Two sisters (ages 16 yr and 15 yr) have been followed by our clinical genetics team for several years. Both girls have severe intellectual disability, hypotonia, seizures, and distinctive craniofacial features. The parents are healthy and have no other children. Oligo array, fragile X testing, and numerous single-gene tests were negative. All four family members underwent research exome sequencing, which revealed a heterozygous nonsense mutation in ASXL3 (p.R1036X) that segregated with disease. Exome data and independent Sanger sequencing confirmed that the variant is de novo, suggesting possible germline mosaicism in one parent. The p.R1036X variant has never been observed in healthy human populations and has been previously reported as a pathogenic mutation. Truncating de novo mutations in ASXL3 cause Bainbridge-Ropers syndrome (BRPS), a developmental disorder with similarities to Bohring-Opitz syndrome. Fewer than 30 BRPS patients have been described in the literature; to our knowledge, this is the first report of the disorder in two related individuals. Our findings lend further support to intellectual disability, absent speech, autistic traits, hypotonia, and distinctive facial appearance as common emerging features of Bainbridge-Ropers syndrome.
Keywords: absent speech; aplasia/hypoplasia of the corpus callosum; autism; broad nasal tip; cleft of chin; clinodactyly of the 5th finger; downslanted palpebral fissures; generalized hirsutism; high forehead; high, narrow palate; hypertelorism; incisor macrodontia; intellectual disability, severe; prominent nasal bridge; recurrent hand flapping; severe global developmental delay; severe muscular hypotonia; short stature; thick eyebrow.
© 2018 Koboldt et al.; Published by Cold Spring Harbor Laboratory Press.