Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition

Abstract

Truncating ASXL3 mutations were first identified in 2013 by Bainbridge et al. as a cause of syndromic intellectual disability in four children with similar phenotypes using whole-exome sequencing. The clinical features - postulated by Bainbridge et al. to be overlapping with Bohring-Opitz syndrome - were developmental delay, severe feeding difficulties, failure to thrive and neurological abnormalities. This condition was included in OMIM as 'Bainbridge-Ropers syndrome' (BRPS, #615485). To date, a total of nine individuals with BRPS have been published in the literature in four reports (Bainbridge et al., Dinwiddie et al, Srivastava et al. and Hori et al.). In this report, we describe six unrelated patients with newly diagnosed heterozygous de novo loss-of-function variants in ASXL3 and concordant clinical features: severe muscular hypotonia with feeding difficulties in infancy, significant motor delay, profound speech impairment, intellectual disability and a characteristic craniofacial phenotype (long face, arched eyebrows with mild synophrys, downslanting palpebral fissures, prominent columella, small alae nasi, high, narrow palate and relatively little facial expression). The majority of key features characteristic for Bohring-Opitz syndrome were absent in our patients (eg, the typical posture of arms, intrauterine growth retardation, microcephaly, trigonocephaly, typical facial gestalt with nevus flammeus of the forehead and exophthalmos). Therefore we emphasize that BRPS syndrome, caused by ASXL3 loss-of-function variants, is a clinically distinct intellectual disability syndrome with a recognizable phenotype distinguishable from that of Bohring-Opitz syndrome.

Figure 1

Facial phenotypes and hands of five individuals with ASXL3 mutation. All six individuals show overlapping craniofacial features characterized by a longish face with a prominent forehead and temporal narrowing, arched eyebrows, downslanting palpebral fissures, a prominent columella and small alae nasi, downturned corners of the mouth and little facial expression with open mouth appearance. A slender habitus with long and slender fingers was a frequent sign. Photographs of the face and the hands are shown for five of the six individuals: patient 2 at age 15 years (a and f), patient 3 at age 2½ years (b and g), patient 4 at age 3¼ years (c and h), patient 5 at age 20 years (d and i) and patient 6 at age 7½ years (e and j).

Figure 2

Localization of ASXL3 variants of all known patients with Bainbridge–Ropers syndrome (adapted from Bainbridge et al.). The nine previously published variants are marked with red bars and references are given in square brackets ([1] subjects 1–4 by Bainbridge et al, [2] the patient by Dinwiddie et al, [3] subjects 1–3 by Srivastava et al. and [4] the patient by Hori et al). Two ASXL3 variants detected in individuals with autism are depicted in gray ([5] De Rubeis et al). The six variants identified in this study (patients 1–6) are depicted by yellow bars. Positions of the 12 exons are marked in light blue/blue. Notably, six of the nine previously published variants as well as two of the newly identified variants (patients 1 and 2) are located in exon 11; 2 mutations described by Srivastava et al, and 4 of the 6 mutations newly described in this study (patients 3-6) are located in the last exon 12.