated in acute myeloid leukemia. We herein report a family with two siblings and their father affected by the syndrome. The proband is a 12 year-old boy with tall stature, macrocephaly, facial dysmorphism, and intellectual disability. His 10-year-old sister also has learning difficulties, overgrowth and mild facial dysmorphism. Their father is a 49 year-old man with tall stature, macrocephaly, learning difficulties, and minor facial dysmorphism. He had a right occipital osteoma removed at 20 years of age. Aheterozygous splice site mutation NM_022552.4 (DNMT3A): c.2323-2A > T was found in the proband by whole exome sequencing analysis and by targeted Sanger Sequencing for the proband's sister and father. This mutation has not been previously reported and is believed to be pathogenic. Indeed, this substitution involves a highly conserved canonical splice site and is predicted to cause exon skipping. This is the first report of a familial transmission of DNMT3A-Overgrowth Syndrome, supporting the autosomal dominant inheritance. The proband's phenotype is more severe than that of his two other affected family members, which illustrates variable expressivity in the syndrome.