De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype

Abstract

The ASXL genes (ASXL1, ASXL2, and ASXL3) participate in body patterning during embryogenesis and encode proteins involved in epigenetic regulation and assembly of transcription factors to specific genomic loci. Germline de novo truncating variants in ASXL1 and ASXL3 have been respectively implicated in causing Bohring-Opitz and Bainbridge-Ropers syndromes, which result in overlapping features of severe intellectual disability and dysmorphic features. ASXL2 has not yet been associated with a human Mendelian disorder. In this study, we performed whole-exome sequencing in six unrelated probands with developmental delay, macrocephaly, and dysmorphic features. All six had de novo truncating variants in ASXL2. A careful review enabled the recognition of a specific phenotype consisting of macrocephaly, prominent eyes, arched eyebrows, hypertelorism, a glabellar nevus flammeus, neonatal feeding difficulties, hypotonia, and developmental disabilities. Although overlapping features with Bohring-Opitz and Bainbridge-Ropers syndromes exist, features that distinguish the ASXL2-associated condition from ASXL1- and ASXL3-related disorders are macrocephaly, absence of growth retardation, and more variability in the degree of intellectual disabilities. We were also able to demonstrate with mRNA studies that these variants are likely to exert a dominant-negative effect, given that both alleles are expressed in blood and the mutated ASXL2 transcripts escape nonsense-mediated decay. In conclusion, de novo truncating variants in ASXL2 underlie a neurodevelopmental syndrome with a clinically recognizable phenotype. This report expands the germline disorders that are linked to the ASXL genes.

Keywords: ASXL2; developmental delay; glabellar nevus flammeus; intellectual disability; macrocephaly; whole-exome sequencing.

Figure 1

Clinical Photographs of Four Individuals with De Novo ASXL2 Mutations (A–C) Individual 1 at ages 3 years (A) and 8.5 years (B and C). Epicanthal folds with a wide nasal bridge, arched eyebrows, ptosis of the eyelids, prominent eyes, hypertelorism, a broad nasal tip, and a V-shaped glabellar nevus flammeus are evident, along with a capillary malformation on the neck and shoulder (C). (D–F) Individual 2 at ages 6 weeks (D), 5 months (E), and 10 months (F). Note the large glabellar nevus flammeus, thick and arched eyebrows with synophrys, proptosis of the eyes, hypertelorism, epicanthal folds, broad nasal tip, and retrognathia. (G–I) Individual 3 presented at the ages of 10 months (G) and 4 years (H [frontal view] and I [lateral view]) with a flat face, broad forehead, prominent glabella, glabellar nevus flammeus, hypertelorism, synophrys, arched eyebrows, ptosis, downslanting palpebral fissures, broad nasal tip, long philtrum, small upper vermilion, and small mouth. (J–L) Individual 4 after birth (J) and at ages 20 months (K) and 3 years (L) presented with proptosis, a small mouth, arched eyebrows, and a glabellar nevus flammeus. (M–O) Individual 5 at ages 3 months (M) and 7 years 10 months (N and O). Note the glabellar nevus flammeus, prominent eyes, hypertelorism, arched eyebrows, and broad nasal tip. (P–R) Individual 6 at ages 6 years (P) and 16 years (Q and R). Note the hypertelorism, likely macrocephaly, a broad nasal tip, and a glabellar nevus flammeus.

Figure 2

Schematic Structure of ASXL2 The ASXN, ASXM, and PHD-type zinc-finger domains, which are conserved throughout the ASXL family, are represented as light-gray boxes, and the LVTQLL motif, a nuclear receptor binding motif, is indicated in dark gray. The amino acid (AA) positions of all domains and motifs, as well as a schematic representation of the exons encoding the above depicted part of the protein, are given underneath. The positions of the de novo mutations identified in this study are marked with vertical red arrows. Small green arrows point to positions of known heterozygous variants (stop gain, frameshift, and splice site) found in apparently healthy individuals (from the ExAC Browser).